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(11) EP 2 292 585 A1
(12) EUROPEAN PATENT APPLICATION
(43) Date of publication:
09.03.2011 Bulletin 2011/10
(21) Application number: 10182288.0
(22) Date of filing: 14.03.2005
(51) Int Cl.:
C07C 217/72
(2006.01)
(84) Designated Contracting States:
AT BE BG CH CY CZ DE DK EE ES FI FR GB GR
HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR
(30) Priority: 12.03.2004 US 552479 P
14.05.2004 US 571248 P
(62) Document number(s) of the earlier application(s) in
accordance with Art. 76 EPC:
05730211.9 / 1 740 930
(71) Applicant: APTUIT (KANSAS CITY), LLC
Greenwich, CT 06831 (US)
(72) Inventors:
Childs, Scott, L.
Atlanta, GA 30307 (US)
Mougin, Patricia
West Lafayette, IN 47906 (US)
Stahly, Barbara, C.
West Lafayette, IN 47906 (US)
(74) Representative: Glas, Holger
Maiwald Patentanwalts GmbH
Elisenhof
Elisenstrasse 3
80335 Mnchen (DE)
Remarks:
This application was filed on 29-09-2010 as a
divisional application to the application mentioned
under INID code 62.
(54) Screening for solid forms by ultrasound crystallization and cocrystallization using ultrasound
(57) The present invention relates to cocrystals of fluoxctinc hydrochloride and benzoic acid. Furthermore,
methods are provided for producing the cocrystals.
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Description
FIELD OF THE INVENTION
[0001] The present disclosure relates to crystallizing a chemical substance using ultrasound. Methods are provided
for screening a chemical substance according to its solid forms by using ultrasound to generate new or unusual solid
forms. Methods are also provided for crystallizing a chemical substance by novel techniques that include sonication.
The present disclosure also relates to cocrystallization using ultrasound. Methods are provided for preparing cocrystals
of an active agent and a guest by sonicating and crystallizing. Methods are also provided for screening a sample according
to solid state phases (such as cocrystals and salts) and include generating a cocrystal from the sample using ultrasound.
BACKGROUND OF THE INVENTION
[0002] Chemical substances (compounds, elements, and mixtures) have properties which tend to be unpredictable
and variable. Certain chemical substances may have utility for numerous different applications, including vital biological
applications, yet a slight change may reduce or eliminate the utility or beneficial purpose. Similarly, certain chemical
processes may have better or worse performance based upon minor differences.
[0003] An active agent may be provided in a variety of solid state phases. For example, it may be provided as a crystal
of the pure compound. Alternatively, the active agent may be provided as a salt. Alternatively, the active agent may be
provided as a cocrystal with another compound.
[0004] Cocrystals are crystals that contain two or more non-identical components (for example, two non-identical
molecules). The properties of cocrystals may be the same or different than the properties of the individual components
or mixtures of crystals of the individual components. Examples of cocrystals may be found in the Cambridge Structural
Database. Examples of cocrystals may also be found at Etter et al., "The use of cocrystallization as a method of studying
hydrogen bond preferences of 2-aminopyridine" J. Chem. Soc. , Chem. Commun. 589-591 (1990); Etter, et al., "Graph-
set analysis of hydrogen-bond patterns in organic crystals" Acta Crystallogr., Sect. B, Struct. Sci. B46 256-262 (1990);
Etter, et al., "Hydrogen bond directed cocrystallization and molecular recognition properties of diarylureas" J. Am. Chem.
Soc. 112 8415-8426 (1990); which are incorporated herein by reference in their entireties. The following articles are also
incorporated herein by reference in their entireties: Grbotz, et al., "On the inclusion of solvent molecules in the crystal
structures of organic compounds" Acta Cryst. B56 625-534 (2000); and Kumar, et al. "Molecular Complexes of Some
Mono- and Dicarboxylic Acids with trans-1,4,-Dithiane-1,4-dioxide" American Chemical Society, Crystal Growth & Design,
Vol. 2, No. 4 (2002). Additional information and details regarding cocrystallization may be found in U.S. Application No.
10/763,987, "Novel Cocrystallization, filed January 21, 2004, which is incorporated by reference herein.
[0005] A salt is a compound formed when the hydrogen of an acid is replaced by a metal or its equivalent (e.g., an
NH
4
+
radical). Hawleys Condensed Chemical Dictionary, p. 977 (14th Ed. 2001). In a salt one or more ionic bonds are
formed. In a cocrystal, two or more compounds retain their own chemical identities, and no new ionic or covalent bonds
are formed, although hydrogen bonds or other interactions may hold different compounds to each other.
[0006] The identification of a desirable solid state phase for an active agent is important in the pharmaceutical field,
as well as in other fields including nutraceuticals, agricultural chemicals, dyes, explosives, polymer additives, lubricant
additives, photographic chemicals, and structural and electronic materials.
[0007] Tn particular, the pharmaceutical industry spends a great deal of time, effort and expense on the identification
of particular compounds, mixtures and formulations that will have beneficial effect. Research is done as to whether such
compounds, mixtures and formulations will be safe and effective. Slight differences in chemical composition or structure
may yield significant differences in biological activity. Thus, researchers frequently test many different compounds,
mixtures and formulations for biological activity and other effects as well as testing different processes and conditions
for the preparation of such chemical compounds and mixtures.
[0008] The process of thorough analysis of different chemical compounds, mixtures, formulations, processes, or struc-
tures is commonly referred to as screening. Screening is partially a function of time and effort, with the quality or results
of screening being related to the number of samples prepared and/or analyzed as well as the quality of preparation
and/or analysis underlying those samples. To that end, it is frequently an objective with screening processes to increase
the number of samples and decrease the amount of each sample used for analysis. Screening plays a vital role in the
pharmaceutical field, as the most advantageous compound, mixture or formulation is frequently found through successful
screening processes.
[0009] In some screening processes, variations are introduced in order to see the result(s), if any, of such variations,
or to confirm that variations do not lead to substantially different results. Generally, at least two samples of a screened
chemical substance (in other words, a compound, element, or mixture that is the subject of the screening process) are
subjected to differing parameters, and one or more properties of the samples are determined to see whether the differing
parameters caused different results.
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[0010] Processes have been used for screening chemical compounds according to their solid form. When a compound
has different solid forms, the different forms are frequently referred to as polymorphs of that compound. A polymorphic
compound as used herein means a compound having more than one solid form. For example, a polymorphic compound
may have different forms of its crystalline structure, or it may exist as different hydrates or solvates.
[0011] The solid form of a chemical substance may have an impact on biological activity. The same chemical compound
may exhibit different properties depending upon whether it is in an amorphous, crystalline or semisolid state. A semisolid
as used herein indicates materials like waxes, gels, creams, and ointments. Furthermore, a chemical compound may
exist in different solid forms within the different states, and those different solid forms may also exhibit different properties.
For example, there may be several different crystalline solid forms of a substance, the different crystalline solid forms
having different properties. As another example, a substance may have different amorphous forms, the amorphous
forms having different properties. As a result, different solid forms, including different crystalline forms, of a chemical
compound may have greater or lesser efficacy for a particular application. The identification of an optimal solid form, or
other possible solid forms, is important in the pharmaceutical field, as well as in other fields including nutraceuticals,
agricultural chemicals, dyes, explosives, polymer additives, lubricant additives, photographic chemicals, and structural
and electronic materials.
[0012] It is desirable in the pharmaceutical field as well as other fields to find the solid form of a chemical substance
that exhibits desired physical and chemical properties. One form may be more stable or have other properties that make
it preferable over other forms. One form of a chemical composition may have better bioavailabilty, solubility, or absorption
characteristics or in other ways be more suitable for delivery of therapeutic doses than other forms. It is frequently
desirable within a screening process to generate, or at least search for, all or most of the possible solid forms of a
compound. Past attempts to generate a variety of solid forms included flash evaporations, cooling under different con-
ditions and/or the addition of seeds of solid material. However, some materials strongly resist the generation of some
of their possible solid forms.
[0013] It is desirable in many fields to find a solid state phase of an active agent that exhibits desired physical and
chemical properties. One solid state phase may be more stable or have other properties that make it preferable over
other solid state phases. One solid state phase may have better bioavailabilty, solubility, or absorption characteristics
or in other ways be more suitable for delivery of therapeutic doses than other forms. It is frequently desirable within a
screening process to generate, or at least search for, all or most of the possible solid state phases of a compound.
[0014] One or more solid forms may be generated by crystallization of a sample. One or more solid state phases may
be generated by cocrystallization of a chemical substance with different guest molecule(s).
[0015] Among the phenomena in crystallization are nucleation and growth. Crystal nucleation is the formation of an
ordered solid phase from liquids, supersaturated solutions, saturated vapors, or amorphous phases. Growth is the
enlargement of crystals caused by deposition of molecules on an existing surface.
[0016] Nucleation may be induced by the presence of "seed" crystals. Some solid particle is present to provide a
catalytic effect and reduce the energy barrier to formation of a new phase. Crystals may originate on a minute trace of
a foreign substance (either impurities or container walls) acting as a nucleation site. Nucleation may also be promoted
by external or nonchemical means, such as stirring the crystallization environment, or by applying ultrasound to the
crystallization environment.
[0017] As mentioned above, ultrasound has been applied to promote nucleation. For example, U.S. Patent No.
6,630,185 discusses a process for the crystallization of a solid phase from a liquid, characterized in that the liquid during
crystallization is subjected to ultrasound in the absence of transient cavitation. According to this patent, it has been
known since 1927 that exposing supercooled melts or supersaturated solutions of various substances to ultrasound has
an influence on the nucleation and/or the growth of crystals. The effect is referred to as sonocrystallisation. A particular
aspect of sonocrystallisation is sononucleation. It deals with the initiation of crystal formation, has been studied extensively
with sugar and is applied since the late 1950s. Sonocrystallisation of supercooled water, supercooled metal melts and
supersaturated solutions of various inorganic materials are said to have received a lot of attention.
[0018] U.S. Patent Application Publication No. 20030051659 A1 discusses a process for crystallizing small particles
with a narrow particle size distribution. The crystals are obtained by introducing ultrasound into a solution or suspension
of the substance to be crystallized while simultaneously adjusting a specific stirring power. U.S. Patent Application
Publication No. 20030166726 A1 discusses a method for reducing the particle size of amino acid crystals using ultrasound.
[0019] U.S. Patent Application Publication No. 20020054892 A1 discusses a method of inducing solidification in a
fluid composition comprising a cosmetic active, a crystalline organic structurant and a carrier. The method comprises
exposing the fluid composition to ultrasound or converting the composition to a soft solid.
[0020] U.S. Patent No. 5,830,418 discusses a method of using ultrasound to promote crystallization of solid substances
contained in a flowable material. A flowable material, such as a supercooled melt or supersaturated solution, is dispensed
onto a take-up member such as a belt or drum. Either prior to, or after being dispensed onto the take-up member, the
material is exposed to ultrasound to promote the crystallization of solid substances in the material.
[0021] None of the foregoing references discloses the use of ultrasound as a variable parameter in a screening method
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to identify the various solid forms of a chemical substance.
[0022] There is a continued need to improve screening methods that identify all or a high percentage of possible forms
of a chemical substance. There is also a need for improved methods of selectively generating the desired form of a
chemical substance.
[0023] There is a continued need to improve screening methods that identify all or a high percentage of possible solid
state phases of a chemical substance. There is also a need for improved methods of selectively generating solid state
phases, including cocrystals, of a chemical substance.
SUMMARY OF THE INVENTION
[0024] As one aspect, a method is provided for screening a chemical substance for possible solid forms. The method
comprises the steps of providing a chemical substance in a plurality of samples, sonicating at least one of the samples,
and solidifying the chemical substance from the samples. The samples will usually be provided as a solution, suspension,
melt, or other mixture of the chemical substance in one or more solvents. The screening method may comprise providing
a first sample of the chemical substance in a first solvent, and a second sample of the chemical substance in a second
solvent. The method may also comprise determining whether one or more solid forms of the chemical substance were
generated.
[0025] As another aspect, a method is provided for crystallizing a chemical substance. This method is beneficial for
searching for and/or generating new or unusual solid forms of a chemical substance. The method comprises forming
an emulsion comprising two or more substantially immiscible solvents and the chemical substance by applying ultrasound
to a mixture of said solvents and the chemical substance. The chemical substance is in solution in one or both of the
solvents. The method also comprises crystallizing the chemical substance from the emulsion.
[0026] As yet another aspect, a method of crystallizing a chemical substance is provided. The method comprising the
steps of providing a sample of the chemical substance in a solvent, sonicating the solution or suspension at a predeter-
mined supersaturation level, and crystallizing the chemical substance from the sample.
[0027] As another aspect, a method is provided for generating the most stable form of a chemical substance. The
method comprises the steps of providing a sample of the chemical substance in a solvent, sonicating the sample at a
predetermined supersaturation level, and crystallizing the chemical substance from the sample, and the crystallized
chemical substance is the most stable solid form of the chemical substance relative to known solid forms of the chemical
substance.
[0028] As a further aspect, a method is provided for generating a solid form of a chemical substance from a metastable
solution (a solution in which the chemical substance remains in solution indefinitely or for relatively long periods). The
method comprises forming a metastable solution of the chemical substance in a solvent, sonicating the metastable
solution, and crystallizing the chemical substance from the solution.
[0029] As yet another aspect, a method is provided for obtaining a substantially pure solid form of a chemical substance.
A substantially pure solid form of a chemical substance is a solid that is exclusively or almost exclusively of one solid
form or has little or no other solid forms present. The method comprises the steps of providing a sample of the chemical
substance in a solvent, sonicating the sample at a predetermined supersaturation level, and crystallizing the chemical
substance from the sample, wherein a substantially pure solid form of the chemical substance is crystallized.
[0030] As another aspect, a method is provided for preparing a solvate of a chemical substance. The method comprises
the steps of providing a sample comprising the chemical substance and a solvent, sonicating the sample, and generating
a solid from the sample, wherein the solid comprises a solvate of the chemical substance and the solvent.
[0031] In the present methods, the solidifying step and the sonicating step may at least partially overlap. In some
embodiments, the solidifying step and the sonicating step may overlap completely or almost completely. For example,
where the solidifying step comprises evaporating a solvent from the samples, the method can comprise sonicating at
least one of the samples until the solvent is substantially completely evaporated. Alternatively, the solidifying step can
comprise at least partially evaporating the solvent from at least one of the samples before sonicating the sample.
[0032] In the present methods, a solvent can be evaporated (to a greater or lesser extent) from at least one of the
samples before, during, or after the sonicating step. The present methods may comprise the step of cooling at least one
of the samples before, during or after the sonicating step. The present methods may comprise the step of crash-cooling
at least one of the samples before, during or after the sonicating step. The present methods may comprise a mixture of
those actions, for example, the samples may be cooled followed by sonication and evaporation of the solvent.
[0033] The sample(s) can be sonicated by sonicating at least once or more than once. In some embodiments, the
samples will be sonicated by ultrasound pulses. For example, one or more samples can be sonicated by at least one
ultrasound pulse, or by at least 5 ultrasound pulses, or by any number of periodic ultrasound pulses. In some embodiments,
the samples will be sonicated for a period of time. For example, one or more samples may be sonicated for about 5 to
about 40 seconds, for at least about 5 minutes, or for another suitable time period.
[0034] In the present methods, one or more samples may be sonicated at least once during the solidification step. In
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some embodiments, sonication will be substantially continuous during the solidification step; in other embodiments,
sonication will be periodic during the solidification step.
[0035] The present methods may also be employed to generate solid solvates and solid hydrates of the chemical
substance.
[0036] In the present methods, a predetermined supersaturation level of the chemical substance in a solvent may be
selected at which to begin sonication. For example, the predetermined supersaturation level may be selected to generate
a relatively stable form of the chemical substance, or the most stable form of the chemical substance, as determined by
comparison of the known solid forms of the chemical substance. The predetermined supersaturation level can be selected
to generate a solvate of the chemical substance.
[0037] The present methods may comprise adding an antisolvent to a solution, suspension, emulsion, slurry or other
composition of matter.
[0038] The present methods increase the likelihood of generating all or a high percentage of possible solid forms of
a chemical substance.
[0039] As another aspect of the present invention, a method is provided for screening for possible cocrystals comprising
an active agent. The method comprises the steps of providing a plurality of samples that contain the active agent. Each
sample also contains at least one guest. It is contemplated that the samples may contain the same guest or a different
guest. In a screening method, the samples will usually contain several different guests being used to evaluate different
cocrystals (different solid state phases). The samples are sonicated, and the active agent and the guest are crystallized
from the samples. The method comprises determining whether a cocrystal was generated in one or more of the samples.
The method can also comprise analyzing the crystallized samples to determine one or more properties.
[0040] As another aspect, a method is provided for preparing a cocrystal comprising an active agent and a guest. The
method comprises providing a sample of an active agent and a guest. The sample is sonicated, and a cocrystal of the
active agent and the guest is crystallized from the sample.
[0041] As yet another aspect, a method is provided for screening for possible solid state phases, including salts, of
an ionizable active agent and a counterion and optionally a guest. The method comprises providing an ionizable active
agent and a counterion in a plurality of samples. An ionizable agent is an agent that can be ionized or has already been
ionized; an ionizable agent is one that can be used to forming an ionic bond with a counterion. The samples are sonicated,
and the ionizable active agent and the counterion form a salt and crystallize from the samples. The method further
comprises determining whether a salt was generated in one or more of the samples.
[0042] As yet another aspect, a method is provided for screening for possible salts comprising an ionizable active
agent. The method comprises providing a plurality of samples comprising an ionizable active agent and one or more
counterions. The samples are sonicated, and one or more crystallized salt compounds are formed from the samples.
The crystallized salt compounds comprise the ionizable active agent and the counterions. The plurality of samples may
contain the same or different counterions. For example, at least one sample may contain a different counterion than at
least one other sample. As another example, the plurality of samples can comprise a plurality of sets, where the sets
differ in having different counterions, and the samples within each set have the same counterion.
[0043] The present techniques may be utilized in methods for screening an ionizable active agent according to its
possible solid state phases, including cocrystals and/or salts. Such methods can comprise providing an ionizable active
agent and one or more counterions in a plurality of samples, sonicating the sample(s), and forming a crystallized salt
compound comprising the active agent and counterion. Suitable counterions include but are not limited to the cations
or anions set forth in the present disclosure. Using the present techniques provides a greater likelihood of generating
possible salts of the ionizable active agent. Moreover, a salt developed by such a method may be employed in connection
with the methods described herein which relate to cocrystals comprising a salt and a guest.
[0044] As yet another aspect, a method is provided for cocrystallizing two or more components, such as an active
agent and a guest. The method comprises determining a concentration for two or more components in a sample effective
for cocrystallization of the components. A sample is prepared which comprise the components, in an effective volume
and an effective concentration. The sample is sonicate and a cocrystal is generated from the sample. The cocrystal
comprises the components.
[0045] The present methods may be used to form at least one new solid state phase of an active agent, including new
solid state phases of active pharmaceutical ingredients. This can provide substantial benefits to the pharmaceutical
industry and the public at large.
[0046] In the foregoing methods, the sonicating step and the crystallizing step will usually overlap at least partially.
The samples may become supersaturated with respect to at least one of the active agent and the guest before, during
or after the sonicating step. In the present methods, each of the samples may comprise more than one solvent, more
than one active agent, and/or more than one guest.
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BRIEF DESCRIPTION OF THE FIGURES
[0047] Figure 1 is an x-ray powder diffraction (XRPD) pattern of sulfathiazole solidified from an acetonitrile solution
which was sonicated.
[0048] Figure 2 is an XRPD pattern of sulfathiazole solidified from an acetonitrile solution which was not sonicated.
[0049] Figure 3 is an XRPD pattern of sulfathiazole solidified from an acetone solution which was sonicated.
[0050] Figure 4 is an XRPD pattern of sulfathiazole solidified from an acetone solution which was not sonicated.
[0051] Figure 5 is an XRPD pattern of carbamazepine solidified from a DMSO solution which was sonicated.
[0052] Figure 6 is an XRPD pattern of sulfathiazole solidified from a methylethylketone solution which was sonicated.
[0053] Figure 7 is an XRPD pattern of sulfathiazole solidified from an ethanol/p-cymene emulsion.
[0054] Figures 8 (a) and (b) illustrate a crystal structure of an active agent and a cocrystal structure containing the
same active agent with a guest.
[0055] Figures 9 (a) and (b) are drawings of two-dimensional and three-dimensional models of a cocrystal of fluoxetine
HCl and benzoic acid (1:1).
[0056] Figure 10 shows examples of general classes of guests.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0057] Ultrasound generally refers to sound vibrations beyond the limit of audible frequencies. Ultrasound is often
used to refer to sound vibrations having a frequency of about 20 kHz or more. In many applications where ultrasound
is used, the frequencies are in the range of 20 kHz to 5 MHz. However, the definition of ultrasound as having a frequency
greater than 20 kHz is related to the average perception limit of the human ear rather than to industrial applications. The
benefits of the present methods may be obtained with frequencies below 20 kHz. In the context of the present specification,
ultrasound refers to sound vibrations having a frequency in the range of from about 10 kHz to about 10 MHz. However,
for certain applications, ultrasound having frequencies in narrower ranges (such as, for example, from about 20 kHz to
about 5 MHz or from about 40 kHz to about 2.5 MHz) may be desired.
[0058] The terms sonicate and sonication are frequently used to refer to the application of ultrasound. A sample (for
example, a solution or suspension) may be sonicated in a variety of ways, and may be sonicated continuously or by one
or more pulses. For example, a sample may be sonicated by a series of ultrasound pulses, each pulse having a duration
of from about 0.1 second to about 10 seconds. As another example, the sample may be sonicated at least once for at
least about 5 minutes. In the present methods, where a method requires sonication or sonicating, it requires at least
one pulse of ultrasonic energy which is generally on the order of seconds (for example, applying ultrasonic energy for
1 second or less, 5 seconds, 10 seconds or more). When a solution, suspension, solvent or other composition is sonicated
"while" or "during" some other step or time period, it means at least one pulse is applied -- it does not necessarily mean
there is sonication over the entire step or period, although in some circumstances, it can be desirable to sonicate
periodically or continuously throughout substantially an entire step or over substantially all of a time period, or for some
portion of the step or period. For example, in some of the present techniques, it is stated that a solution is sonicated
while a solvent is evaporated. Sonication in this situation may be a single pulse (for example, 5 seconds) to a solution,
as well as multiple pulses or continuous sonication of a solution over substantially the entire time period of evaporation,
or any application of ultrasound in between.
[0059] Ultrasound can be applied to a chemical substance or a sample by conventional techniques such as by im-
mersing a receptacle containing the chemical substance or the sample in an ultrasonic bath, or by placing the tip of an
ultrasonic probe directly into the sample. Sonication may be performed using commercially available equipment. For
example, a quarter-inch diameter (6 mm) ultrasonic probe operating at 20 kHz and a power input of 130 watts has been
found convenient, but there will be many other commercially available devices which are suitable. Lower power ultrasound
apparatus may also be suitable for crystallization. Suitable ultrasound devices are advertised by Cole-Palmer Instrument
Co., of Vernon Hills, Illinois, or Misonix Corporation, of Farmingdale, New York. For larger scale operations, a sonoreactor
is advertised by AEA Technologies of the United Kingdom. Techniques and equipment include the use of ultrasonic
probes or transducers, which techniques will be familiar to those skilled in the art.
[0060] Where the samples are provided in a well plate, a well-plate sonicator may be used to sonicate the samples.
Sonication of the sample may be performed using commercially available equipment. For example, a quarter-inch
diameter (6 mm) ultrasonic probe operating at 20 kHz and a power input of 130 watts has been found convenient, but
there will be many other commercially available devices which are suitable. As another example, a probe sonicator may
be used for 2-5 seconds at 40 mW of power using a 1/8-inch probe. Lower power ultrasound apparatus may also be
suitable for crystallization. The amount of time and power of the sonication are variable. In the example described below,
sonication times of about 10 to 15 seconds applied every 5 minutes or so were used with a Misonix well-plate sonicator
at medium power.
[0061] The application of ultrasound to a sample containing a chemical substance to be crystallized can reduce the
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Metastable Zone Width for the sample (for example, a solution containing the chemical substance and solvent). For
example, the sample may have a metastable zone, and the metastable zone has a width of at least about 1C, alternatively
at least about 2C, alternatively at least about 5C, alternatively at least about 10C. The application of ultrasound to
the sample may narrow the metastable zone, for example from a width of greater than about 10C to a width of at most
about 5C, or by reducing it by at least about 1C. A reduction of the Metastable Zone width offers a way to limit the
level of supersaturation at which nucleation occurs. For a chemical substance that has two unsolvated polymorphic
forms, where one is stable and one is metastable at a given temperature, the polymorph of higher free energy (that is,
lower stability) has a higher solubility in any solvent compared to the polymorph of lower energy. If there is sufficient
reduction of the Metastable Zone Width by application of ultrasound, such that the system becomes supersaturated with
respect to the most stable form while being undersaturated with respect to the other form, then polymorphic selection
favoring the most stable form will occur. This "zone of action" may be used in order to increase the chances to generate
the most stable form of a chemical substance. In practice, as ultrasound does not typically reduce the Metastable Zone
Width to zero, cases may occur where two polymorphs of similar of energy can be formed. Ultrasound can therefore be
used as a tool to increase the probability of generating the most stable form, when working under low levels of super-
saturation, or selectively crystallizing the more stable of two solid forms.
[0062] Sometimes the most stable solid form is more difficult to generate than a less stable form. For example, with
the compound WAY, the yellow form is frequently the first and most common form generated in screening method using
small-scale crystallization and a variety of solvent mixtures. This may be explained by a faster nucleation and/or growth
rate of the less stable form, compared to the more stable form.
[0063] The application of ultrasound to a chemical substance to be crystallized from a solution can induce nucleation
of supersaturated solutions in cases where the substance otherwise remains indefinitely or for relatively long periods in
solution (in other words, in metastable solution) . In this respect, the application of ultrasound is of considerable interest
to find new solid forms difficult to find due to difficult conditions of crystallization. For example, the present techniques
are beneficial for crystallization and finding new solid forms from viscous solutions, or from systems having a large
Metastable Zone Width.
[0064] Sonication generally increases the rate of nucleation in samples that are sufficiently supersaturated relative to
the desired multi-component phase (the active agent(s) and the guest(s)). For example, sonication may increase the
rate of cocrystallization by at least about 25%, alternatively at least about 100%, alternatively at least about 200%.
Sonication generally reduces the activation barrier to nucleation and increases the number of successfully nucleated
samples. The precise nature of the physical perturbations that cause nucleation when a sample is sonicated are not
known with certainty. While the inventor does not intend to be bound by theory, it is presently theorized that entropic
contributions may be more significant in multi-component samples because the independent components must be
organized not only on a molecular level via aggregation through hydrogen bonding, but also in terms of mass transport.
The growth of a cocrystal requires a consistent addition of a 1:1 mixture (or other fixed ratio) of the components to the
cocrystal structure. Accordingly, local concentration gradients within the sample are undesirable. Sonication has a
homogenizing effect and may assist in generating a more homogeneous distribution of the components in the sample.
Thus, sonication is especially well-suited for methods of screening cocrystals where multiple compounds are to be
brought together in a crystal. Sonication is also well-suited for methods of screening salts where an ionizable active
agent and a counterion are to be brought together in a crystal.
[0065] Ultrasound may be particularly beneficial where multi-component crystal growth is nucleation-limited. A system
is nucleation-limited where crystals are generally not observed if nucleation does not occur during evaporation, and an
amorphous solid results instead. In a nucleation-limited system, if nucleation occurs, then subsequent growth occurs
efficiently and substantially completely. For example, a combination of fluoxetine HCl and benzoic acid in a 1:1 molar
ratio is nucleation-limited in solutions of acetonitrile. This is a difficult system to nucleate and a minimum desired super-
saturation level has been identified for cocrystallization. The minimum desired supersaturation level for fluoxetine HCl
and benzoic acid in a 1:1 ratio in acetonitrite is about 35 mg/ml. Using the technique disclosed herein, minimum desired
supersaturation levels for other systems can also be found.
[0066] It has also been discovered that, even with ultrasound, it is desirable to maintain certain levels of supersaturation
in the sample. In experiments using fluoxetine hydrochloride and benzoic acid in samples that included acetonitrile as
a solvent, it was observed that sonication had a positive effect on cocrystallization. When concentrations of above 200
mg/ml of the mixture of active agent and guest in acetonitrile were used, sonication consistently nucleated the cocrystal.
Between 35 and 100 mg/ml, nucleation could be caused by sonication, but nucleation was not observed spontaneously
in unsonicated samples with concentrations below 100 mg/ml. Sonication provides a clear advantage in this case with
respect to intermediate concentrations.
[0067] Experiments at a concentration of about 200 mg/ml nucleated with sonication using either a probe or a well-
plate sonicator. About 50% of wells nucleated and about 98% of the solids were cocrystals. In a control experiment
without sonication, only about 15% of the wells nucleated, and the solid was benzoic acid gather than a cocrystal of
fluoxetine HCl and benzoic acid.
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[0068] The application of ultrasound to the solution or suspension may narrow the metastable zone, for example,
reducing it to less than 1C or from a width of greater than about 10C to a width of at most about 5C. It appears that
sonication reduces the metastable zone width, causing nucleation at lower supersaturation levels compared to slow
evaporation (SE) results.
[0069] Sonication can increase the rate of nucleation in systems where nucleation is slow. Among the advantages of
sonication are that nucleation can occur faster, more completely, and can be initiated at lower concentrations. In addition,
the rapid nature of the growth is more likely to produce a consistent form (the first form that nucleates) because of the
massive secondary nucleation that occurs during sonication - one seed becomes many very quickly due to sonication.
Ultrasound can therefore be used as a tool to increase the probability of generating a cocrystal, to generate cocrystals
more rapidly, and/or to generate cocrystals at relatively low levels of supersaturation.
[0070] Ultrasound may also be useful as a tool to increase the probability of generating a crystallized salt, to generate
salts more rapidly, and/or to generate crystallized salts at relatively low levels of supersaturation.
[0071] The present methods are useful for the generation of new solid forms as well as for screening a chemical
substance according to its solid forms. The chemical substance may be a compound, element, or mixture. Chemical
substances include organic and inorganic substances. Examples of chemical substances for use in the present techniques
include, but are not limited to, pharmaceuticals, dietary supplements, alternative medicines, nutraceuticals, agricultural
chemicals, dyes, explosives, polymer additives, lubricant additives, photographic chemicals, and structural and electronic
material. Preferably, the chemical substance is a pharmaceutical agent. Pharmaceutical agents suitable for use in the
present technique include known pharmaceutical agents as well as those which may be developed. A pharmaceutical
agent can be a large molecule (in other words, a molecule having a molecular weight of greater than about 1000 g/mol),
such as oligonucleotides, polynucleotides, oligonucleotide conjugates, polynucleotide conjugates, proteins, peptides,
peptidomimetics, or polysaccharides. A pharmaceutical agent can be a small molecule (in other words, a molecule
having a molecular weight of about 1000 g/mol or less), such as hormones, steroids, nucleotides, nucleosides, or
aminoacids. Examples of suitable small molecule pharmaceuticals include, but are not limited to, cardiovascular phar-
maceuticals; anti-infective components; psychotherapeutic components; gastrointestinal products; respiratory therapies;
cholesterol reducers; cancer and cancer-related therapies; blood modifiers; antiarthritic components; AIDS and AIDS-
related pharmaceuticals; diabetes and diabetes-related therapies; biologicals; hormones; analgesics; dermatological
products; anesthetics; migraine therapies; sedatives and hypnotics; imaging components; and diagnostic and contrast
components.
[0072] The chemical substances can have any utility, including utility as a pharmaceutical agent or other active agent.
The present methods increase the likelihood of determining whether a chemical substance is polymorphic. A polymorphic
chemical substance is a compound, element, or mixture having more than one solid form. The form of a compound,
element, or mixture refers to the arrangement of molecules in the solid. The term solid form herein includes semisolids.
Semisolids are materials like waxes, suspensions, gels, creams, and ointments. The forms which may be sought or
generated may include amorphous forms, mixtures of amorphous forms, eutectic mixtures, mixed crystal forms, solid
solutions, co-crystals, and other forms.
[0073] A chemical compound, element, or mixture may be amorphous, meaning that it is not characterized by a long-
range order of the molecules. Alternatively (or even to a limited extent within a mostly amorphous form), a compound,
element, or mixture may be arranged in a crystalline state, where the molecules exist in fixed conformations and are
arranged in a regular way. The same compound, element, or mixture may exhibit different properties depending upon
which solid form that compound, element or mixture is in.
[0074] Examples of compounds having more than one solid form include 5-methyl-2-[(2-nitrophenyl)amino]-3-thi-
ophenecarbonitrile and 4-methyl-2-nitroacetanilide, each of which has different colors in connection with different forms.
Carbon, novobiocin, and furosemide are also examples of substances having more than one solid form.
[0075] The present disclosure provides techniques for preparing cocrystals and for screening a chemical substance
according to its possible solid state phases, in which one or more active agents are cocrystallized with one or more
guests. It has been found that ultrasound may be used to facilitate cocrystallization and screening.
[0076] Cocrystals are crystals that contain two or more non-identical molecules (two or more components) such as
an active agent and a guest. Figures 8(a) and (b) illustrate a crystal structure of an active agent (a one-component
crystal) and a cocrystal structure containing the same active agent with a guest (a two-component crystal), respectively.
[0077] Generating a variety of solid forms is an object of screening. A sufficient number of diverse processes and
parameters should be employed to maximize the likelihood that a high percentage of possible solid forms of a chemical
substance is generated. Samples should be generated under various thermodynamic and kinetic conditions. In the
present methods, sonication is another parameter that is varied as part of the screening process.
[0078] A compound is a substance composed of atoms or ions in chemical combination. A compound usually is
composed of two or more elements, though as used in accordance with the present methods, a compound may be
composed of one element.
[0079] A mixture is a heterogeneous association of compounds or elements. The components of a mixture may or
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may not be uniformly dispersed.
[0080] The present methods include providing samples comprising the chemical substance(s). In some embodiments,
the samples may contain the chemical substance(s) alone, for example, in a melt or a physical mixture. More commonly,
the sample will also contain a solvent(s) in which the active agent(s) and the guest(s) are dissolved, dispersed or otherwise
disposed. The active agent(s) and the guest(s) may be completely or partially soluble in the solvent(s) or one or more
of them may be substantially insoluble in the solvents. Accordingly, the sample may be in a solution, suspension,
dispersion, mixture, slurry or emulsion, or other physical state. The samples physical state going into the present methods
is not critical to the broader applicability of the present methods, though in some embodiments, use of particular physical
states for samples can be beneficial, as described in more detail herein. For example, the present methods may have
additional benefits when the samples are metastable solutions, viscous solutions, emulsions or slurries.
[0081] In the present methods, the chemical substance is solidified from the sample using a suitable solidification
technique. As used herein, solidification includes any suitable technique for preparing a solid from the sample including
but not limited to crystallization.
[0082] The solidification technique(s) employed will depend in part on the sample(s). The samples may be provided
as solutions, suspensions, melts, slurries, emulsions, or any other composition of matter which includes the chemical
substance.
[0083] Suitable crystallization. (solidification) techniques include cooling, heating, evaporation, addition of an antisol-
vent, reactive crystallization, and using supercritical fluids as solvents. A fluid is an antisolvent with respect to a given
solution of a chemical substance when the chemical substance is less soluble in that fluid than in the solvent used to
form the solution; preferably, an antisolvent is a fluid in which the chemical substance is essentially insoluble or has a
low solubility. Reactive crystallization refers to processes where means a chemical substance is formed from reactants
and crystallized substantially simultaneously, for example, where the reaction is a driving force toward crystallization. A
supercritical fluid is a fluid above its critical temperature and critical pressure which combines properties of gases and
liquids. Examples of compounds employed as supercritical fluids include xenon, ethane and carbon dioxide.
[0084] Alternatively, the mechanism by which crystallization is accomplished may include gel diffusion methods, thin-
layer deposition methods, or other suitable methods. Other thermodynamic and kinetic conditions may be employed to
solidify the compound or mixture. Slow cooling of a saturated solution is a typical thermodynamic condition. An addition
of a solution of the compound or mixture to an excess of cold anti-solvent is a typical kinetic condition.
[0085] Additionally, melt crystallization techniques may be used to generate a solid form. Through such techniques,
the use of a solvent can be avoided. In such techniques, formation of crystalline material is from a melt of the crystallizing
species rather than a solution. Additionally, the crystallization process may be done through-sublimation techniques.
[0086] In many embodiments, the samples will comprise the chemical substance in a solvent. Any suitable solvent
can be used. Suitable solvents include acetone, acetonitrile, chloroform, dioxane, ethanol, ethyl acetate, heptane, bu-
tanone, methanol, nitromethane, tetrahydrofuran, toluene, water, dichloromethane, diethyl ether, isopropyl ether, cy-
clohexane, methylcyclohexane, isopropyl alcohol, isopropyl acetate, trimethylpentane, n-octane, trichloroethane, trif-
luoroethanol, pyridine, propanol, butanol, tetrachloroethylene, chlorobenzene, xylene, dibutyl ether, methyl- tert-butyl
ether, tetrachloroethane, p-cymene, dimethyl sulfoxide, formamide, and dimethylformamide. It is also contemplated that
the samples may be provided as the chemical substance in two or more solvents, either as a homogeneous solution or
as an emulsion.
[0087] In the solidifying step, the chemical substance is generally separated from the solvent though solids such as
hydrates or solvates may be formed which include some solvent molecules. For example, the solvent may be evaporated
either slowly (for example, evaporating to dryness over a time period of four days, alternatively two days or more) or
quickly (for example, evaporating to dryness over a time period of 24 hours, alternatively under two days). By varying
the rate of evaporation, one can introduce desired variability into a screening method. For example, in a screening
method, a first portion of samples can be subjected to relatively slow evaporation, and a second portion of the samples
can be subjected to relatively fast evaporation.
[0088] In the present methods, ultrasound may be applied at different stages of a screening process or a crystallization
process (or other solidification process). For example, a solution which comprises a solute to be crystallized can be
sonicated at some point during the screening process. One may sonicate such a solution before, during, or after the
initiation of cooling of the solution from an undersaturated, saturated, or supersaturated state. As other examples, one
may sonicate a solution before, during, or after the beginning of evaporation of solvent, or before, during, or after the
addition of an immiscible antisolvent to the solution.
[0089] In the present methods, the solidifying step and the sonicating step can overlap. For example, where the
samples are provided as a solution of the chemical substance in a solvent, the solidifying step may be performed by
evaporating the solvent, and the sample may be sonicated during that evaporation. Furthermore, the sonication can be
periodic during the evaporation. For example, the sample can be periodically sonicated for about 20 seconds, and the
periods can be about 30 minutes (in other words, the sample is sonicated for about 20 seconds every 30 minutes).
Furthermore, the sonication can be a single pulse. For example, the sonication could be carried out one time for 5 to 40
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seconds or multiple times for a like period, or for other suitable period(s).
[0090] In the present methods, the samples can 5 comprise a solution, suspension, or melt of the chemical substance.
Such a solution, suspension, or melt will typically be prepared by heating above room temperature to achieve supersat-
uration. It may be desirable to begin cooling the samples (for example, to room temperature) before the sonicating step.
Alternatively, the samples may be cooled and sonicated at the same time. Alternatively, the method can include crash-
cooling the samples (rapidly lowering the temperature, for example, by immersing in an ice bath) before the sonicating
step. Alternatively, the samples may be crash-cooled and sonicated at the same time.
[0091] The present methods can include the step of adding a second solvent to a solution containing the ) chemical
substance. For example, the second solvent may be added to facilitate solidification.
[0092] The solidification step can be initiated by sonication, and/or it may be initiated by seed materials or other
techniques. In the various embodiments of the present methods, solidification may start before, during, or after the
application of ultrasound. Frequently solidification will start during sonication and continue after sonication ceases. In
many cases, the solidification and sonication steps will overlap. For example, sonication may begin before solidification
but continue even after solidification begins. As another example, solidification may begin before sonication. As yet
another example, the chemical substance may be sonicated in a pulsing manner throughout the solidification process.
Alternatively, sonication may be employed to initiate solidification and be discontinued when solidification (such as
nucleation) begins.
[0093] As a broad example, solidification may be performed as follows: A solution containing a solvent and a chemical
substance (such as a compound, element, or mixture) to be solidified is disposed in a receptacle, such as a vial, well-
plate (such a 96 well plate) or capillary tube. The solution may be formed in the receptacle or formed outside the receptacle
and then placed in it. The chemical substance can be present in a solution below, at or above its saturation point at a
given temperature at the time it is placed in the receptacle. Through evaporation, the use of an antisolvent, temperature
variation, and/or other suitable means, the solution reaches a point of supersaturation. The solution is sonicated, and
further evaporation, the use of an antisolvent, temperature variation, and/or other suitable solidification technique may
be employed. After a suitable amount of time, solidification progresses until a sufficient amount of solid or semisolid
appears, and is ready for analysis to determine the solid form.
[0094] The most preferred solidification techniques foster crystallization of the chemical substance. Suitable crystal-
lization techniques may be employed with and without ultrasound in the present methods. Indeed, in a screening method,
it may be desirable that some samples are sonicated and other samples are unsonicated.
[0095] Crystallization may be performed as a seeded operation or an unseeded operation. In a seeded operation, a
selected quantity of seed crystals is included in the system. The characteristics of the seed crystals typically influence
the characteristics of the crystals generated from the system. Crystallization may be performed by heterogeneous or
homogeneous mechanisms. However, it is noted that ultrasound may be applied as a way of omitting the presence of
seed crystals.
[0096] In other embodiments of the present methods, solids are generated other than by crystallization. The sample
may be provided as a melt that is then added to the receptacle or may be provided within the receptacle and melted
therein and allowed to solidify in an amorphous form.
[0097] Another technique for crystallizing a chemical substance employs an emulsion. An emulsion is a mixture of
two or more immiscible liquids where one liquid is in a discontinuous phase within the other liquids. Emulsions are
frequently formedand/or stabilized by the use of agents called emulsifiers. However, sonication of an immiscible mixture
of solvents also allows the generation of emulsions.
[0098] The present methods may also include the step of forming an emulsion comprising two or more substantially
immiscible solvents and the chemical substance. The emulsion can be formed during the sonicating step, wherein an
immiscible mixture of said solvents is sonicated to form the emulsion. Alternatively, the emulsion can be formed before
the sonicating step. Where an emulsion is employed, the chemical substance can be substantially soluble in one of the
immiscible solvents and substantially insoluble in another of the immiscible solvents. The chemical substance is in
solution in one or both of the solvents.
[0099] Emulsions can be employed as part of a screening method and/or solidification method to generate additional
solid forms of a chemical substance. Emulsions can allow interface between the two solvents over a high surface area.
At such interfaces, nucleation and/or growth of some polymorphs may be favored, based on the influence of each solvent
on the growth of each polymorph.
[0100] An emulsion may be prepared by combining a solution of a chemical substance in a first solvent with a second
solvent, wherein the first solvent and the second solvent are substantially immiscible with each other. The combined
solvents may then be sonicate while evaporating, cooling, adding antisolvent, or using other solidification techniques
until a precipitate containing the chemical substance appears.
[0101] Another technique for crystallizing a chemical substance employs a slurry. A slurry is a dispersion of solid
particles in a liquid phase. The liquid phase comprises one or more solvents in which the chemical substance is not
completely soluble. The process of slurrying a metastable form of a chemical substance, aiming at finding a form of
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lower solubility in the solvent used, in other words, a form of lower energy (in the case of the transition between two
unsolvated polymorphs) or a solvated form (in the case of a transition between an unsolvated form or solvated form
from a different solvent to a solvated form), is foreseen to be accelerated by the use of ultrasound during the slurrying
process.
[0102] The present methods may also include the step of forming a slurry comprising a solvent and the chemical
substance. The slurry can be formed during the sonicating step, wherein a mixture of the chemical substance and the
solvent are sonicated to form the slurry. Alternatively, the slurry can be formed before the sonicating step.
[0103] It is preferable in a screening method that the generation of solid forms is carried out under a wide variety of
conditions. For example, solids should be generated in the presence and absence of various solvents, as the solvent
may play a role in the formation of certain forms, and with and without sonication. As another example it is also preferable
to prepare solid forms under different conditions of temperature and pressure, as different solid forms may be favored
by different conditions. In some embodiments of the screening method, at least one sample is unsonicated so that the
effect of ultrasound on solid form for that chemical substance can be determined.
[0104] It is also contemplated that the present methods are advantageous for generating solid forms from viscous
solutions. For example, the present methods may be used with samples that are solutions having a viscosity greater
than about 5 cPoise, alternatively greater than 10 cPoise, alternatively greater than 20 cPoise, before the solution is
sonicated.
[0105] It is also contemplated that the present methods are advantageous for generating solid forms from amorphous
forms of the chemical substance. Samples can be formed or provided by preparing a solution from an amorphous solid
comprising the chemical substance and a solvent. The solvent may be sonicated while the amorphous solid is added
to the solvent.
[0106] It is contemplated that, in the context of a comprehensive screening method, the samples can be divided into
subsamples or sets of subsamples. A multiplicity of subsamples and sets are useful so that more than one parameter
may be varied and the cumulative effect of multiple varied parameters may be assessed. For example, a first sample
(and/or a second sample) may be divided into subsamples, such as a first set of subsamples, a second set, a third set,
and a fourth set. The first set and the second set can comprise a solution of the chemical substance in a first solvent,
such as acetone, while the third set and the fourth set comprise a solution of the chemical substance in a second solvent,
such as tetrahydrofuran. The first set and the third set can be sonicated, and the second set and the fourth set can be
unsonicated. The benefit of this method is that the effects of ultrasonic crystallization on acetone and tetrahydrofuran
solutions can be analyzed and compared.
[0107] Solid forms generated after the solidification and sonication steps may be identified by any suitable method,
including but not limited to visual analysis (such as when different forms exhibit different colors), microscopic analysis
including electron microscopy (such as when, different forms happen to have different morphologies), thermal analysis
(such as determining the melting points), conducting diffraction analysis (such as x-ray diffraction analysis, electron
diffraction analysis, neutron diffraction analysis, as well as others), conducting Raman or infrared spectroscopic analysis,
or conducting other spectroscopic analysis. Any appropriate analytical technique that is used to differentiate structural,
energetic, or performance characteristics may be used in connection with the present methods.
[0108] In a preferred embodiment, the samples are placed in a well plate and then sonicated. The chemical substances
solidify in the wells of the well plate. The solidified chemical substances are then analyzed in the well plate or a portion
of the well plate. The solidified chemical substances can be analyzed by any one of the foregoing analysis techniques,
preferably by x-ray diffraction (such as transmission x-ray diffraction or reflection x-ray diffraction) and/or by Raman
spectroscopy. Well plates may be used which have a detachable portion, such as a detachable bottom portion. For
example, well plates may be used which have polymer films, glass plates, or other substrates that are detachable from
another portion of the well plates. Solidified chemical substances can be analyzed in the well plate or the detachable
portion of the well plate. In particular, x-ray diffraction techniques such as transmission or reflection x-ray diffraction may
be used to analyze the solidified chemical substances in well plates or the detachable portion of well plates (for example,
the polymer film, glass plate, or other substrate).
[0109] A synchrotron may be used as the source of radiation for conducting diffraction analyses. A synchrotron is a
type of particle accelerator, which emits high energy, focused radiation. Synchrotron radiation is the byproduct of circu-
lating electrons or positrons at speeds very close to the speed of light. Synchrotron radiation contains all the wavelengths
of the electromagnetic spectrum and comprises the most intense source of wavelengths available in the x-ray and
ultraviolet region. Synchrotron radiation allows analysis of smaller quantities of sample that would be difficult to analyze
using other sources of x-ray radiation.
[0110] One location for research using synchrotron radiation is the Stanford Synchrotron Radiation Laboratory (SSRL),
which is funded by the Department of Energy as a national user facility. Another location is Argonne National Laboratory,
which is available to outside users on a fee basis.
[0111] Synchrotron radiation may be used to study structural details of solid samples with a resolution not practically
attainable musing traditional x-ray instrumentation. This may enable differentiation between different polymorphic forms
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or compounds that is not attainable with other x-ray radiation sources.
[0112] The present methods can significantly assist in the identification of the solid form of a chemical substance that
is most stable or has other properties that make it preferable over other forms. For example, the present methods can
be used as part of a screening method and can improve the likelihood of identifying a form having biological activity
such as better stability, bioavailability, solubility, or absorption characteristics. In some cases, an identified form may
have better activity as an active agent.
[0113] After a chemical substance (including a solution, melt, emulsion, slurry, suspension, or mixture containing the
chemical substance) is placed in a receptacle, the receptacle may be centrifuged. Centrifugation may be employed for
a variety of reasons. First, use of a centrifugal evaporator may assist evaporation while concentrating solid or semisolid
material at one end of a capillary space. This has advantages in connection with in-situ analysis, in that the generated
form will be located at a consistent place in the receptacle. Also or alternatively, centrifuging may be used to provide
additional environmental variation, which is desirable in a screening method.
[0114] The application of ultrasound to solutions containing multiple components to be crystallized can induce nucle-
ation in cases where the components otherwise remain indefinitely or for relatively long periods in solution (in other
words, in metastable solution). In this respect, the application of ultrasound is of considerable interest to find new
cocrystals and salts which are otherwise difficult to find. For example, the present techniques are beneficial for cocrys-
tallization from viscous solutions, or from systems having a large Metastable Zone Width.
[0115] The present techniques are applicable to cocrystallize two or more active agents. (It is contemplated that more
than one active agent may be employed in a cocrystal.) An active agent is a molecule whose activity is desirable or the
object of interest. For example, where the active agent is an active pharmaceutical ingredient, the pharmaceutical activity
of the active agent is desired or the object of interest. Active agents include organic and inorganic substances. Examples
of active agents for use in the present techniques include, but are not limited to, pharmaceuticals, dietary supplements,
alternative medicines, nutraceuticals, agricultural chemicals, dyes, explosives, polymer additives, lubricant additives,
photographic chemicals, and structural and electronic materials. Preferably, the active agent is an active pharmaceutical
ingredient (API). Pharmaceutical agents suitable for use in the present technique include known pharmaceutical agents
as well as those which may be developed. A pharmaceutical agent can be a large molecule (in other words, a molecule
having a molecular weight of greater than about 1000 g/mol), such as oligonucleotides, polynucleotides, oligonucleotide
conjugates, polynucleotide conjugates, proteins, peptides, peptidomimetics, or polysaccharides. A pharmaceutical agent
can be a small molecule (in other words, a molecule having a molecular weight of about 1000 g/mol or less), such as
hormones, steroids, nucleotides, nucleosides, aminoacids, acetaminophen, nonsteroidal anti-inflammatory drugs, and
others. Examples of suitable small molecule pharmaceuticals include, but are not limited to, cardiovascular pharmaceu-
ticals; anti-infective components; psychotherapeutic components; gastrointestinal products; respiratory therapies; cho-
lesterol reducers; cancer and cancer-related therapies; blood modifiers; antiarthritic components; AIDS and AIDS-related
pharmaceuticals; diabetes and diabetes-related therapies; biologicals; hormones; analgesics; dermatological products;
anesthetics; migraine therapies; sedatives and hypnotics; imaging components; and diagnostic and contrast components.
[0116] The active agent may be provided as a salt. It is contemplated that one or more salts may be employed in a
cocrystal, according to any of the present techniques. The salt may be prepared from an ionizable active agent or
obtained from a commercial source. Hydrochloride salts of active pharmaceutical ingredients, especially of amine APIs,
are especially preferred in the pharmaceutical industry.
[0117] In general, it is contemplated that the present techniques will have particularly good results as applied to amine
HCl salts as well as other Ammonium salts as described in more detail herein. In ammonium acid salts, the active agent
has at least one amine moiety which is relatively basic (at least one relatively basic nitrogen), and a salt is formed with
an acid that reacts with the amine moiety. Cocrystals may be then formed between the ammonium salts and guests
which act as hydrogen-bond donors to the salts. Cocrystals may be formed of chloride salts of APIs, for example buspirone
hydrochloride and fluoxetine hydrochloride.
[0118] While the inventors do not wish to be bound to theory, it is believed that excellent cocrystals may be formed
using hydrochloride salts and similar salts which are strong hydrogen bond acceptors yet contain relatively undercoor-
dinated ions. "Undercoordinated" in this case refers to ions, for example a chloride ion, that are able to form a number
of strong hydrogen bonds. An undercoordinated counterion may have hydrogen bonds within a crystal of that salt, but
it could form additional hydrogen bonds in a cocrystal and/or form relatively stronger hydrogen bonds in a cocrystal with
a guest. An ion is "undercoordinated" when the system is limited in the number of hydrogen bond donors that are available
and bonded to the ion. In these cases, the extra hydrogen bond acceptor sites are typically filled by weakly interacting
donors such as C-H groups. Chloride ions are strong hydrogen bond acceptors in a crystal structure. In a crystal structure
such as fluoxetine hydrochloride, the chloride ion coordinates to the two strong hydrogen bond donors available in the
system, and the chloride ion also has three weaker CH-Cl interactions resulting in a pseudo-octahedral coordination
environment. There is an opportunity for bonding with these coordination sites, by displacing the weak CH donors that
the chloride has recruited to fill its coordination sphere with somewhat stronger hydrogen bond donors from a guest
such as benzoic acid, succinic acid, fumaric acid, or another carboxylic acid.
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[0119] It is useful in forming cocrystals to recognize that relatively weak interactions may be replaced by stronger
interactions, even though those stronger interactions may be relatively weak themselves, compared to other interactions.
For example, an undercoordinated chloride may have one strong hydrogen bond donor and several weak hydrogen
bond donors or two strong hydrogen bond donors and several weak hydrogen bond donors. In a cocrystal, weaker
interactions may be replaced by stronger interactions, although those stronger interactions may still be weaker than the
strong interactions (charge-assisted hydrogen bonds) present in fluoxetine HCl crystals. The strongest interactions
involving chloride ions in crystal structures of organic salts are the charge assisted hydrogen bonds that invariably form
between the protonated nitrogen base and the chloride ion. The strongest interactions between neutral molecular groups
and the chloride ion involve acids and the chloride ion. Carboxylic acids, for instance, have strong interactions with
chloride ions. It can be seen that a combination of carboxylic acids and hydrochloride salts of nitrogen containing bases
are especially well suited to cocrystal formation (as demonstrated by the examples included). Furthermore, it can be
anticipated that different combinations of these elements could lead to other cocrystals. For example, the active molecule
of interest may contains either the neutral carboxylic acid moiety or the protonated nitrogen. The potential exists to
cocrystallize an API having a neutral carboxylic acid moiety with a guest that is a hydrochloride salt of a nitrogen-
containing organic base.
[0120] It is further contemplated that the nature of the protonated nitrogen base will affect the potential for cocrystal-
lization. Numerous strong hydrogen bond donor groups will compete with the carboxylic acid guest for the open acceptor
sites on the chloride ion. In order to favor cocrystal formation, the nitrogen base is preferably a tertiary amine because
this presents a situation where only one strong charged hydrogen bond donor exists and thus will only occupy one site
on the chloride acceptor. Additionally, systems that have only this one tertiary amine and no other strong donors present
an especially favorable system for potential cocrystallization. Protonated secondary amines with two N-H donor groups
are also favored, although protonated primary amines may also be used. Special consideration must be taken for systems
with additional strong hydrogen bond donor and acceptor sites in order to determine the potential for cocrystallization
and the optimal guest molecule type for cocrystallization. The potential for cocrystallization involving a carboxylic acid
and a hydrochloride salt may be reduced as the number of available strong donors in the system is increased. Additional
guidance as to evaluating undercoordination particularly in its discussion of nonbonded motifs may be found in: Scott
L. Childs, "Nonbonded Interactions In Molecular Crystal Structures", Emory Univ., USA, available from UMI, Order No.
DA3009424 (288 pp.), Dissertation Abstract Int. Ref. B2001, 62(3), 1394 (which is incorporated by reference herein). In
some circumstances, the undercoordination can be determined by measuring distances, comparing profiles in the Cam-
bridge Structural Database, measuring the pKa of the donors and acceptors, or evaluating the ratio of strong hydrogen
bond donors to available acceptors. Other crystal engineering theories may also be used.
[0121] By cocrystallizing an active agent with a guest, one can create new solid state phases which may have improved
properties over existing solid state phases of that active agent. For example, new drug formulations comprising salt of
active pharmaceutical ingredients may have superior properties over existing drug formulations. The active agent and
guest will vary depending on the industry. For example, in the pharmaceutical field, the active agent or guest may be
an API, and the other component of the salt must be a pharmaceutically acceptable compound. The present techniques
are also applicable to active agents from other fields including nutraceuticals, agricultural chemicals, pigments, dyes,
explosives, polymer additives, lubricant additives, photographic chemicals, and structural and electronic materials.
[0122] The present techniques may be employed to generate a wide variety of cocrystals of active agents and guests.
For example, the present techniques may be used to generate cocrystals of a salt of an active agent, such as a salt of
an active pharmaceutical ingredient, with a neutral guest. Alternatively, a cocrystal of a neutral or zwitterionic active
agent (or a salt of an active agent) may be generated with a guest salt, which includes a positive ion and a negative ion
of its own. Where the active agent is provided in a salt, it may be positively or negatively charged and have a negative
or positive counterion. As an example, for fluoxetine HCl, the active agent fluoxetine is positively charged by virtue of
accepting a proton from HCl to form a protonated amine, and chloride is present as a negative counterion. Furthermore,
some of the present methods may be employed with a neutral or zwitterionic active agent to form a cocrystal with a
neutral guest or ionic guest.
[0123] The present techniques provide an opportunity to create a stable solid estate phase of a hydrochloride salt of
an API (or other active agents) that was previously found to have properties that were unsuitable for development.
Opportunities for continued development in such a situation have often relied on the fortuitous formation of a stable
hydrate or solvate, but the pres ent techniques present the ability to systematically examine alternative formulations of
the hydrochloride salt by cocrystallizing the hydrochloride salt of the API with appropriate guest molecules.
[0124] Cocrystallization may be an attractive technique for salts of APIs that have been rejected due to problems
relating to physical properties. Since cocrystals may have different physical properties than the individual components,
APIs with unfavorable physical properties can be cocrystallized with suitable guest molecules and the physical properties
of the resulting crystalline solids can be evaluated.
[0125] Cocrystals of fluoxetine HCl provide examples of the modification of a physical property (solubility) of an API
salt. Cocrystals of fluoxetine HCl:benzoic acid are less soluble and have a lower dissolution rate than crystals of fluoxetine
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HCl, while cocrystals of fluoxetine HCl:succinic acid are more soluble and have a faster dissolution rate than crystals of
fluoxetine HCl.
[0126] Other physical properties of APIs or their salts that may be modified by forming a cocrystal include: melting
point, density, hygroscopicity, crystal morphology, loading volume, compressibility, and shelf life. Furthermore, other
properties such as bioavailability, toxicity, taste, physical stability, chemical stability, production costs, and manufacturing
method may be modified by the use of the present cocrystallization techniques.
[0127] An active agent can be screened for possible cocrystals where polymorphic forms, hydrates or solvates are
especially problematic. A neutral compound that can only be isolated as amorphous material could be cocrystallized.
Forming a cocrystal may improve the performance of a drug formulation of an active pharmaceutical ingredient by
changing physical properties. Some APIs are problematic during wet granulation and compression stages. A bioequiv-
alent cocrystal could rectify this problem.
[0128] An active agent can also be screened for possible salts. Forming a salt may improve the performance of a drug
formulation by changing physical properties. A salt screen refers to a screening method in which one attempts to make
one or more salts comprising an active agent under a variety of conditions and/or parameters, preferably incl-uding a
variety of different counterions.
[0129] A cocrystal or salt can be used to isolate or purify an active agent during manufacturing. If it is desirable to
identify the solid state phases of an active pharmaceutical ingredient, then cocrystallization and/or salt formation may
be particularly desirable.
[0130] The present techniques provide new methods of developing and screening active pharmaceutical ingredients
or other active agents. Non-toxic cocrystalline forms of neutral active pharmaceutical ingredients may be prepared,
screened, tested, and commercialized. Furthermore, new types of HCl salt structures may be prepared. The properties
of hydrochloride salts can be tuned and perfected. New, unique, stable, and marketable phases of hydrochloride salts
may be prepared. One can choose whether to make the formulation more soluble or less soluble.
[0131] As another aspect, the present techniques may also be used to remove or reduce the water of hydration, and/or
to prepare a cocrystal substantially free of water of hydration. Water and guest acids perform a similar role in the
stabilization of the crystal structure. In fact, about 28% of the hydrochloride salts of API in the Cambridge Structure
Database are hydrates, compared to about 8% of all other organic structures. This indicates an affinity for hydration.
The present techniques both capitalize and rectify this affinity, in that an affinity for cocrystallization (as evidence by
hydration) is likely indicated, and this affinity for cocrystallization may be employed for the formation of cocrystals with
a suitable guest, such as an acid, for example a carboxylic acid. Indeed, in many cocrystals, an acid may have stronger
interactions than water molecules and may displace the water of hydration during the formation of the cocrystal. Accord-
ingly, the present techniques provide a method of preparing a cocrystal from a hydrate. A hydrate of a salt is provided,
and the hydrate comprises water of hydration. A guest is selected to coordinate with the counterion. Preferably, the
guest coordinates more strongly with the counterion than the water of hydration does. A solution, melt or physical mixture
is prepared which comprises the hydrate and the guest. The solution or melt is subjected to a crystallization process,
or the physical mixture is subjected to grinding, and a cocrystal comprising the salt of the active agent and the guest is
formed, and the salt comprises the active agent and a counterion. Similarly, the present techniques provide a method
of preparing a cocrystal from a solvate. A solvate of a salt is provided, and the solvate comprises solvent molecules
coordinated with the salt. A guest is selected to coordinate with the counterion. Preferably, the guest coordinates more
strongly with the counterion than the solvent does. A solution, melt or physical mixture is prepared comprising the solvate
and the guest. The solution or melt is subjected to a crystallization process, or the physical mixture is subjected to
grinding, and a cocrystal comprising the salt of the active agent and the guest is formed. The salt comprises the active
agent and a counterion.
[0132] Figures 9 (a) and (b) are drawings of two-dimensional and three-dimensional models of a cocrystal of fluoxetine
HCl and benzoic acid (1:1). Figure 9 (a) shows a two-dimensional model in which the chloride ion interacts with the
hydrogens of the amine group of fluoxetine and of the hydroxyl group of benzoic acid. Through these interactions, which
may be characterized as hydrogen bonding, fluoxetine hydrochloride and benzoic acid form a supramolecular structure
that may be the basis of a cocrystal. Figure 9(b) shows a three-dimensional model of the supramolecular organization
of fluoxetine hydrochloride and benzoic acid.
[0133] The present cocrystals may comprise salts other than chloride salts -- the hydrochloride API salts that are listed
above are only a sampling of the relevant compounds because the starting material need not be a known hydrochloride.
Indeed, many relevant APIs are salts that are not HCl salts because the HCl salt was not believed to be an appropriate
material and a different salt was commercialized instead. The present techniques may enable one to employ an HCl
salt of an API that is marketed as another type of salt. Alternatively, it may be desirable to employ a salt other than an
HCl salt, by replacing the HCl or by forming a salt comprising an active agent that acts as a base with an acid other than
HCl. The following acids provide anionic counterions that would be used to replace chlorine. These are relatively strong
acids, and include but are not limited to mineral acids, and the carboxylic acid guest is expected to form one or more
hydrogen bonds with a hydrogen bond acceptor on the anionic counterion. The list is the conjugate acid that would react
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with a basic active agent to form a salt:
sulfuric acid
phosphoric acid
hydrobromic acid
nitric acid
pyrophosphoric acid
methanesulfonic acid
thiocyanic acid
naphthalene-2-sulfonic acid
1,5-naphthalenedisulfonic acid
cyclamic acid
p-toluenesulfonic acid
maleic acid
L-aspartic acid
2-hydroxy-ethanesulfonic acid
glycerophosphoric acid
ethanesulfonic acid
hydroiodic acid
[0134] The present techniques also extend beyond salts as starting materials and also include many weak bases that
may have been marketed as neutral forms because the known salts did not have appropriate properties. These salts
could be revisited and attempts could be made to cocrystallize the HCl salt. For example, a drug formulation marketed
as a tartrate salt of an API could be reformulated by cocrystallizing the HCl salt of the active molecule with an appropriate
guest molecule. Thus, cocrystallization could make a useful HCl cocrystal out of the API that is currently marketed as
a tartrate, sulfate, or other salt formulation. For this reason the present disclosure includes APIs that are not HCl salts
as starting materials.
[0135] Furthermore, the present techniques relate to salts other than chloride salts. It is contemplated that hydrobromide
salts and sodium salts of APIs may especially benefit from the present techniques, since they form relatively strong
nonbonded interactions. For example, the hydrobromide salts citalopram hydrobromide and galantamine hydrobromide
are contemplated for cocrystallization with benzoic acid, succinic acid, and other guests compatible with hydrochloride
salts.
[0136] The present techniques may be employed to form cocrystals of sodium salts of APIs such as, for example,
naproxen sodium, tolmetin sodium, and warfarin sodium. When a sodium salt (or other salt of an API having a positive
counterion) is employed, different guests are expected to be suitable for cocrystallization than when a hydrochloride salt
(or other anionic salt) of an API is employed.
Anions and Cations
[0137] As one aspect, the active agent is provided as a salt. The salt of the active agent may be formed as part of
sample preparation or separately. Alternatively or additionally, the guest is provided as a salt or a salt of the guest is
formed. The salt may comprise the active agent and a counterion that is either a cation or an anion. Among the preferred
cations (including cations as well as compounds that can form cations) are aluminum, ammonium, benzathine, calcium,
diethanolamine, diethylamine, dimeglumine, disodium, lithium, lysine, magnesium, meglumine, potassium, sodium, and
zinc. Among the preferred anions are acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate,
citrate, edisylate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, D-lactate, L-lactate, DL-lactate,
D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate, sulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tar-
trate, benzoate, gluceptate, D-glucuronate, hybenzate, isethionate, malonate, methylsufate, 2-napsylate, nicotinate,
nitrate, orotate, stearate, tosylate, acefyllinate, aceturate, aminosalicylate, ascorbate, ascorbate, borate, butyrate, cam-
phorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate,
fusidate, galactarate (mucate), galacturonate, gallate, gentisate, glutamate, glutamate, glutarate, glycerophosphate,
heptanoate (enanthate), hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate,
maleate, mandelate, methanesufonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate,
pyrophosphate, salicylate, salicylsulfate, sulfosalicylate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribroph-
enate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocy-
anate, and undecylenate.
[0138] When a metal cation is employed as a counterion of the active agent, the interaction between guest and cation
is not a hydrogen bond but rather is an intermolecular interaction between an electron rich group such as a carbonyl
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and the metal cation. This interaction is often not as strong as a hydrogen bond, but is still a favorable interaction and
thus can contribute to the stabilization of a cocrystal.
[0139] The HCl salt of an active pharmaceutical ingredient is especially preferred to create a new type of cocrystal.
In this type of solid state phase, one can cocrystallize the HCl salt with a neutral guest molecule. By doing this one can
create solid state phases with specific properties. For instance one can make a solid comprising an active pharmaceutical
ingredient having greater or lesser intrinsic solubility and/or a faster or slower dissolution rate, depending on the guest
compound that is chosen.
[0140] The present techniques may be utilized in methods for screening an ionizable active agent according to its
possible salts or for preparing a salt comprising an ionizable active agent and a guest. Such methods can comprise
providing a plurality of samples comprising the active agent and one or more counterions; sonicating the sample(s); and
forming crystallized salt compounds comprising the active agent and counterions. The counterions may be any of the
cations or anions set forth above or elsewhere in the present disclosure. Using the present techniques provides a greater
likelihood of generating possible salts of the ionizable active agent. Moreover, a salt developed by such a method may
be employed in connection with the methods described herein which relating to cocrystals comprising a salt and a guest.
Guests
[0141] The guest is present in order to form the cocrystal with the active agent. It is contemplated that one or more
guests may be employed in a cocrystal, according to any of the present techniques. Accordingly, the guest is not required
to have an activity of its own, although it may have some activity that does not overly derogate from the desired activity
of the active agent. In some situations, the guest may have the same activity as or an activity complementary to that of
the active agent. The guest may be another API. For example, some guests may facilitate the therapeutic effect of an
active pharmaceutical ingredient. For pharmaceutical formulations, the guest may be any pharmaceutically acceptable
molecule(s) that forms a cocrystals with the API or its salt. The RTECS database is a useful source for toxicology
information, and the GRAS list contains about 2500 relevant compounds.
[0142] The guest may be neutral (such as benzoic acid and succinic acid in the examples below) or ionic (such as
sodium benzoate or sodium succinate). Neutral guests are nonionic guests. Ionic guests are compounds or complexes
having ionic bonds. Figure 10 shows several general classes of guests (organic bases, organic salts, alcohols & alde-
hydes, amino acids, sugars, ionic inorganics, aliphatic esters & ketones, organic acids, and aromatic esters & ketones).
[0143] The guest may be an acid that forms hydrogen bonds with the chloride (or other anion). For example, suitable
guests which are acids include (but not are not limited to):
ascorbic acid
glucoheptonic acid
sebacic acid
alginic acid
cyclamic acid
ethane-1,2-disulfonic acid
2-hydroxyethanesulfonic acid
2-oxo-glutaric acid
naphthalene-1,5-disulfonic acid
nicotinic acid
pyroglutamic acid
4-acetamidobenzoic acid
[0144] Table 8 sets forth a group of presently preferred guests. It is contemplated that the guests set forth in the Table
may be arranged in subgroups based upon molecular structure and/or physiological effect. Furthermore, the foregoing
list is intended to provide a written description of any sublist that omits one or more guests.
[0145] Table 9 sets forth another group of preferred guests. It is contemplated that the guests set forth in the Table
may be arranged in subgroups based upon molecular structure and/or physiological effect. Furthermore, the foregoing
list is intended to provide a written description of any sublist that omits one or more guests.
[0146] Table 10 sets forth the group comprising molecules believed at present to be suitable guests. It is contemplated
that the guests set forth in the Table may be arranged in subgroups based upon molecular structure and/or physiological
effect. Furthermore, the foregoing list is intended to provide a written description of any sublist that omits one or more
guests.
[0147] Ionic guests are salts themselves, and may be formed from bases and acids prior to being used to form
cocrystals. For example, the following bases and acids may be reacted to form ionic guests:
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Bases
[0148]
Ammonia
L-A-rginine
Benethamine
Benzathine
Betaine
Calcium Hydroxide
Choline
Deanol
Diethanolamine
Diethylamine
2-(Diethylamino) ethanol
2-Aminoethanol
Ethylenediamine
N-Methylglucamine
Hydrabamine
1H-Imidazole
Lysine
Magnesium Hydroxide
Morpholine
4-(2-Hydroxyethyl) Morpholine
Piperazine
Potassium Hydroxide
Pyrrolidine
1- (2-Hydroxyethyl) Pyrrolidine
Sodium Hydroxide
Triethanolamine
Tromethamine
Zinc Hydroxide
Acids
[0149]
(+) -L-Tartaric Acid
1,2,2-Trimethyl-1,3-cyclopentanedicarboxylic Acid
10-Undecylenic Acid
1-Hydx-oxy-2-naphthoic Acid
(+)-Camphor-10-sulfonic Acid
2,5-Dihydroxybenzoic Acid
2-Furancarboxylic Acid
2-Mercaptobenzoic Acid
3-Cyclopentylpropionic Acid
3-Phenylpropionic Acid
4-Aminosalicylic Acid
4-Hydroxybenzoic Acid
Acetic Acid
Adipic Acid
alpha-Hydroxypropionic Acid
Benzenesulfonic Acid
Benzoic Acid
Carbonic Acid
Cholic Acid
Citric Acid
(-)-D-Tartairic Acid
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(+)-D-Camphoric Acid
(+)-D-Malic Acid
(+)-L-Malic Acid
2,2-Dichloroacetic Acid
DL-10-Camphorsulfonic Acid
DL-Glutamic Acid
DL-Malic Acid
DL-Tartaric Acid
Dodecylsulfuric Acid
Ethanesulfonic Acid
Ethylenediaminetetraacetic Acid
Ethylsulfuric Acid
Fumaric Acid
Galactaric Acid
Gallic Acid
Gluconic Acid
Glutaric Acid
Glycolic Acid
Hippuric Acid
Hydriodic Acid
Hydrobromic Acid
Hydrochloric Acid
(-)-L-Apple Acid
(+)-L-Lactic Acid
(+)-L-Tartaric Acid
D,L-Lactic Acid
Lactobionic Acid
L-Aspartic Acid
Lauric Acid
L-Glutamic Acid
Maleic Acid
(-)-L-Malic Acid
Malonic Acid
D,L-Mandelic Acid
Methanesulfonic Acid
Naphthalene-2-sulfonic acid
n-Butyric Acid
n-Decanoic Acid
n-Hexanoic Acid
Nitric acid
n-Tetradecanoic Acid
Octanoic Acid
Oleic Acid
Orotic Acid
Orthoboric Acid
Oxalic Acid
4-Acetamidobenzoic Acid
Palmitic Acid
Pamoic Acid
Phosphoric Acid
Picric Acid
Pivalic Acid
Propionic Acid
p-Toluenesulfonic Acid
Pyrophosphoric Acid
Salicylic Acid
Stearic Acid
Succinic Acid
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Sulfosalicylic Acid
Sulfuric Acid
Terephthalic Acid
Thiocyanic Acid
Valeric Acid
Valproic Acid
[0150] Typically, suitable guests will have complementary ability to noncovalently bond to the active agent or its salt,
for example the ability to form hydrogen bonds with the active agent or its salt. Suitable guests for active agents having
negative counterions include, but are not limited to, compounds having alcohol, ketone, ester, and/or carboxylic acid
functionalities. Suitable guests may include organic acids, organic bases, organic salts, alcohols, aldehydes, amino
acids, sugars, ionic inorganic compounds, aliphatic esters and ketones, and aromatic esters and ketones.
[0151] Among the presently preferred neutral guests are those which are not liquids at room temperature. Also among
the presently preferred neutral guests are carboxylic acids having at least three carbon atoms, alternatively at least four
carbon atoms, and which do not form solvates. For example, if the following acids were combined with active agents,
the combination would more properly be considered a solvate than a cocrystal: acetic acid, propionic acid, and butyric
acid. However, in certain embodiments of the present invention (for example, in certain cocrystals, cocrystallization
methods, and screening methods), the use of solvents and solvates may still be desirable, and the use of solvents and
solvates is not excluded from the scope of any cocrystal or method except where explicitly stated.
[0152] In the present methods, the active agent(s) and guest(s) to be cocrystallized are provided as one or more
samples to be used within the present techniques. The samples may be provided by being formed, created or prepared
as an initial step in the present methods, or they may be obtained ready-to-use from another source.
[0153] In some embodiments, the samples may contain the active agent(s) and the guest(s) alone, for example, in a
melt or a physical mixture. Alternatively, the sample will also contain a solvent(s) in which the active agent (s) and the
guest(s) are dissolved, dispersed or otherwise disposed. The active agent(s) and the guest(s) may be completely or
partially soluble in the solvent(s) or one or more of them may be substantially insoluble in the solvents. Accordingly, the
sample may be in a solution, dispersion, suspension, mixture, slurry or emulsion, or other physical state. The samples
physical state going into the present methods is not critical to the broader applicability of the present methods, though
in some embodiments, use of particular physical states for samples can be beneficial, as described in more detail herein.
For example, the present methods may have additional benefits when the samples are metastable solutions, viscous
solutions, emulsions or slurries.
Cocrystallization
[0154] In the present methods, the active agent and the guest are cocrystalized from the sample using a suitable
crystallization technique. As used herein, crystallization includes any suitable technique for preparing a crystal from the
sample.
[0155] The crystallization technique(s) employed will depend in part on the sample(s). Sui table crystallization tech-
niques include cooling, heating, evaporation, addition of an antisolvent, reactive crystallization, and using supercritical
fluids as solvents. A fluid is an antisolvent with respect to a given solution of components to be cocrystallized when at
least one component is less soluble in that fluid than in the solvent used to form the solution; preferably, an antisolvent
is a fluid in which both components are essentially insoluble or have a low solubility. Reactive crystallization refers to
processes where a chemical compound is formed from reactants and crystallized substantially simultaneously, for ex-
ample, where the reaction is a driving force toward crystallization. A supercritical fluid is a fluid above its critical temperature
and critical pressure which combines properties of gases and liquids. Examples of compounds employed as supercritical
fluids include xenon, ethane and carbon dioxide.
[0156] Alternatively, the mechanism by which crystallization is accomplished may include gel diffusion methods, thin-
layer deposition methods, or other suitable methods. Other thermodynamic and kinetic conditions may be employed for
cocrystallization. Slow cooling of a saturated solution is a typical thermodynamic condition. An addition of a solution of
the components to be cocrystallized to an excess of cold anti-solvent is a typical kinetic condition.
[0157] Additionally, melt crystallization techniques may be used to generate a cocrystal. Through such techniques,
the use of a solvent can be avoided. In such techniques, formation of crystalline material is from a melt of the crystallizing
components rather than a solution. Additionally, the crystallization process may be done through sublimation techniques.
[0158] In many embodiments, the samples will comprise a solvent. Any suitable solvent can be used. Suitable solvents
include acetone, acetonitrile, chloroform, 1,4-dioxane, ethanol, ethyl acetate, heptane, 2-butanone, methanol, nitrometh-
ane, tetrahydrofuran, toluene, water, dichloromethane, diethyl ether, isopropyl ether, cyclohexane, methylcyclohexane,
isopropyl alcohol, trimethylpentane, n-octane, trichloroethane, trifluoroethanol, pyridine, 1-butanol, tetrachloroethylene,
chlorobenzene, xylene, dibutyl ether, tetrachloroethane, p-cymene, dimethyl sulfoxide, formamide, and dimethylforma-
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mide. It is also contemplated that the samples may comprise the components to be cocrystallized in two or more solvents,
either as a homogeneous solution, as an emulsion, or in another physical state.
[0159] The crystallization may be accomplished in a variety of ways, and preferably includes evaporation of the solvent
(s). For example, the solvent may be evaporated either slowly (for example, evaporating to dryness over a time period,
of four days, alternatively two days or more) or quickly (for example, evaporating to dryness over a time period of 24
hours, alternatively under two days). By varying the rate of evaporation among separate samples, one can introduce
desired variability into a screening method. For example, in a screening method, a first portion of samples can be
subjected to relatively slow evaporation, and a second portion of the samples can be subjected to relatively fast evap-
oration.
[0160] In the present methods, ultrasound may be applied at different stages of a screening process or a crystallization
process. For example, a solution which comprises the components to be cocrystallized can be sonicated at some point
during the screening process. One may sonicate such a solution before, during, or after the initiation of cooling of the
solution from an undersaturated, saturated, or supersaturated state. As other examples, one may sonicate a solution
before, during, or after the beginning of evaporation of solvent, or before, during, or after the addition of an immiscible
antisolvent to the solution.
[0161] In the present methods, the crystallizing step and the sonicating step can overlap. For example, where the
samples are provided as a solution of the components to be cocrystallized in a solvent, the crystallizing step may be
performed by evaporating the solvent, and the sample may be sonicated during that evaporation. Furthermore, the
sonication can be periodic during the evaporation. For example, the sample can be periodically sonicated for about 20
seconds, and the periods can be about 30 minutes (in other words, the sample is sonicated for about 20 seconds every
30 minutes). Furthermore, the sonication can be a single pulses. For example, the sonication could be carried out one
time for 5 to 40 seconds or multiple times for a liked period, or for other suitable period(s).
[0162] In the present methods, the samples can comprise a solution, suspension (such as a melt), or other mixture
of the components to be cocrystallized. The sample will typically be prepared by heating above room temperature to
achieve supersaturation of the components. It may be desirable to begin cooling the samples (for example, to room
temperature) before the sonicating step. Alternatively, the samples may be cooled and sonicated at the same time.
Alternatively, the method can include crash-cooling the samples (rapidly lowering the temperature, for example, by
immersing in an ice bath) before the sonicating step. Alternatively, the samples may be crash-cooled and sonicated at
the same time.
[0163] The present methods can include the step of adding a second solvent to a solution containing the components
to be cocrystallized. For example, the second solvent may be added to facilitate crystallization.
[0164] The crystallization step can be initiated by sonication, and it may additionally be initiated by seed materials or
other techniques. In the various embodiments of the present methods, crystallization may start before, during, or after
the application of ultrasound. In many cases, the crystallization and sonication steps will overlap. For example, sonication
may begin before crystallization but continue even after crystallization begins. As another example, crystallization may
begin before sonication. As yet another example, the samples may be sonicated in a pulsing manner throughout the
crystallization process. Alternatively, sonication may be employed to initiate crystallization and be discontinued when
crystallization (such as nucleation) begins.
[0165] The sample containing two or more components to be cocrystallized is provided in a receptacle suitable for
crystallization, such as a vial, well-plate or capillary tube. The sample may be formed in the receptacle or formed outside
the receptacle and then placed in it. The components can initially be present in the sample below, at or above the point
of saturation at a given temperature at the time of placement in the receptacle. Through evaporation, the use of an
antisolvent, temperature variation, and/or other suitable means, the sample will reach a point where crystallization begins.
After a suitable amount of time, when a solid or semisolid appears, the resulting sample (more particularly, the solid
formed from the sample) is ready for analysis.
[0166] Crystallization may be performed as a seeded operation or an unseeded operation. In a seeded operation, a
selected quantity of seed crystals is included in the system. The characteristics of the seed crystals typically influence
the characteristics of the crystals generated from the system. Crystallization may be performed by heterogeneous or
homogeneous mechanisms. However, it is noted that ultrasound may be applied as a way of omitting the presence of
seed crystals.
[0167] Another technique for cocrystallizing chemical substances employs an emulsion. An emulsion is a mixture of
two or more immiscible liquids where one liquid is in a discontinuous phase within the other liquid. Emulsions are
frequently formed and/or stabilized by the use of agents called emulsifiers. However, sonication of an immiscible mixture
of solvents also allows the generation of emulsions.
[0168] The present methods may also include the step of forming an emulsion comprising two or more substantially
immiscible solvents and the components to be cocrystallized. The emulsion can be formed during the sonicating step,
wherein an immiscible mixture of said solvents is sonicated to form the emulsion. Alternatively, the emulsion can be
formed before the sonicating step.
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[0169] Emulsions can be employed as part of a screening method and/or solidification method to generate additional
solid state phases of an active agent. Emulsions can allow interface between the two solvents over a high surface area.
At such interfaces, nucleation and/or growth of some solid state phases may be favored, based on the influence of each
solvent on the growth of each solid state phase.
[0170] An emulsion may be prepared by combining a solution of an active agent and a guest in a first solvent with a
second solvent, wherein the first solvent and the second solvent are substantially immiscible with each other. The
combined solvents may then be sonicated while evaporating cooling, adding and antisolvent, or using other solidification
techniques until a precipitate containing the active agent and the guest appears.
[0171] Another technique for cocrystallizing employs a slurry. A slurry is a dispersion of solid particles in a liquid phase.
The liquid phase comprises one or more solvents in which at least one of the active agent and a guest is not completely
soluble. The process of slurrying a metastable form of an active agent and/or guest, aiming at finding a cocrystal or a
solvated form, is foreseen to be accelerated by the use of ultrasound during the slurrying process.
[0172] The present methods may also include the step of forming a slurry comprising a solvent and the active agent
and the guest. The slurry can be formed during the sonicating step, wherein a mixture of the active agent and the guest
and the solvent are sonicated to form the slurry. Alternatively, the slurry can be formed before the sonicating step.
[0173] Generating a variety of solid state phases is an important object of screening. A sufficient number of diverse
processes and parameters should be employed to maximize the likelihood that a high percentage of possible solid state
phases is generated. Samples should be generated under various thermodynamic and kinetic conditions.
[0174] It is preferable that the generation of solid state phases is carried out under a wide variety of conditions. For
example, solids should be generated in the presence and absence of various solvents, as the solvent may play a role
in the formation of certain forms, and with and without sonication. As another example it is also preferable to prepare
solid forms under different conditions of temperature and pressure, as different solid forms may be favored by different
conditions.
[0175] It is also contemplated that the present methods are advantageous for generating solid state phases from
viscous solutions. For example, the present methods may be used with samples that are solutions having a viscosity
greater than about 0.9 poise before the solution is sonicated.
[0176] It is also contemplated that the present methods are advantageous for generating solid state phases from
amorphous forms of the active agent. Samples can be formed or provided by preparing a solution from a solvent and
an amorphous solid comprising the active agent. The solvent may be sonicated while the amorphous solid is added to
the solvent.
[0177] It is contemplated that, in the context of a comprehensive screening method, a plurality of samples can be
divided into a large number of sets and subsets. A multiplicity of sets and subsets are useful so that more than one
parameter may be varied and the cumulative effect of multiple varied parameters may be assessed. For example, a
plurality of samples may be divided into a first set, a second set, a third set, and a fourth set. The first set and the second
set can comprise a solution of the active agent in a first solvent or with a first guest, while the third set and the fourth
set comprise a solution of the active agent in a second solvent or with a second guest. The first set and the third set can
be sonicated, and the second set and the fourth set can be unsonicated. The benefit of this method is that the effects
of ultrasonic crystallization with different solvents and/or different guests can be analyzed and compared.
Detection of Cocrystals and Crystals
[0178] Cocrystals (as well as other crystals) may be detected by x-ray diffraction analysis, Raman analysis, or other
suitable techniques. The observation of physical properties of a solid (particularly its melting point) which differ from the
physical properties of the starting materials and the polymorphs and/or solvates and/or hydrates of the starting materials,
is an indicator that a cocrystal has been formed.
[0179] Cocrystals and other crystals generated after crystallization and sonication steps may be identified by any
suitable method, including but not limited to visual analysis (such as when different forms exhibit different colors),
microscopic analysis including electron microscopy (such as when different forms happen to have different morphologies),
thermal analysis (such as determining the melting points), conducting diffraction analysis (such as x-ray diffraction
analysis, electron diffraction analysis, neutron diffraction analysis, as well as others), conducting Raman or infrared
spectroscopic analysis, or conducting other spectroscopic analysis. Any appropriate analytical technique that is used to
differentiate structural, energetic, or performance characteristics may be used in connection with the present methods.
[0180] In a preferred embodiment, the samples are placed in a well plate and then sonicated. The chemical substances
solidify in the wells of the well plate (for example, a 96-well plate or 384-well plate). The solidified chemical substances
are then analyzed in the well plate by one of the foregoing analysis techniques, preferably by x-ray diffraction (such as
transmission x-ray diffraction) and/or by Raman spectroscopy. A synchrotron may be used as the source of radiation
for conducting diffraction analyses.
[0181] Synchrotron radiation may be used to study structural details of solid samples with a resolution not practically
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attainable using traditional x-ray instrumentation. This may enable differentiation between different solid state phases
that is not attainable with other x-ray radiation sources.
[0182] The present methods can significantly assist in the identification of the possible cocrystals of a chemical sub-
stance(s). For example, the present methods can be used as part of a screening method and can improve the likelihood
of identifying a solid state phase having properties such as better stability, bioavailability, solubility, or absorption char-
acteristics. In some cases, an identified cocrystal of an active agent and a guest may have better biological activity than
a crystal of the active agent.
[0183] After samples (including a solution, emulsion, slurry, or mixture containing the active agent and guest) are
placed in a receptacle, the receptacle may be centrifuged. Centrifugation may be employed for a variety of reasons.
First, use of a centrifugal evaporator may assist evaporation while concentrating solid or semisolid material at one end
of a capillary space. This has advantages in connection with in-situ analysis, in that the generated form will be located
at a consistent place in the receptacle. Also or alternatively, centrifuging may be used to provide additional environmental
variation, which is desirable in a screening method.
EXAMPLE 1
[0184] In this Example, a new solid form of sulfathiazole was prepared from solution in acetonitrile using sonication.
This form was not seen without sonication under the same conditions. Form II of sulfathiazole was generated without
sonication.
[0185] A saturated solution of sulfathiazole in acetonitrile at 45C was prepared, filtered hot and split between two
pre-heated 1-dram vials (about 1ml each). The samples were left to slowly cool to room temperature. One sample was
then nucleated by ultrasound treatment using 5 pulses of one second each at 20 kHz, amplitude control set at 40, using
a Cole Palmer ultrasonic processor CP130 fitted with a 6mm tip stainless steel probe, while the other sample was left
undisturbed (unsonicated). Both samples were then left to evaporate slowly to dryness. XRPD patterns of the sonicated
and unsonicated samples showed that the sonicated sample gave an unknown pattern (Figure 1) whereas the unsonicated
sample yielded the known Form II of sulfathiazole (Figure 2). The sonicated sample is believed to be a novel solid form
of sulfathiazole.
EXAMPLE 2
[0186] In this Example, an unusual solid form of an acetone solvate of sulfathiazole was prepared. Without sonication,
this form was only seen in a mixture with the known form of an acetone solvate of sulfathiazole.
[0187] A saturated solution of sulfathiazole in acetone at 45C was prepared, filtered hot and split between two pre-
heated 1-dram vials (about 1ml each). The samples were left to slowly cool to room temperature. One sample was then
nucleated by ultrasound treatment using 5 pulses of one second each at 20 kHz, amplitude control set at 40, using a
Cole Palmer ultrasonic processor CP130 fitted with a 6mm tip stainless steel probe, while the other sample was left
undisturbed (unsonicated). Both samples were then left to evaporate slowly to dryness. XRPD patterns of the sonicated
and unsonicated patterns showed that the sonicated sample gave an unknown pattern (Figure 3) whereas the unsonicated
sample yielded a mixture of this same form with the known acetone solvate of sulfathiazole (Figure 4). The sonicated
sample is believed to contain an unusual solid form which is novel in its purity.
EXAMPLE 3
[0188] In this Example, a new DMSO solvate of carbamazepine was prepared.
[0189] Three 100Pl samples of a saturated solution of carbamazepine in DMSO at 50C were placed in 3 pre-heated
HPLC vials. The samples were allowed to cool to ambient temperature. One sample was nucleated by ultrasound
treatment (5 one-second pulses, 20 kHz, amplitude control set at 40, using the Cole Palmer ultrasonic processor with
a 3mm tip stainless steel probe), while another was stirred using a stir bar and the other was left undisturbed (unsonicated).
While the sonicated sample yielded a new DMSO solvate, the other samples remained as solutions indefinitely. The
XRPD pattern of the new DMSO solvate is shown in Figure 5.
EXAMPLE 4
[0190] In this Example, a new form of sulfathiazole was made from a sonicated supersaturated solution in methyl-
ethylketone.
[0191] A saturated solution of sulfathiazole in methylethylketone at 55C was split in 3 pre-heated vials (about 0.5-1
ml each). The samples were crash-cooled by placing them in an ice/water bath. One sample was then sonicated for five
minutes (amplitude 20 kHz, amplitude control set at 40, using the Cole Palmer ultrasonic processor with a 6mm probe),
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while another was stirred using a magnetic stir bar. The last sample was left undisturbed. The three samples were then
placed in the refrigerator (5-6C). While the sonicated sample was found to have crystallized, the unsonicated samples
remained indefinitely as solutions (still solutions after three weeks). The solids in the sonicated sample were filtered and
an XRPD pattern taken (Figure 6), indicative of an unknown form, and it was determined that this solid was unsolvated
according to TGA and DSC scans.
EXAMPLE 5
[0192] In this Example, crystallization of the most stable form of 4-methyl-2-nitroacetanilide was performed on a small
scale. The compound 4-methyl-2-nitroacetanilide is known to crystallize in three polymorphic forms, White, Amber, or
Yellow. The compound is known as "WAY" due to the colors of its forms. The relative stability of the three forms has
been studied and it was demonstrated that the white form was the most stable form, and the yellow form was more
stable than the amber form. (See, for example, Yeadon, PhD thesis, Burnel University, West Yorkshire, UK (1985), and
Xiaorong He, "Thermodynamic and kinetic control of the crystallization of polymorphs", PhD thesis, Purdue University,
West Lafayette, Indiana USA (2000)). The least stable amber form has rarely been seen. All three crystal structures
have been solved and published. (See, for example, Moore et al., "Yellow and white forms", J. Cryst. Spect. Res., 13,
279 (1983), and Moore et al., "Amber form", J. Cryst. Spect. Res., 14, 283 (1984).
[0193] Sixty-four evaporative experiments in various solvents and combinations of solvents (32 sonicated samples
and 32 unsonicated samples) were carried out on the compound WAY.
[0194] A weighed amount of the compound WAY was placed in a vial and a measured volume (V) of solvent added
(solvent 1), so as to dissolve the solids. In some samples, an additional volume of a second solvent (solvent 2) was
added to the solution. All solutions were filtered using a 0.2 Pm nylon filter and split 4-ways into 4 1-dram vials. The vials
were then covered individually with aluminum foil. The aluminum foil was pierced with one hole for slow evaporations
(SE) and 5 holes for fast evaporations (FE). Half of the vials were then sonicated twice a day, every day, until complete
evaporation of the solvents. The other half of the vials were left to evaporate undisturbed. Table 1 summarizes the
solvent conditions used for these evaporations, each set of solvent conditions being used for four vials (two for samples
to be sonicated while evaporating (SE and FE), two for control experiments without sonication (SE and FE)).
TABLE 1
Solutions used for crystallization of 4-methyl-2-nitroacetanilide
WAY (mg) Solvent 1 V (S1) Solvent 2 V (S2)
146.3 1,4-dioxane 3 ml - -
149.8 acetone 3 ml - -
155.2 tetrahydrofuran 3 ml - -
149.9 ethanol 10 ml - -
147.7 2-butanone 3 ml - -
155.6 dichoromethane 1 ml - -
146.2 chloroform 1 ml - -
155.0 trifluroethanol 1 ml - -
151.0 ethyl acetate 3 ml - -
1.48.9 dichloroethane 1 ml - -
149.1 pyridine 1 ml - -
156.5 methanol 5 ml - -
150.2 acetonitrile 2 ml - -
144.9 dichloromethane 2 ml nitromethane 2 ml
155.5 dichloromethane 2 ml heptane 2 ml
146.7 trifluoroethanol 2 ml water 2 ml
154.3 acetone 3 ml toluene 1 ml
146.4 acetone 3 ml water 1 ml
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[0195] The results are presented in Table 2, showing the occurrences of mixtures of the white and yellow solid forms
and of the most stable solid form of the compound, the white form of WAY. All other solids were the faster growing, less
stable yellow form. These results show that using ultrasound as part of a screening process can increase the likelihood
of obtaining the possible solid forms of a chemical substance. These results also show that using ultrasound in a
crystallization process can facilitate the generation of the most stable form of the chemical substance.
EXAMPLE 6
[0196] In this Example, a micro-scale crystallization study was performed to yield the most stable form of 4-methyl-2-
nitroacetanilide (WAY).
[0197] Solutions of WAY were prepared in various solvents by dissolution of a weighed amount of the solid compound
in a measured volume of solvent (solvent 1). These solutions were then filtered using a 0.2Pm nylon filter. The weights
and volumes used to prepare each solutions are summarized in Table 3.
[0198] Each solution was then used directly or was diluted with a second solvent in a 3:1 ratio of the first solvent to
the second solvent. Aliquots of 200Pl of the solutions were placed in wells of a flat bottom polypropylene 96-well plate
and covered by a polypropylene mat. The mat was pierced to provide one hole per well. Two identical plates were
prepared. The solvent(s) used in each of the wells are shown in Table 4. One plate was sonicated for 20 seconds every
30 minutes until evaporation to dryness of all or the majority of the samples in each well. Sonication was performed
using a Misonix 3000 sonicator with microplate horn. The second plate was kept undisturbed (unsonicated) during the
time of the evaporation.
TABLE 2
Sonicated Sonicated Unsonicated Unsonicated
Evaporative conditions SE FE SE FE
# of samples 16 16 16 16
Solids 16 16 14 16
White + yellow mixture 5 3 1 1
Pure White Form 4 2 0 1
TABLE 3
Summary Table Of Experimental Conditions For The Preparation Of Solutions Of Way
WAY (mg) Solvent V (ml)
103.2 chloroform 5.16
107.7 1,4-dioxane 5.37
101.9 acetone 5.1
100.8 tetrahydrofuran 5.04
112.7 ethanol 11.3
105.7 2-butanone 5.27
108.6 acetonitrile 5.43
94.0 methanol 4.7
TABLE 4
Solvent Conditions Used For Individual Wells Of The 96-Well Plate Evaporation Experiment
1 2 3 4 5 6 7 8 9 10 11 12
A CH CH CH:
WA 3:
1
CH:
WA 3:
1
CH:
NM 3:
1
CH:
NM 3:
1
CH:
TO 3:
1
CH:
TO 3:1
CH:EA
3:1
CH:EA
3:1
CH:HE
3:1
CH:HE
3:1
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[0199] In Table 4, the solvent mixtures are described as X:Y volume:volume ratio of solvents. In Table 4, the following
abbreviations are used: AC = acetone; AN = acetonitrile; CH = chloroform; DX = 1,4-dioxane; EO = ethanol; EA = ethyl
acetate; HE = heptane; MK = 2-butanone; MO = methanol, NI = nitromethane; TH = tetrahydrofuran; TO = toluene; WA
= water.
[0200]
[0201] In Table 5, the following abbreviations are used: Y = Yellow form; W = White form; N = Nucleated = mostly
liquid with a small fraction of indeterminate solids; NC = Not Crystallized).
[0202]
(continued)
Solvent Conditions Used For Individual Wells Of The 96-Well Plate Evaporation Experiment
1 2 3 4 5 6 7 8 9 10 11 12
B DX DX DX:
WA 3:
1
DX:
WA 3:
1
DX:
NM 3:
1
DX:
NM 3:
1
DX:
TO 3:
1
DX:
TO 3:1
DX:EA
3:1
DX:EA
3:1
DX:HE
3:1
DX:HE
3:1
C AC AC AC:
WA 3:
1
AC:
WA 3:
1
AC:
NM 3:
1
AC:
NM 3:
1
AC:
TO 3:
1
AC:
TO 3:1
AC:EA
3:1
AC:EA
3:1
AC:HE
3:1
AC:HE
3:1
D TH TH TH:
WA 3:
1
TH:
WA 3:
1
TH:
NM 3:
1
TH:
NM 3:
1
TH:
TO 3:
1
TH:
TO 3:1
TH:EA
3:1
TH:EA
3:1
TH:HE
3:1
TH:HE
3:1
E EO EO EO:
WA 3:
1
EO:
WA 3:
1
EO:
NM 3:
1
EO:
NM 3:
1
EO:
TO 3:
1
EO:
TO 3:1
EO:EA
3:1
EO:EA
3:1
EO:HE
3:1
EO:HE
3:1
F MK MK MK:
WA 3:
1
MK:
WA 3:
1
MK:
NM 3:
1
MK:
NM 3:
1
MK:
TO 3:
1
MK:
TO 3:1
MK:EA
3:1
MK:EA
3:1
MK:HE
3:1
MK:HE
3:1
G AN AN AN:
WA 3:
1.
AN:
WA 3:
1
AN:
NM 3:
1
AN:
NM 3:
1
AN:
TO 3:
1
AN:
TO 3:1
AN:EA
3:1
AN:EA
3:1
AN:HE
3:1
AN:HE
3:1
H MO MO MO:
WA 3:
1
MO:
WA 3:
1
MO:
NM 3:
1
MO:
NM 3:
1
MO:
TO 3:
1
MO:
TO 3:1
MO:EA
3:1
MO:EA
3:1
MO:
HE 3:1
MO:
HE 3:1
TABLE 5
Summary Table Of Results Obtained For The Sonicated Plate
Table 5 shows which solid form of WAY was generated in each of the wells of the 96-well plate that was sonicated.
1 2 3 4 5 6 7 8 9 10 11 12
A Y W Y Y Y Y Y Y Y Y Y Y
B NC NC N N NC NC NC NC NC NC NC NC
C W W Y Y NC W W W Y Y W W
D W W W W Y Y W W W W W Y
E NC NC NC NC NC Y NC Y NC NC NC NC
F W NC W NC NC W W Y W Y W W
G Y W W NC NC W W NC W NC Y Y
H W W W W W Y W W NC W Y Y
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[0203] In Table 6, the following abbreviations are used: Y = Yellow form; W = White form; N = Nucleated = mostly
liquid with a small fraction of indeterminate solids; NC = Not Crystallized.
[0204] This shows that a screening process in which samples are sonicated yielded more occurrences of the most
stable (but less-frequently generated) white form.
EXAMPLE 7
[0205] In this Examples, a micro-scale crystallization study of sulfamerazine was performed. The study showed that
sonication facilitated the generation of a difficult-to-make more stable form.
[0206] Sulfamerazine is known to crystallize in two polymorphic forms, Form I and Form II, with Form I being the most
commonly encountered form. Despite the elusive character of Form II, it has been demonstrated that Form II was the
most stable form at room temperature. Zhang et al., J. Pharm. Sci., 91(4), 1089-1100 (2002).
[0207] Solutions of sulfamerazine at a concentration of 10mg/ml were prepared in acetone and in tetrahydrofuran by
dissolution of a weighed amount of sulfamerazine in a measured volume of solvent. The solutions were then filtered
using a 0.2Pm nylon filter. Aliquots of 150Pl of solution (acetone or tetrahydrofuran) were added to 50Pl of a second
solvent in the wells of a flat bottom polypropylene 96-well plate. The plate was covered by a polypropylene mat, and the
mat was pierced with one hole per well. Two identical plates were prepared. One of the plates was sonicated for 20
seconds every 30 minutes until evaporation to dryness of all samples in each well. Sonication was performed using a
Misonix 3000 sonicator with microplate horn. The second plate was kept undisturbed (unsonicated), during the time of
the evaporation. Table 7 summarizes the results obtained for the sonicated and unsonicated plates for each condition
of evaporation. The difficult-to-make but more stable Form II was found in the sonicated plate but not in the unsonicated
plate.
TABLE 6
Summary Table Of Results Obtained For The Unsonicated Plate
Table 6 shows which solid form of WAY was generated in each of the wells of the 96-well plate that was not sonicated.
1 2 3 4 5 6 7 8 9 10 11 12
A Y Y Y Y Y Y Y Y Y Y W Y
B NC NC N N NC NC NC NC NC NC NC NC
C Y Y Y Y Y NC Y Y Y Y Y Y
D Y Y Y Y Y Y Y Y Y Y Y Y
E NC NC NC NC NC NC Y Y NC Y NC NC
F Y Y Y Y NC NC NC NC Y Y Y NC
G Y Y Y Y NC Y Y Y Y Y Y Y
H Y Y Y Y Y Y Y Y Y NC Y Y
TABLE 7
Conditions of Evaporations From Mixture Of Solvents
Solvent 1 Solvent 2 Sonicated Non-sonicated
Form Form
acetone Acetonitrile II
a
I
a
acetone Chloroform I I
acetone 1,4-dioxane I A
c
acetone Ethanol I I
acetone ethyl acetate I I
acetone Heptane I I
acetone 2-butanone I I
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[0208] In this example, the elusive, more stable Form II of sulfamerazine was generated by a crystallization process
that included ultrasound application, but was not generated without ultrasound application. This example shows that a
screening process that includes sonication is more likely to generate the more stable solid forms of the chemical sub-
stance. This example also demonstrates that it may be desirable to include some unsonicated samples in a screening
process, as this can increase the likelihood of obtaining the possible solid forms of the chemical substance.
EXAMPLE 8
[0209] In this Example, the difficult-to-make Form I of sulfathiazole was generated by crystallization from a solvent
mixture with sonication used to form an emulsion.
[0210] Sulfathiazole Form I is a disappearing polymorph, today rarely seen crystallized directly from solution. This
result is of interest for polymorph screening purposes. Blagden et al., "Crystal structure and solvent effects in polymorphic
systems: sulfathiazole," J. Chem. Soc. Faraday, 94, 1035-1045 (1998)
[0211] A 500Pl aliquot of a saturated solution of sulfathiazole in ethanol at 50C was filtered hot and added to 500Pl
of warm p-cymsne in a pre-heated 1-dram vial on a hotplate at 55C. The biphasic sample was then sonicated while
evaporating until a precipitate appeared (40 minutes sonication, using a Cole-Palmer ultrasonic processor fitted with a
6mm tip stainless steel probe, amplitude control set at 60). The solids obtained were filtered and analyzed by XRPD.
The XRPD pattern was characteristic of sulfathiazole Form I (Figure 7).
EXAMPLE 9
[0212] In this example a polymorph screen is carried out. Solutions of chemical substance A in the following solvents
or solvent mixtures (with volume:volume ratio indicated) are prepared by robotic weighing of chemical substance and
(continued)
Conditions of Evaporations From Mixture Of Solvents
Solvent 1 Solvent 2 Sonicated Non-sonicated
Form Form
acetone Methanol I I
acetone Nitromethane II
b
I
a
acetone Tetrahydrofuran I I
acetone Toluene I I
acetone Water I I
tetrahydrofuran Acetone I I
tetrahydrofuran Acetonitrile I I
tetrahydrofuran Chloroform I I
tetrahydrofuran 1,4-dioxane I A
c
tetrahydrofuran Ethanol I I
tetrahydrofuran ethyl acetate I I
tetrahydrofuran heptane I I
tetrahydrofuran 2-butanone I I
tetrahydrofuran methanol I I
tetrahydrofuran nitromethane I I
tetrahydrofuran toluene I I
tetrahydrofuran Water I I
a
duplicate experiment gave the same result
b
duplicate experiment gave form I
c
new form
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solvent delivery and mixing: acetone, acetonitrile, chloroform, 1,4-dioxane, ethanol, ethyl acetate, heptane, 2-butanone,
methanol, nitromethane, tetrahydrofuran, toluene, water, dichloromethane, diethyl ether, isopropyl ether, cyclohexane,
methylcyclohexane, isopropyl alcohol, trimethylpentane, n-octane, trichloroethane, trifluoroethanol, pyridine, 1-butanol,
tetrachloroethylene, chlorobenzene, xylene, dibutyl ether, tetrachloroethane, p-cymene, dimethyl sulfoxide, formamide,
dimethylformamide, 2:1 methanol:acetonitrile, 2:1 methanol:dichloromethane, 3:1 methanol:ethyl acetate, 4:1 methanol:
methyl-tert-butyl ether, 1:1 methano1:2-butanone, 3:1 trifluoroethanol:isopropyl acetate, 2:1 trifluoroethanol:isopropyl
ether, 1:1 trifluoroethanol:nitromethane, 1:5 water:acetone, 1:4 water:acetonitrile, 1:5 water:dioxane, 1:9 water:2-pro-
panol, and 1:5 water:tetrahydrofuran.
[0213] Aliquots of 200 PL of each solution are delivered in duplicate using a liquid handler to the wells of a 96 well
plate. Concentrations of the solutions are selected such that the final amount of chemical substance in each well is
between 0.1 mg and 1.0 mg. The well plate body is made of polypropylene. The well plate is a thin bottom well plate
suitable for x-ray diffraction analysis of crystals in the well plate. Two wells contain samples of an x-ray powder diffraction
standard. The well plate solutions are left uncovered and are allowed to evaporate to dryness while being sonicated for
20 seconds every hour using a Misonix 3000 sonicator with microplate horn. Nitrogen flow into wells is used when
evaporation needs to be facilitated. The well plate is mounted on edge on the stage of a Bruker D8 microdiffractometer
with the well openings facing the x-ray source. The solids at the bottom of each well are analyzed by automated stage
movement. It is expected that a useful variety of different solid forms of the chemical substance will be produced in the
wells.
EXAMPLE 10
[0214] Cocrystals of fluoxetine HCl:benzoic acid were formed using the following procedures. A solution of fluoxetine
HCl and benzoic acid in acetonitrile was prepared. A physical mixture of fluoxetine HCl and benzoic acid in a 1:1 molar
ratio was used to make a solution having a concentration of about 200 mg/mL. The solution was placed in four 96-well
plates. The only difference among well plates was the amount of solution put into each well. Two well plates were charged
with 15 PL per well, and two plates were charged with 50 Pper well. One of the well plates containing 15 PL samples
and one of the well plates containing 50 PL samples were sealed and left standing at room temp. The other well plate
containing 15 PL samples and the other well plate containing 50 PL samples were sealed and sonicated with a Misonix
96-well plate sonicator.
[0215] None of the wells in the 15 PL plates (either standing or sonicated) nucleated (even after very strong sonication
with the Misonix plate sonicator or the probe). The plate left standing at room temp with 50 PL volumes nucleated in
about 15% of the wells nucleated on standing (but the majority of the wells had benzoic acid growth, not cocrystal
nucleation). For the 50 PL plate that was sonicated, almost half of the wells nucleated (with only one well of benzoic
acid and the rest as cocrystal).
[0216] In a system comprising a 1:1 molar ratio of fluoxetine HCl and benzoic acid in acetonitrile, concentrations of
about 200 mg/ml of the API:guest mixture in CH
3
CN (acetonitrile) were used. Nucleation could be caused by sonication
in a concentration range of from about 35 to about 100 mg/ml. Sonication indicates a clear advantage in this case of
intermediate concentrations. Almost all of the samples having a concentration of 200 mg/ml nucleated with sonication
using either a probe or the well-plate sonicator. In contrast, about 15% of the wells in a plate at 200 mg/ml nucleated
the cocrystal without sonication.
EXAMPLE 11
[0217] Cocrystal screening of chlorzoxazone is carried out using the following procedures. Solutions of chlorzoxazone
and various guests are prepared in acetonitrile, methanol, aqueous ethanol, and acetone in 1:1 molar ratios having a
concentrations of about 10 mg/mL. The guests used include benzoic acid, gallic acid, and 2,5-dihydroxybenzoic acid.
Aliquots of 20 microliters of the solutions are placed in different capillary tubes. The samples are sonicated for 1 minute
by placement of the capillary tubes in a sonication bath after the volume of the solutions are reduced to the point where
both components are supersaturated. This concentration is calculated based on the solubility of the individual compo-
nents. The sonication is repeated every hour for 24 hours as the solutions evaporate. A duplicate set of capillary tubes
is allowed to evaporate at room temperature without sonication.
[0218] Solids are present in most of the capillary tubes and are analyzed by Raman spectroscopy and by x-ray powder
diffraction. It is expected that a number of cocrystals are present in the sonicated capillary tubes and that different
polymorphs, hydrates, or solvates of the cocrystals may also be present. It is expected that solids in the unsonicated
capillary tubes will have a different variety of solid forms present compared to the sonicated samples and that there will
not be as many cocrystals formed.
[0219] This example demonstrates the use of capillary tubes for cocrystallization. This example also demonstrations
that samples having low concentrations and/or low volumes may be employed in a cocrystallization process.
EP 2 292 585 A1
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EXAMPLE 12
[0220] Cocrystal and salt screening of imipramine hydrochloride is carried out using the following procedures. Solutions
of imiprimine hydrochloride and various guests are prepared in acetonitrile, methanol, aqueous ethanol, and acetone in
1:1 molar ratios having a concentrations of about 10 mg/mL. The guests include benzoic acid, gallic acid, and 2,5-
dihydroxybenzoic acid. Aliquots of 100 microliters of the solutions are placed in different wells of 96-well polypropylene
plates that have thin walls. The plates are sonicated for 1 minute in a sonication bath after the volume of the solutions
are reduced to the point where both components are supersaturated. This concentration is calculated based on the
solubility of the individual components. The sonication is repeated every hour for 24 hours as the solutions continue to
evaporate. A duplicate set of well plates is allowed to evaporate at room temperature without sonication.
[0221] Solids are present in most of the wells and are analyzed in situ, automatically by transmission x-ray powder
diffraction through the well plates. It is expected that a number of cocrystals and/or salts are present in the sonicated
plates and that different polymorphs, hydrates, solvates, desolvates, and dehydrates of the cocrystals and/or salts may
also be present. It is expected that solids in the unsonicated plates will have a different variety of solid forms present
compared to the sonicated samples and that there will not be as many cocrystals and/or salts formed.
[0222] All patents, test procedures, and other documents cited herein, including priority documents, are fully incorpo-
rated by reference to the extent such disclosure is not inconsistent with this invention and for all jurisdictions in which
such incorporation is permitted.
[0223] While the present invention has been described and illustrated by reference to particular embodiments, it will
be appreciated by those of ordinary skill in the art that the invention lends itself to many different variations not illustrated
herein. For these reasons, then, reference should be made solely to the appended claims for purposes of determining
the true scope of the present invention.
[0224] Although the appendant claims have single appendencies in accordance with U.S. patent practice, each of the
features in any of the appendant claims can be combined with each of the features of other appendant claims or the
main claim.
Table 8
10-camphorsulfonic acid
10-undecylenic acid
1-hydroxy-2-naphthoic acid
2,4-dihydroxybenzoic acid
2,5-dihydroxybenzoic acid
2 -aminopropionic acid
2-ethylbutyrinc acid
2-furancarboxylic acid
2-mercaptobenzoic acid
3-methylbutanoic acid
3-phenylpropionic acid
4-aminobenzoic acid
4-aminosalicylic acid
4-hydroxybenzoic acid
adipic acid
alginic acid
anisic acid
arginine
ascorbic acid
asparagine
aspartic acid
aspirin
benzenesulfonic acid
benzoic acid
4-acetamidobenzoic acid
beta-alanine
camphoric acid
camphorsulfonic acid
EP 2 292 585 A1
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(continued)
carbonic acid
cholic acid
cinnamic acid
citric acid
cyclamic acid
cyclohexanecarboxylic acid
cyclohexylacetic acid
cysteine
diphenylacetic acid
dodecylsulfonic acid
ethane-1,2-disulfonic acid
ethanesulfonic acid
ethanesulfonic acid, 2-hydroxy
ethylenediaminetetraacetic acid
ethylsulfuric acid
fumaric acid
galactaric acid
gallic acid
gentisic acid
glucoheptonic acid
gluconic acid
glutamic Acid
glutamine
glutaric acid
glutaric acid, 2-oxo-
glycine
glycolic acid
hippuric acid
histidine
hydroxyproline
isoleucine
lactobionic acid
lauric acid
leucine
levulinic acid
lysine
maleic acid
malic acid
malonic acid
mandelic acid
m-methoxybenzoic acid
naphthalene-1,5-disulfonic acid
naphthalene-2-sulfonic acid
n-decanoic acid
niacin
nicotinic acid
n-tetradecanoic acid
oleic acid
o-methylbenzoic acid
orotic acid
orthoboric acid
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(continued)
o-toluic acid
p-acetamidobenzoic acid
palmitic acid
pamoic acid
phenoxyacetic acid
phenylacetic acid
phenylalanine
picric acid
pivalic acid
proline
p-toluenesulfonic acid
pyroglutamic acid
pyruvic acid
salicylic acid
sebacic acid
serine
sorbic acid
stearic acid
succinic acid
sulfosalicylic acid
tartaric acid
terephthalic acid
thiocyanic acid
threonine
tiglic acid
tryptophan
tyrosine
valeric acid
valine
Table 9
Name CAS #
Potassium bicarbonate 298-14-6
Potassium carbonate 584-08-7
Potassium chloride 7447-40-7
Potassium hydroxide 1310-58-3
Potassium metabisulfite 16731-55-8
Potassium nitrate 7757-79-1
Potassium nitrite 7758-09-0
Potassium permanganate 7722-64-7
Potassium persulfate 7727-21-1
Potassium phosphate, dibasic 2139900
Potassium Phosphate Monobasic 7778-77-0
potassium phosphate, tribasic, n-hydrate 7778-53-2
Potassium sulfate 7778-80-5
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(continued)
Name CAS #
Sodium bicarbonate 144-55-8
Sodium bisulfite 7631-90-5
Sodium borohydride 16940-66-2
Sodium carbonate 497-19-8
Sodium Carbonate Monohydrate 1486118
Sodium chloride 7647-14-5
Sodium dithionite 7775-14-6
Sodium fluoride , 7681-49-4
Sodium hexametaphosphate 10124-56-8
Sodium hydroxide _ 1310-73-2
Sodium hypochlorite 7681-52-9
Sodium Metabisulfite 7681-57-4
Disodium metasilicate 6834-92-0
sodium monophosphate 7681-53-0
Sodium nitrate 7631-99-4
Sodium nitrite 7632-00-0
sodium hydrogen phosphate 7558-79-4
sodium Phosphate Monobasic 7558-80-7
Sodium Pyrophosphate 7722-88-5
Sodium silicate 1344-09-8
Sodium Sulfate Decahydrate 7727-73-3.
Sodium sulfite 7757-83-7
Sodium Thiosulfate Pentahydrate 10102-17-7
Calcium acetate 5743-26-0
Calcium Carbonate 471-34-1
Calcium Chloride Dihydrate 10035-04-8
Calcium gluconate 299-28-5
Calcium hydroxide 1305-62-0
Calcium oxide _ 1305-78-8
Calcium phosphate, dibasic 7757-93-9
Calcium Phosphate Monobasic 7758-23-8.
Calcium sulfate 7778-18-9
Magnesium hydroxide 1309-42-8
Magnesium Sulfate Heptahydrate 10034-99-8
Aluminum 7429-90-5
Aluminum ammonium sulfate 7784-26-1
Aluminum chloride 7446-70-0
Aluminum hydroxide 21645-51-2
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(continued)
Name CAS #
Aluminum potassium sulfate, dodecahydrate 7784-24-9
Orthoboric acid 10043-35-3
formaldehyde 50-00-0
DL-Isoleucine 443-79-8
(25,75)-(-)-Cystine 56-89-3
DL-Alanine 302-72-7
beta-Alanine 107-95-9
(S)-(+)-Arginine 74-79-3
(S)-(-)-Cysteine 52-90-4
DL-Glutamic acid 617-65-2
Glycine 56-40-6
(S)-(-)-Histidine 71-00-1
(S)-(+)-Lysine 56-87-1
DL-Methionine 59-51-8
DL-Phenylalanine 150-30-1
(S)-(-)-Phenylalanine 63-91-2
D-(+)-Proline 344-25-2
(S)-(-)-Tryptophan 73-22-3
(S)-(-)-Tyrcsine 60-18-4
Carvone 99-49-0
Citral 5392-40-5
Ethyl butyrate 105-54-4
Isobutyl propionate 540-42-1
Methyl butyrate 623-42-7
n-Propyl acetate . 109-60-4
Isobutyl formate 542-55-2
Benzyl acetate 140-11-4
6-Methyl-5-hepten-2-one 110-93-0
Butyl acetate 123-86-4
Ethyl acetoacetate 141-97-9
Isopentyl Acetate 123-92-2
Cinnamaldehyde 104-55-2
Methyl benzoate 93-58-3
Butyl sulfide 544-40-1
Ethyl benzoate 93-89-0
2,4-Hexadienoic acid, potassium salt, (E,E)- 24634-61-5
Potassium bitartrate 868-14-4
Lauric acid 143-07-7
EP 2 292 585 A1
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(continued)
Name CAS #
Benzyl benzoate 120-51-4
Picric acid 88-89-1
Benzoyl peroxide 94-36-0
Palmitic acid 57-10-3
Dibutyl phthalate 84-74-2
Stearic acid 57-11-4
Succinic anhydride 108-30-5
Diethylenetriamine 111-40-0
Diethanolamine 111-42-2
Benzaldehyde 100-52-7
Phenethyl amine 64-04-0
Salicylylaldehyde 90-02-B
Sodium Benzoate 532-32-1
Cinnamic acid 621-82-9
Triethanol amine 102-71-6
L-(+)-Tartaric Acid 87-69-4
Eugenol 97-53-0
D-mannitol 69-65-8
Butyl paraben 94-26-8
Benzoin 119-53-9
Diethyl phthalate 84-66-2
Oleic acid 112-80-1
Sodium lactate 72-17-3
Indole 120-72-9
ethyl lactate 97-64-3
quinoline 91-22-5
Thymol 39-63-8
Methyl anthranilate 134-20-3
Methyl salicylate 119-36-6
Diethyl malonate 105-53-3
Citric acid 77-92-9
Sodium dodecyl sulfate 151-21-3
Morpholine 110-91-8
Furfural 98-01-1
Niacin 59-67-6
Choline chloride 67-48-1
L-Menthol 2216-51-5
Meso-inositol 87-89-8
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(continued)
Name CAS #
ethylenediaminetetraacetic acid 60-00-4
EDTA, calcium derivative, disodium salt 62-33-9
Calcium pantothenate 137-08-6
Riboflavin 83-88-5
Zinc carbonate 3486-35-9
Amyl alcohol 71-41-0
Mineral oil 8012-95-1
Triton(R) X-100 9002-93-1
Acetaldehyde 75-07-0
Acetic Acid 64-19-7
Acetone 67-64-1
Acetophenone 98-86-2
4-Aminobenzoic acid 150-13-0
Anisole 100-66-3
Vitamin C 50-81-7
Benzoic Acid 65-85-0
Biphenyl 92-52-4
2-Methyl-1-propanol 78-83-1
n-Butanol 71-36-3
n-Butylamine 109-73-9
ethyl acetate 141-78-6
Caffeine 58-08-2
Chloroacetic Acid 79-11-8
Dichloroacetic Acid 79-43-6
Diethylamine 109-89-7
Ethanol Amine 141-43-5
n-Butyric Acid 107-92-6
Ethylenediamine 107-15-3
Formic acid 64-18-6
n-Hexanol 111-27-3
Methanol 67-56-1
Methyl Acetate 79-20-9
Methyl 4-hydroxybenzoate 99-76-3
m-Cresol 108-39-4
p-Cresol 106-44-5
Phenol 108-95-2
n-Propanol 71-23-8
Propionic Acid 79-09-4
EP 2 292 585 A1
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(continued)
Name CAS #
Salicylic acid 69-72-7
Sucrose 57-50-1
Vanillin 121-33-5
Vitamin E 59-02-9
Potassium citrate, monohydrate 1534146
p-toluenesulfonic acid monohydrate 6192-52-5
D-(+)-Maltose 69-79-4
Tetrasodium ethylenediaminetetraacetate 64-02-8
Saccharin sodium 128-44-9
Sodium Acetate Trihydrate 6131-90-4
Quinine sulfate, dihydrate 6119-70-6
Sulfosalicylic acid, dihydrate 5965-83-3
L-(+)-Arginine monohydrochloride 1119-34-2
Procaine Hydrochloride 51-05-8
Pyridoxine Hydrochloride 58-56-0
Thiamine hydrochloride 67-03-8
Propionaldehyde 123-38-6
Urea 57-13-6
2-Propanol 67-63-0
Pyrrole 109-97-7
Sodium formate 141-53-7
Pyrrolidine 123-75-1
Methyl ethyl ketone 78-93-3
Ethyl formate 109-94-4
Propylene glycol 57-55-6
Thiourea 62-56-6
Ammonium acetate 631-61-8
Benzene 71-43-2
Sodium acetate 127-09-3
Cyclopentanone 120-92-3
Cyclohexane 110-82-7
piperidine 110-89-4
2-Pentanone 107-87-9
hexane 110-54-3
Isoamyl Alcohol 123-51-3
Lactic acid 50-21-5
2-Ethoxyethanol 110-80-5
Propionic acid, sodium salt 137-40-6
EP 2 292 585 A1
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(continued)
Name CAS #
Potassium acetate 127-08-2
cyclohexyl amine 108-91-8
methyl methacrylate 80-62-6
methyl isobutyl ketone 108-10-1
Acetic anhydride 108-24-7
Isopropyl Acetate 108-21-4
2,2-Oxybisethanol 111-46-6
Benzyl alcohol 100-51-6
Resorcinol 108-46-3
2-Butoxy ethanol 111-76-2
Cumene 98-82-8
2-Amino-2-(hydroxymethyl)-1,3-propanediol 77-86-1
Phenethyl alcohol 60-12-8
2-Ethyl-1-hexanol 104-76-7
2-Octanol 123-96-6
2-(2-Ethoxyethoxy)ethanol 111-90-0
2,6-Dimethyl-4-heptanone 108-83-8
Benzophenone 119-61-9
D-(-)-Fructose 57-48-7
D-Glucose 50-99-7
D-Ribose 50-69-1
D-(+)-Xylose 58-86-6
Pectin sugar 5328-37-0
D-(+)-Lactose 63-42-3
Camphene 79-92-5
Isoquinoline 119-65-3
2,4-Dimethylphenol 105-67-9
2,5-Dimethylphenol 95-87-4
2,6-Dimethylphenol 576-26-1
Methanesulfonic Acid 75-75-2
o-Methoxybenzoic Acid 579-75-9
Saccharin 81-07-2
Thiazole 288-47-1
Trifluoromethanesulfonic Acid 1493-13-6
Trimethylamine 75-50-3
Coumarin 91-64-5
Dimethylamine 124-40-3
Ethyl Alcohol 64-17-5
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(continued)
Name CAS #
Butyl benzyl phthalate 85-68-7
2,6-dimethylpyrazine 108-50-9
taurocholic acid 81-24-3
geraniol 106-24-1
linalool 78-70-6
ethyl isovalerate 108-64-5
ethyl 2-methylbutyrate 7452-79-1
1-octen-3-ol 3391-86-4
ethyl 2-trans-4-cis-decadienoate 3025-30-7
Dihydromyrcenol 18479-58-8
citronellal 106-23-0
linalyl acetate 115-95-7
8-mercapto-p-menthan-3-one 38462-22-5
Ammonium citrate 3012-65-5
Ammonium bicarbonate 1066-33-7
Ammonium chloride 12125-02-9
Ammonium hydroxide 1336-21-6
Ammonium persulfate 7727-54-0
Ammonium phosphate, dibasic 7783-28-0
Ammonium Phosphate Monobasic 7722-76-1
Ammonium sulfate 7783-20-2
Ammonium sulfide 12135-76-1
Hydrazine 302-01-2
Nitric acid 7697-37-2
phosphoric acid 7664-38-2
Phosphorus oxychloride 10025-87-3
Hydriodic acid 10034-85-2
Hydrobromic acid 10035-10-6
Hydrochloric acid 7647-01-0
hydrogen peroxide 7722-84-1
Periodic Acid 10450-60-9
Sulfamic acid 5329-14-6
Sulfuric acid 7664-93-9
Sulfurous acid 7782-99-2
Dexpanthenol 81-13-0
4-oxoisophorone 1125-21-9
Copper(II) sulfate 7758-98-7
ferric chloride 7705-08-0
EP 2 292 585 A1
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(continued)
Name CAS #
Ferric oxide 1309-37-1
ferric sulfate 10028-22-5
Iron(II) Sulfate Heptahydrate 7782-63-0
Iron 7439-89-6
Manganese (II) Sulfate Monohydrate 10034-96-5
Nickel 7440-02-0
Titanium dioxide 13463-67-7
Zinc chloride 7646-85-7
Zinc oxide 1314-13-2
1,1-Azobisformamide 123-77-3
1,3-Butanediol 107-88-0
1-Methylnaphthalene 90-12-0
2,6-Di-tert-Butyl-p-Cresol 128-37-0
2,6-Dimethylpyridine 108-48-5
Disodium cyanodithioimidocarbonate 138-93-2
3-Methyl-2-Cyclopentene-2-ol-one 80-71-7
6-Methylcoumarin 92-48-8
acetoin 513-86-0
alpha-Phellandrane 99-B3-2
alpha-Terpinene 99-86-5
Benzenesulfonic Acid 98-11-3
Benzothiazole 95-16-9
borates, tetrasodium salts 1330-43-4
Butyl butyrate 109-21-7
Butyl Mercaptan 109-79-5
Butyraldehyde 123-72-8
Capsaicin 404-86-4
Chloromethyl Methyl Ether 107-30-2
Cymene 99-87-6
Diallyl Disulfide 2179-57-9
Diethylaminoethanol 100-37-8
dimethyldisulfide 624-92-0
Dimethyl Succinate 106-65-0
Dimethyl Sulfate 77-78-1
Dimethyl Sulfide 75-18-3
Dipropyl Disulfide 629-19-6
Dipropyl Ketone 123-19-3
Ethyl Acrylate 140-88-5
EP 2 292 585 A1
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(continued)
Name CAS #
Ethyl Butyl Ketone . 106-33-4
Ethyl Propionate 105-37-3
Furfuryl Alcohol 98-00-0
gamma-Butyrolactone 96-48-0
Glutaraldehyde 111-30-8
glycerin 56-81-5
Glycolic Acid 79-14-1
Isobutyl Acetate 110-19-0
Isobutyl Isobutyrate 97-85-8
Isobutyraldehyde 78-84-2
Isoheptanol 543-49-7
Isophorone 78-59-1
Isopropyl Mercaptan 75-33-2
Methyl isobutenyl ketone 141-79-7
Methyl n-amyl ketone 110-43-0
methyl acrylate 96-33-3
Methyl Isobutyrate 547-63-7
Methyl Mercaptan 74-93-1
N,N-Dimethylethanolamine 108-01-0
n-Butyl Lactate 138-22-7
n-Hexyl Acetate 142-92-7
n-Valeraldehyde 110-62-3
Nitrous Oxide 10024-97-2
p-Anisaldehyde 123-11-5
2-Methylcyclohexanone 583-60-8
Octanoic Acid 124-07-2
Oxalic Acid 144-62-7
Phenyl ether 101-84-8
Phenylmercaptan 108-98-5
Propargyl Alcohol 107-19-7
Propyl paraben 94-13-3
sec-Butyl Alcohol 78-92-2
Sodium Gluconate 527-07-1
Sodium Tripolyphosphate 7758-29-4
Tetrahydro-2-furanmethanol 97-99-4
Valeric Acid 109-52-4
3,4-xylenol 95-65-8
3-hexanol 623-37-0
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(continued)
Name CAS #
3-methyl-1-pentanol 589-35-5
1,1-diethoxyethane 105-57-7
Aluminum Sulfate 10043-01-3
ammonium sulfite 10196-04-0
amyl butyrate 540-18-1
borneol 507-70-0
butyl formate 592-84-7
calcium peroxide 1305-79-9
n-Hexanoic Acid 142-62-1
cyclohexyl acetate 622-45-7
diacetyl 431-03-8
dimethyl carbonate 616-38-6
ethyl butyraldehyde 97-96-1
Ethyl crotonate 623-70-1
ethyl isobutyrate 97-62-1
ethyl nitrite 109-95-5
fumaric acid 110-17-8
hexaldehyde 66-25-1
isobutyric acid 79-31-2
methyl isovalerate 556-24-1
methyl propionate 554-12-1
methyl valeraldehyde 123-15-9
nitrosyl chloride 2696-92-6
octafluorocyclobutane 115-25-3
peroxyacetic acid 79-21-0
propyl formate 110-74-7
propyl mercaptan 107-03-9
Sodium aluminate 1302-42-7
sodium chlorite 7758-19-2
Terephthalic Acid 100-21-0
allyl isothiocyanate 57-06-7
Vitamin B1 59-43-8
Valproic acid 99-66-1
Ethoxyquin 91-53-2
n-Amyl Ethyl Ketone 106-68-3
Nabam 142-59-6
Sodium sulfide 1313-82-2
Thiocyanic acid 463-56-9
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(continued)
Name CAS #
2-Methyl-5-(1-methylethenyl)-2-cyclohexene-1-one 2244-16-8
4-(2,6,6-Trimethyl-2-cyclohexen-1-yl)-3-buten-2-one 127-41-3
4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-one 14901-07-6
Isoamyl propionate 105-68-0
3-Methylbutanoic acid 503-74-2
L-Menthone 14073-97-3
4-Ethylphenol 123-07-9
o-cresol 95-48-7
dimethyl-Carbamodithioic acid, sodium salt 128-04-1
Anethole 104-46-1
Dimethyl terephthalate 120-61-6
propyl gallate 121-79-9
L-Ascorbic Acid Sodium Salt 134-03-2
4-Hexylresorcinol 136-77-6
Estragole 140-67-0
L-monosodium glutamate 142-47-2
Malonaldehyde, sodium salt 24382-04-5
Butylated hydroxyanisole 25013-16-5
allyl 3-methylbutyrate 2835-39-4
DL-monosodium glutamate 32221-81-1
3-Acetyl-6-methyl-2,4-pyrandione 520-45-6
L-Glutamic Acid 56-86-0
DL-alpha-tocopheryl acetate 58-95-7
D-limonene 5989-27-5
Calcium Acetate 62-54-4
Erythorbic Acid Monosodium Salt 6381-77-7
Ethyl methylphenylglycidate 77-83-8
2,4,6-Trinitro-1,3-dimethyl-5-tert-butylbenzene 81-15-2
Dimethoxane 828-00-2
3,5-Di-tert-butyl-4-hydroxybenzyl alcohol 88-26-6
6-Methylquinoline 91-62-3
alpha-Methylbenzyl alcohol 98-85-1
Nicotinamide 98-92-0
3,4-Dihydrocoumarin 119-84-6
Geranyl Acetate 105-87-3
Sodium (2-Ethylhexyl)Alcohol Sulfate 126-92-1
Cyclohexanol, 5-methyl-2-(1-methylethyl)-, (1alpha,2beta,5alpha)- 89-78-1
(+)-Camphor 464-49-3
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(continued)
Name CAS #
(1S)-(-)-alpha-Pinene 7785-26-4
1,3-Dihydroxy-5-methylbenzene 504-15-4
1,5-Naphthalenedisulfonic Acid Disodium Salt 1655-29-4
1-Hydroxy-2-naphthoic Acid 86-48-6
1-Penten-3-ol 616-25-1
1-Phenyl-1-propanol 93-54-9
10-Undecylenic Acid 112-38-9
2-Hydroxyacetophenone 118-93-4
2,4-Dihydroxybenzoic Acid 89-86-1
2-Acetylfuran 1192-62-7
2-Furancarboxylic Acid 88-14-2
2-Isopropylphenol 88-69-7
2-Ketoglutaric Acid 328-50-7
2-Ketovaline 759-05-7
2-n-Propylphenol 644-35-9
2-Naphthalenethiol 91-60-1
2-Phenyl-1-propanol 1123-85-9
3,3-Thiodipropionic Acid 111-17-1
3,5,5-Trimethylhexanal 5435-64-3
3-Phenyl-1-propanol 122-97-4
3-Phenylpropionic Acid 501-52-0
4-Aminosalicylic Acid 65-49-6
4-Ethoxyphenol 622-62-8
4-Hydroxybenzoic Acid 99-96-7
4-Phenyl-2-butanol 2344-70-9
4-tert-Octylphenol 140-66-9
Allyl Cinnamate 1866-31-5
Allyl Mercaptan 870-23-5
alpha-L-Rhamnose 3615-41-6
Alpha-Terpineol 98-55-5
Anisic Acid 100-09-4
Benzalacetone 122-57-6
Benzaldehyde Dimethylacetal 1125-86-8
Benzyl Ether 103-50-4
Benzyl Formate 104-57-4
Benzyl Mercaptan 100-53-8
Benzyl Salicylate 118-58-1
Calcium Citrate 813-94-5
EP 2 292 585 A1
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(continued)
Name CAS #
Calcium Glycerophosphate 27214-00-2
Calcium Hypophosphite 7789-79-9
Calcium Iodate 7789-80-2
Propanoic acid, 2-hydroxy-, calcium salt (2:1) 814-80-2
Calcium Phosphate Tribasic 7758-87-4
Calcium Propionate 4075-81-4
Calcium Pyrophosphate 7790-76-3
Cholic Acid 81-25-4
Choline 123-41-1
Choline Bitartrate 87-67-2
trans-Cinnamic Aldehyde 14371-10-9
Cinnamyl Alcohol 104-54-1
Citronellol 106-22-9
Copper(I)Iodide 7681-65-4
D-(+)-Glucono-1,5-lactone 90-80-2
D-(-)-Tartaric Acid 147-71-7
D-Isoascorbic Acid 89-65-6
D-Tyrosine 556-02-5
Sodium dehydroacetate 4418-26-2
Deoxycholic Acid 83-44-3
Dibenzyl Ketone 102-04-5
Diethyl L-(+)-Tartrate . 87-91-2
Diethyl Succinate 123-25-1
Dimethylacetal 534-15-6
DL-Cystine 923-32-0
DL-Proline 609-36-9
DL-Tartaric Acid 133-37-9
DL-Tyrosine 556-03-6
DL-Valine 516-06-3
Enanthoic Acid 111-14-8
Erythorbic Acid Sodium Salt 7378-23-6
Ethyl 2-Aminobenzoate 87-25-2
Ethyl Cinnamate 103-36-6
Ethyl n-Valerate 539-82-2
Ethyl Phenylacetate 101-97-3
Ethyl Salicylate 118-61-6
Ethyl Sulfide 352-93-2
Ethyl Vanillin 121-32-4
EP 2 292 585 A1
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(continued)
Name CAS #
Ethylene Mercaptan 540-63-6
Farnesene 502-61-4
Folic acid 59-30-3
gamma-Nonanolactone 104-61-0
gamma-Valerolactone 108-29-2
Gluconic Acid 526-95-4
Gluconic Acid Potassium Salt 299-27-4
Glutaric Acid 110-94-1
Guanosine-5-monophosphate, disodium salt 1333479
Heliotropine 120-57-0
Hippuric Acid 495-69-2
Hydroquinone Dimethyl Ether 150-78-7
Inowine-5-monophosphate Sodium Salt 4691-65-0
iso-Amyl Mercaptan 541-31-1
Isoamyl Salicylate 87-20-7
iso-Butyl n-Hexanoate 105-79-3
isovaleraldehyde, 590-86-3
Isoamyl Benzoate 94-46-2
Isoamyl Formate 110-45-2
Isoamyl n-Butyrate 106-27-4
Isoamylamine 107-85-7
Isobutyl n-Butyrate 539-90-2
Isocaproic Acid 646-07-1
Isoeugenol 97-54-1
Isopropyl Benzoate 939-48-0
Isopropyl Formate 625-55-8
Isopropyl N-Butyrate 638-11-9
Isopropyl Propionate 637-78-5
isobutyl Mercaptan 513-44-0
L-(+)-Isoleucine 73-32-5
L-(-)-Apple Acid 97-67-6
L-2-Aminopropionic Acid 56-41-7
L-Aspartic acid 56-84-8
L-Carnitine 541-15-1
L-Cysteine Hydrochloride 52-89-1
L-Glutamic Acid Hydrochloride 138-15-8
L-Glutamine 56-85-9
L-Hydroxyproline 51-35-4
EP 2 292 585 A1
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(continued)
Name CAS #
L-Proline 147-85-3
L-Serine 56-45-1
L-Threonine 72-19-5
L-Valine 72-18-4
N-Acetylglycine 543-24-8
n-Amyl Formate 638-49-3
n-Amyl n-Caproate 540-07-8
n-Butyl n-Caproate 626-82-4
n-Butyl Propionate 590-01-2
n-Butyl Salicylate 2052-14-4
n-Decanoic Acid 334-48-5
n-Hexyl Mercaptan 111-31-9
n-Propyl Benzoate 2315-68-6
n-Propyl Isobutyrate 644-49-5
n-Tetradecanoic Acid 544-63-8
Nitrilotriacetic Acid Trisodium Salt 5064-31-3
o-Toluenethiol 137-06-4
Orotic Acid 65-86-1
p-Acetamidobenzoic Acid 556-08-1
p-Anise Alcohol 105-13-5
Phenoxyacetic Acid 122-59-8
Phenyl Acetate 122-79-2
Piperine 94-62-2
Pivalic Acid 75-98-9
Potassium Benzoate 582-25-2
Potassium Diphosphate 7320-34-5
Potassium Hypophosphite 7782-87-8
Potassium Metaphosphate 7790-53-6
Potassium Sulfite 10117-38-1
Quinine Hydrochloride 130-89-2
sec-Amyl Alcohol 6032-29-7
Sodium D-Pantothenate 867-81-2
Di(2-ethylhexyl) sulfosuccinic acid, sodium salt 577-11-7
Sodium Sorbate 7757-81-5
Succinic acid, disodium salt 150-90-3
Sodium Taurocholate 145-42-6
Taurine 107-35-7
Thiamine Nitrate 532-43-4
EP 2 292 585 A1
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(continued)
Name CAS #
Thioanisole 100-68-5
Tiglic Acid 80-59-1
Tri-n-butyrin 60-01-5
Triacetin 102-76-1
Trisodium Citrate 68-04-2
Veratraldehyde 120-14-9
Veratrole 91-16-7
Vitamin P 520-26-3
Vitamin U Chloride 582174
L-methionine 63-68-3
2-Chloro-1-propanol 78-89-7
2-Ethylbutyric acid 88-09-5
2-Methylbutyraldehyde 96-17-3
2-Methyl-5-ethylpyridine 104-90-5
n-propyl butyrate 105-66-8
Ethyl caprylate 106-32-1
Propyl propionate 106-36-5
2-Methylpyrazine 109-08-0
3,3,5-Trimethyl-1-cyclohexanol 116-02-9
Ethyl caproate 123-66-0
o-methoxybenzaldehyde 135-02-4
2,4-Hexadienal 142-83-6
3-Hexanone 589-38-8
3-Methyl-2-butanol 598-75-4
Methyl isopropenyl ketone 814-78-8
3-Methyl-2-butanethiol 2084-18-6
3,5,5-Trimethylhexanol 3452-97-9
Methylglyoxal 78-98-8
Malonaldehyde 542-78-9
1,4-Dithiane 505-29-3
Amylcinnamaldehyde 122-40-7
Benzyl cinnamate 103-41-3
tert-Butylhydroquinone 1948-33-0
Fusidic Acid Sodium Salt 751-94-0
Hydroxycitronellal 107-75-5
Musk ketone 81-14-1
L-Asparagine 70-47-3
phenethyl acetate 103-45-7
EP 2 292 585 A1
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(continued)
Name CAS #
Riboflavin-5-Phosphate 146-17-8
Potassium Sodium Tartrate 304-59-6
Galactaric acid 526-99-8
Sodium Tartrate 868-18-8
trisodium phosphate 7601-54-9
Disodium Pytophosphate 7758-16-9
Magnesium chloride 7786-30-3
Sodium Polymethacrylate 54193-36-1
propiophenone 93-55-0
2-ethylhexanoic acid 149-57-5
3,7,7-trimethyl bicyclohep-3-ene 13466-78-9
2,6-dimethyl-4-heptanol 108-82-7
5-isopropyl-2-methyl-phenol 499-75-2
L-Bornyl acetate 5655-61-8
caryophyllene 87-44-5
hydroxymethylpyrone 118-71-8
neosperidin dihydrochalcone 20702-77-6
2,2-Dibromo-3-nitrilopropionamide 1022-01-2
Xylitol 87-99-0
Sulfosalicylic acid 97-05-2
Riboflavin 5-(dihydrogen phosphate), monosodium salt 130-40-5
Ethylenediaminetetraacetic acid, disodium salt 139-33-3
Gallic acid 149-91-7
Carbonic acid 463-79-6
Potassium carbonate, sesquihydrate 6381-79-9
Magnesium phosphate tribasic 7757-87-1
diallyl sulfide 592-88-1
ethyl 4-oxopentanoate 539-88-8
methyl caproate 106-70-7
isopropyl isobutyrate 617-50-5
diethyl hydroxybutanedioate 2065419
propyl isopentanoate 557-00-6
benzyl ethyl ether 539-30-0
isobutyl isopentanoate 589-59-3
propyl hexanoate 626-77-7
4-methylquinoline 491-35-0
methyl cinnamate 103-26-4
cumic alcohol 536-60-7
EP 2 292 585 A1
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(continued)
Name CAS #
thujone 471-15-8
dihydrocarveol 619-01-2
fenchyl alcohol 1632-73-1
Nerol 106-25-2
isopentyl isopentanoate 659-70-1
methyleugenol 93-15-2
methyl 2-naphthyl ketone 93-08-3
diphenyldisulfide 882-33-7
citronellyl acetate 150-84-5
menthyl acetate 89-48-5
menthyl isovalerate 16409-46-4
5-Ethyl-3-hydroxy-4-methyl-2(5H)-furanone 698-10-2
malic acid 6915-15-7
3-methylbutanoic acid butyl ester 109-19-3
3-phenyloxiranecarboxylic acid ethyl ester 121-39-1
1,2-Benzirothiazol-3(2H)-one 1,1-dioxide, ammonium salt 6381-61-9
1-methyl-4-(1-methylethyl)-1,4-Cyclohexadiene 99-85-4
3-mercapto-2-Butanol 54812-86-1
(1R)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene 7785-70-8
(1S)-6,6-dimethyl-2-methylenebicycio[3.1.1]heptane 18172-67-3
1-methyl-4-(1-methylethylidene)cyclohexene 586-62-9
1-(3-pyridinyl) ethanone 350-03-8
1-pyrazinylethanone 22047-25-2
1-(2-furyl)-2-propanone 6975-60-6
1-Penten-3-one 1629-58-9
2,3-pentanedione 600-14-6
2,5-dimethylpyrazine 123-32-0
2-isobutyl-3-methoxypyrazine 24683-00-9
4-methyl-2,3-pentanedione 7493-58-5
5-methylfurfural 620-02-0
Dimethyltrisulfide 3658-80-8
furfuryl acetate 623-17-6
furfurylmethylether 13679-46-4
terpinen-4-ol 562-74-3
Calcium sorbate 7492-55-9
Potassium lactate 996-31-6
1-Hydraxyethylidene-1,1-diphosphonic acid 2809-21-4
L-glutamic acid monopotassium salt 19473-49-5
EP 2 292 585 A1
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(continued)
Name CAS #
3-methyl-2-buten-1-ol 556-82-1
phenylethanal 122-78-1
4-Methoxyacetophenone 100-06-1
L-borneol 464-45-9
2,4-Hexadien-1-ol 111-28-4
D-Fenchone 4695-62-9
3-Phenylpropyl formate 104-64-3
Cinnamyl formate 104-65-4
D-galacturonate 685-73-4
D-glucuronate 1700908
5 IMP 131-99-7
1-Methoxy-4-methylbenzene 104-93-8
2-Methylbutanoic acid 116-53-0
2,4,6-Tribromophenol 118-79-6
3-Ethyl pyridine 536-78-7
Zinc acetate 557-34-6
Methyl pentanoate 624-24-8
Methylthioethane 624-89-5
3-Penten-2-one 625-33-2
Glycocholic acid 475-31-0
m-Methoxybenzoic acid 586-38-9
alpha-Hydroxypropionic acid 598-82-3
Methyl 2-furoate 611-13-2
2-Furancarboxylic acid, propyl ester 615-10-1
Benzylacetoacetic acid, ethyl ester 620-79-1
2,5-Dimethyl pyrrole 625-84-3
4-methyl-1,1-biphenyl 644-08-6
p-Isopropylacetophenone 645-13-6
4-methyl-thiazole 693-95-8
gamma-Decalactone 706-14-9
2-acetylpyrrole 1072-83-9
2-acetylpyridine 1122-62-9
tetramethyl-pyrazine 1124-11-4
Methyl 4-phenylbutyrate 2046-17-5
2,3,6-trimethyl-phenol 2416-94-6
2-Methoxypyrazine 3149-28-8
2-Ethylfuran 3208-16-0
2,3-dimethyl-pyrazine 5910-89-4
EP 2 292 585 A1
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(continued)
Name CAS #
Thiophenethiol 7774-74-5
o-Tolyl isobutyrate 36438-54-7
cis-3-Hexenyl pyruvate 68133-76-6
cis-3-Hexenyl cis-3-hexenoate 61444-38-0
trans-2-Hexenyl isovalerate 68698-59-9
trans-2-Hexenyl formate 53398-78-0
trans-2-Hexenyl valerate 56922-74-8
1-Octen-3-yl butyrate 16491-54-6
Methyl 4-(methylthio)butyrate 53053-51-3
2,4-Octadien-1-ol 18409-20-6
2,4-Nonadien-1-ol 62488-56-6
2,4-Decaclien-1-ol 18409-21-7
(e,z)-2,6-Nonadienyl acetate 68555-65-7
3-Hexenal 4440-65-7
Tetrahydro-2-furanmethanol acetate 637-64-9
Methyl benzaldehyde 1334-78-7
Dodecylsulfonic acid 1510-16-3
Methylethyl disulfide 4253-89-8
Farnesol 4602-84-0
Thiobenzoic acid, S-methyl ester 5925-68-8
Hexyl benzoate 6789-88-4
2,5-Diethyltetrahydrofuran 41239-48-9
Zinc hydrosulfite 7779-86-4
(2R,3S)-Tartaric Acid 147-73-9
Ethylsulfuric acid 540-82-9
1,2,2-Trimethyl-1,3-cyclopentanedicarboxylic acid 5394-83-2
2-Methyl-3-buten-2-ol 115-18-4
trans-2-Hexenal 6728-26-3
4-Hexen-3-one 2497-21-4
1-Hexen-3-ol 4798-44-1
2-Methyl-1-butanethiol 1878-18-8
4-Methylcyclohexanone 569-92-4
3-Heptanol 589-82-2
o-methylanisole 578-58-5
trans-2-octenal 2363-89-5
2,3,4-Trimethyl-3-pentanol 3054-92-0
Acetylacetaldehyde dimethyl acetal 5436-21-5
p-methylacetophenone 122-00-9
EP 2 292 585 A1
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(continued)
Name CAS #
o-aminoacetophenone 551-93-9
4-Propylphenol 645-56-7
2,4-Dimethylanisole 6738-23-4
Benzyl methyl sulfide 766-92-7
Methyl phenylacetate 101-41-7
4-Ethoxybenzaldehyde 10031-82-0
p-tolyl acetate 140-39-6
2,6-Dimethoxyphenol 91-10-1
Isoborneol 124-75-5
Methyl 2-methoxybenzoate 606-45-1
Phenylacetaldehyde dimethyl acetal 101-48-4
3-Phenylpropyl acetate 122-72-5
Ethyl 3-phenylpropionate 2021-28-5
Benzyl butyrate 103-37-7
Anisyl acetate 104-21-2
Isobutyl phenylacetate . 102-13-6
p-vinylphenol 2628-17-3
o-tolyl acetate 533-18-6
2,5-Dihydroxybenzoic acid 490-79-9
o-methoxyphenyl acetate 613-70-7
Lactobionic acid 96-82-2
Magnesium hydrogen phosphate trihydrate 7782-75-4
Iberverin 505-79-3
alpha-methylcinnamaldehyde 101-39-3
benzyl phenylacetate 102-16-9
1,3-dimercaptopropane 109-80-8
p-cymen-8-ol 1197-01-9
phenethyl anthranilate 133-18-6
trihydroxybutyrophenone 1421-63-2
o-methoxycinnamaldehyde 1504-74-1
3-propylidene phthalide 17369-59-4
trans,trans-2,4-decadienal 25152-84-5
piperonyl acetate 326-61-4
2,3-hexanedione 3848-24-6
isopropyl phenylacetate 4861-85-2
ethyl 3-hydroxybutyrate 5405-41-4
furfural acetone 623-15-4
beta-(2-furyl)acrolein 623-30-3
EP 2 292 585 A1
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(continued)
Name CAS #
Linalyl anthranilate 7149-26-0
citral diethyl acetal 7492-66-2
allyl anthranilate 7493-63-2
acetyl tributyl citrate 77-90-7
butyl anthranilate 7756-96-9
cyclohexyl anthranilate 7779-16-0
isoamyl cinnamate 7779-65-9
isobutyl anthranilate 7779-77-3
carvyl acetate 97-42-7
carveol 99-48-9
3-(Methylthio)propionaldehyde 3268-49-3
Alpha-damascone 43052-87-5
Dimethyldicarbonate 4525-33-1
Procaine 59-46-1
5-hydroxy-6-methyl-3,4-pyridinedimethanol 65-23-6
2-methoxy-Naphthalene 93-04-9
Methyl nicotinate 93-60-7
Ethyl benzoylacetate 94-02-0
Phenethyl benzoate 94-47-3
2-methyl-pentanoic acid 97-61-0
Cyclohexanecarboxylic acid 98-89-5
Methyl b-phenylpropionate 103-25-3
Benzyl 3-methyl butanoate 103-38-8
Naphthalene-2-sulfonic acid 120-18-3
Methyl 4-methoxybenzoate 121-98-2
3-Phenylprop-2-enyl cinnamate 122-69-0
7-methyl-3-methylene-1,6-Octadiene 123-35-3
Levulinic acid 123-76-2
2-Mercaptobenzoic acid 147-93-3
m-Dimethoxybenzene 151-10-0
-3-butyl-1(3H)-isobenzofuranone 6066-49-5
5-Methylquinoxaline 13708-12-8
2-Ethyl Pyrazine 13925-00-3
trimethyl-pyrazine 14667-55-1
2-ethyl-3-methyl-pyrazine 15707-23-0
2,3-diethyl-pyrazine 15707-24-1
2,3-diethyl-5-methyl-pyrazine 18138-04-0
2-Methylthiopyrazine 21948-70-9
EP 2 292 585 A1
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(continued)
Name CAS #
5-Methyl-3H-furan-2-one 591-12-8
cis-3-Hexen-1-ol 928-9-6-1
3,7-Dimethyl-1,3,6-octatriene 13877-91-3
calcium cyclamate 139-06-0
aconitic acid 499-12-7
2-Dehydrolinalool 29171-20-8
2-Mercaptopropionic acid 79-42-5
3-Methyl-2-butenal 107-86-8
Allylacetic acid 591-80-0
Allyl cyclohexylacetate 4728-82-9
Allyl cyclohexylpropionate 2705-87-5
Allyl phenoxyacetate 7493-74-5
Allyl phenylacetate 1797-74-6
Allyl alpha-ionone 79-78-7
Butyl butyrolactate 7492-70-8
Cinnamyl isobutyrate 103-59-3
Cinnamyl propionate 103-56-0
Dibenzyl disulfide 150-60-7
Isobornyl acetate 125-12-2
Methyl heptyne carbonate 111-12-6
Triethyl citrate 77-93-0
gamma-Undecalactone 104-67-6
alpha-Amylcinnamyl alcohol 101-85-9
1,3,4,6,7,8-Hexahydro-4,6,6,7,8,6-hexamethyl cyclopenta[g][2]benzopyran 1222-05-5
2-Ethylbutyl acetate 10031-87-5
Triphosphoric acid, pentapotassium salt 13845-36-8
L-(+)-Lactic acid 79-33-4
Mannitol 87-78-5
2-Methoxy-4-methylphenol 93-51-6
1,2,3-Propanetricarboxylic acid, 2-hydroxy-, disodium salt 144-33-2
Ethanesulfonic acid, 2-hydroxy-, monosodium salt 1562-00-1
2-Methoxy-4-propylphenol 2785-67-7
3,7-Dimethyl-3-octanol 78-69-3
2-Pentyl furan 3777-69-3
Butanoic acid, 3-oxo-, butyl ester 591-60-6
4-(4-Hydroxy-4-methyl pentyl)-3-cyclohexene-1-carboxaldehyde 31906-04-4
Methyl 3-oxo-2-pentylcyclopentaneacetate 24851-98-7
Naphthalene, 2-(2-methylpropoxy) - 2173-57-1
EP 2 292 585 A1
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(continued)
Name CAS #
Perillol 536-59-4
2-Acetyl-1-methylpyrrole 932-16-1
4-Allyl-2,6-dimethoxyphenol 6627-88-9
Butyl levulinate 2052-15-5
D-(+)-Camphoric acid 124-83-4
D(+)-10-Camphorsulfonic acid 3144-16-9
L-(-)-Carvone 6485-40-1
(-)-Carvyl propionate 97-45-0
(-)-Caryophyllene oxide 1139-30-6
Cyclohexylacetic acid 5292-21-7
3-Cyclopentylpropionic acid 140-77-2
(-)-Dihydrocarvyl acetate 20777-49-5
3,3-Dimethylacrylic acid 541-47-9
2,4-Dimethylbenzaldehyde 15764-16-6
1,4-Dithiane-2,5-diol 40018-26-6
Ethanesulfonic acid 594-45-6
Ethyl butyrylacetate 3249-68-1
Ethyl (methylthio) acetate 4455-13-4
Ethyl pyruvate 617-35-6
Ethyl sorbate 2396-84-1
5-Formyl-2-furansulfonic acid, sodium salt 31795-44-5
Furfuryl mercaptan 98-02-2
1,6-Hexanedithiol 1191-43-1
trans-2-Hexenoic acid 13419-69-7
trans-2-Hexen-l-ol 928-95-0
4-(4-Hydroxyphenyl) -2-butanone 5471-51-2
Isopulegol 89-79-2
Isopulegyl acetate 89-49-6
2-Ketobutyric acid 600-18-0
(-)-Limonene 5989-54-8
4-Methoxyphenylacetone 122-84-9
Methyl cyclohexanecarboxylate 4630-82-4
3-Methylcyclohexanone 591-24-2
3-Methyl-2-Cyclohexen-1-one 1193-18-6
3-Methyl-1,2-cyclopentanedione 765-70-8
3-Methyl-2-cyclopenten-1-one 2758-18-1
N-Methyl-D-glucamine 6284-40-8
Methyl 3-(methylthio)propionate 13532-18-8
EP 2 292 585 A1
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(continued)
Name CAS #
4-Methyl-5-thiazoleethanol 137-00-8
5-Methyl-2-thiophenecarboxaldehyde 13679-70-4
DL-3-Methylvaleric acid 105-43-1
(-)-Myrtenal 564-94-3
Nopol 128-50-7
gamma-Octanoic lactone 104-50-7
3-Octanol 589-98-0
E-2-Octenoic acid 1871-67-6
Pamoic acid 130-85-8
4-Phenyl-2-butyl acetate 10415-88-0
1-Phenyl-1,2-propanedione 579-07-7
2-Phenylpropyl butyrate 80866-83-7
2-Phenylpropyl isobutyrate 65813-53-8
cis-2-Hexen-1-ol 928-94-9
Bis(methylthio)methane 1618-26-4
Magnesium carbonate hydroxide, Light 39409-82-0
N-Acetyl-L-methionine 65-82-7
4-Methyl-5-vinylthiazole 1759-28-0
2-Methyl-1-phenyl-2-propanol 100-86-7
3-Phenylpropionaldehyde 104-53-0
N-Benzyl-2-phenylethylamine 3647-71-0
1-Phenylethyl propionate 120-45-6
3-Phenylpropyl isobutyrate 103-58-2
Allyl hexanoate 123-68-2
alpha,4-Dimethylbenzylalcohol 536-50-5
(-)-Menthyl lactate 59259-38-0
2,6-Dimethylthiophenol 118-72-9
2,4,5-Trimethylthiazole 13623-11-5
Ethyl 3-(methylthio)propionate 13327-56-5
Phenylethyl isovalerate 140-26-1
2-Propylpyrazine 18138-03-9
2-Methyltetrahydrofuran-3-one 3188-00-9
Ethyl 2-(methyldithio)propionate 23747-43-5
3,4-Dimethyl-1,2-cyclopentanedione 13494-06-9
Difurfurylsulfide 13678-67-6
Difurfuryldisulfide 4437-20-1
3-(Methylthio)propanol 505-10-2
Methyl phenyl disulfide 14173-25-2
EP 2 292 585 A1
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(continued)
Name CAS #
2- (Methyldithio)-isobutyraldehyde 67952-60-7
Methyl 2-thiofuroate 13679-61-3
2-Isobutylthiazole 18640-74-9
4-Methyl-5-thiazolylethyl acetate. 656-53-1
2-Acetylthiazole 24295-03-2
2-Ethyl-3,5(6)-dimethylpyrazine 27043-05-6
5-Methyl-6,7-dihydro-5H-cyclopenta(b)pyrazine 23747-48-0
cinnamyl acetate 103-54-8
2,5-Dihydroxy-2,5-dimethyl-1,4-dithiane 55704-78-4
5,6,7,8-Tetrahydroquinoxaline 34413-35-9
2-Methyl-3-furanethiol 28588-74-1
Styrallyl acetate 93-92-5
2-Methylhexanoic acid 4536-23-6
2-Methylheptanoic acid 1188-02-9
2,2,6-Trimethylcyclohexanone 2408-37-9
L-Tyrosine ethyl ester hydrochloride 4089-07-0
Ethyl 4-methoxybenzoate 94-30-4
4-Ethylbenzaldehyde 4748-78-1
N-Ethyl-p-menthane-3-carboxamide 39711-79-0
1-(2-Furyl)-1,3-butanedione 25790-35-6
Menthofuxan 494-90-6
Methylsulfuric acid sodium salt 512-42-5
Sucrose diacetate hexaisobutyrate 126-13-6
N,2,3-Trimethyl-2-isopropylbutamide 51115-67-4
Tripropionin 139-45-7
(+/-)-citronellic acid 502-47-6
5-Acetyl-2,4-dimethylthiazole 38205-60-6
Neryl acetate 141-12-8
Benzyl propionate 122-63-4
1R-(-)-Camphorsulfonic acid 35963-20-3
3,4-Hexanedione 4437-51-8
eis-3-Hexenoic acid 4219-24-3
cis-4-Heptenal 6728-31-0
(E,Z)-2,6-nonadienal 557-48-2
traLns-2,trans-6-Nonadienal 17587-33-6
4-Methyl-2-pentenal 5362-56-1
cis-6-Nonenal 2277-19-2
Methyl propyl disulfide 2179-60-4
EP 2 292 585 A1
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(continued)
Name CAS #
8-p-Menthen-1-ol 138-87-4
p-Menthan-2-one 499-7-7
Bisabolene 495-62-5
Ethyl cyclohexanecarboxylate 3289-28-9
Phenylpyruvate 156-06-9
Hydroxypyruvate 1113-60-6
4-Methyl-2-oxopentanoate 816-66-0
(+)-Neomenthol 2216-52-6
trans-Citral 141-27-5
Piperitenone 491-09-8
Sabinene hydrate 546-79-2
Perillyl aldehyde 2111-75-3
2-Hydroxyethanesulfonate 107-36-8
Acetyl isovaleryl 13706-86-0
Acetyl valeryl 96-04-8
Butylidene phthalide 551-08-6
Carvacryl ethyl ether 4732-13-2
Ethyl vanillin propylene glycol acetal 68527-76-4
Hexyl hexanoate 6378-65-0
2-Methyl-5-(methylthio)-furan 13678-59-6
2-Methyl-4-pentenoic acid 1575-74-2
2-Methyl-4-propyl-1,3-oxathiane 67715-80-4
3-Methylthio-1-hexanol 51755-66-9
cis-6-Nonenol 35854-86-5
Rose oxide 16409-43-1
L-Linalool 126-91-0
5,6-Dimethyl-8-isopropenylbicyclo[4.4.0]dec-1-en-3-one 4674-50-4
2-Ethyl-3,5-dimethylpyrazine 13925-07-0
2-Isopropylpyrazine 29460-90-0
2-Isobutyl-3-methyl-pyrazine 13925-06-9
2-Methoxy-3-sec-butyl-pyrazine 24168-70-5
2-Methylthio-3(6)-methyl-pyrazine 67952-65-2
Benzylcarbinyl propionate 122-70-3
Bornyl acetate 76-49-3
furaneol 3658-77-3
Methoxycinnamaldehyde 1963-36-6
Methylphenol, hydrogen sulfate 68127-34-4
Lactitol monohydrate 81025-04-9
EP 2 292 585 A1
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(continued)
Name CAS #
2H-Pyrrole, 3,4-dihydro- 5724-81-2
2-Butenal, 2-methyl-, (E)- 497-03-0
2-Pentenal . 764-39-6
Ethanethioic acid, S-methyl ester 1534-08-3
2-Hexenal 505-57-7
2-Methyl-2-pentenal 623-36-9
Cyclopentanethiol 1679-07-8
Butane, 2-ethoxy- 2679-87-0
S-Ethyl thioacetate 625-60-5
ethyl methyl carbonate 623-53-0
3(2H)-Furanone, 2,5-dimethyl- 14400-67-0
Allyl propionate 2408-20-0
methyl 2-methylbutanoate 868-57-5
2-Butanone, 1-(methylthio)- 13678-58-5
Ethanethioic acid, S-propyl ester 2307-10-0
1,2-Butanedithiol 16126-68-0
6-Methyl-2,5-heptadiene-2-one 1604-28-0
2-Octen-4-one 4643-27-0
2,5-dimethyl-3-furanthiol 55764-23-3
2-Heptenoic acid 18999-28-5
Butanoic acids, 2-propenyl ester 2051-78-7
6-Methyl-5-hepten-2-ol 1569-60-4
trans-2-octen-4-ol 20125-81-9
cis-3-Octen-1-ol 20125-84-2
1-Butanol, 2-methyl-, acetate 624-41-9
4-methyl-alpha-methylstyrene 1195-32-0
trans-3-Phenyl-2-propen-1-ol 4407-36-7
Benzeneacetaldehyde, alpha-methyl- 93-53-8
Benzene, (2-methoxyethyl) - 3558-60-9
Cyclohexene, 1-methyl-4-(1-methylethenyl)-, (+-)- 7705-14-8
Phenol, 2-(methylthio)- 1073-29-6
2-Hexen-1-yl acetate 2497-18-9
3-Hexen-1-ol, acetate, (Z)- 3681-71-8
5-Hydroxy-4-octanone 496-77-5
butyl 2-methylpropanoate 97-87-0
Benzofuran-2-carboxaldehyde 4265-16-1
DL-Lysine 70-54-2
1-Hexanethiol, 2-ethyl- 7341-17-5
EP 2 292 585 A1
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(continued)
Name CAS #
2,4-Dimethylacetophenone 89-74-7
2-Pentylpyridine 2294-76-0
1-Methoxy-4-propyl benzene 104-45-0
1-Hyclroxy-2-methoxy-4-ethyl benzene 2785-89-9
Nonalactone 6008-27-1
Cyclohexyl propionate 6222-35-1
Allyl 2-ethylbutyrate 7493-69-8
Butanoic acid, 3-oxo-, 2-methylpropyl ester 7779-75-1
n-Butyl pentanoate 591-68-4
3,7-Dimethyl-1-octanol 106-21-8
3-Buten-2-one, 3-methyl-4-phenyl- 1901-26-4
2-Prcpenoic acid, 3-phenyl-, methyl ester, (E)- 1754-62-7
Benzene, 4-ethenyl-1,2-dimethoxy- 6380-23-0
Benzenepropanol, alpha,alpha-dimethyl- 103-05-9
Benzene, (butoxymethyl)- 58B-67-0
Dimethyl anthranilate 85-91-6
2-Hexanoylfuran 14360-50-0
Cyclohexyl butyrate 1551-44-6
Naphthalene, 2-ethoxy- 93-16-5
Acetoacetic acid isoamyl ester 2308-18-1
Propanoic acid, 2-methyl-, 4-methylphenyl ester 103-93-5
4-(4-Methoxyphenyl)-2-butanone 104-20-1
Isobutyl benzoate 120-50-3
Benzene, 1,2-dimethoxy-4-(1-propenyl)- 93-16-3
beta-Phenylethylmethylethylcarbinol 10415-87-9
1,1-Dimethoxy-2-phenylpropane 90-87-9
Geranyl formate 105-86-2
Bornyl formate 7492-41-3
6-Octen-1-ol, 3,7-dimethyl-, formate 105-85-1
Benzeneacetic acid, butyl ester 122-43-0
3,5,9-Undecatrien-2-one, 6,10-dimethyl- 141-10-6
Anisyl propionate 7549-33-9
Butanoic acid, 3-phenyl-2-propenyl ester 103-61-7
2-Propenoic acid, 3-phenyl-, 2-methylpropyl ester 122-67-8
Eugenyl acetate 93-28-7
3-Methylbutyl phenylacetate 102-19-2
Benzoic acid, 2-(methylamino)-, 2-methylpropyl ester 65505-24-0
Phenoxy ethyl isobutyrate 103-60-6
EP 2 292 585 A1
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(continued)
Name CAS #
Anisyl butyrate 6963-56-0
2,6-Octadien-1-ol, 3,7-dimethyl-, propanoate, (Z)- 105-91-9
Isobornyl propionate 2756-56-1
1,3,5-Trithiane, 2,2,4,4,6,6-hexamethyl- 826-26-2
Geranyl N-butyrate 106-29-6
Geranyl isobutyrate 2345-26-9
Thiophene, 2,2-dithiobis- 6911-51-9
2-Propenoic acid, 3-phenyl-, cyclohexyl ester 7779-17-1
Benzeneacetic acid, 3-phenyl-2-propenyl ester 7492-65-1
Anisyl phenylacetate 142-17-0
2-Propenoic acid, 3-phenyl-, 3-phenylpropyl ester 122-68-9
Geranyl phenylacetate 102-22-7
hexyl 2-methylbutyrate 10032-15-2
4-heptanolide 105-21-5
Neral 106-26-3
(E) -2-octenol 18409-17-1
Ethyl 3-hydroxyhexanoate 2305-25-1
isopropyl hexanoate 2311-46-8
hexyl butanoate 2639-63-6
bis(2-methyl-3-furyl)disulfide 28588-75-2
3-hydroxy-4,5-dimethyl-2(5H)-furanone 28664-35-9
2-acetyl-2-thiazoline 29926-41-8
(E,E)-2,4-octadienal 30361-28-5
geranyl acetone 3796-70-1
1-octen-3-one 4312-99-6
3-mercapto-2-pentanone , 67633-97-0
(Z)-3-hexenal 6789-80-6
4-hexanolide 695-06-7
5-octanolide 698-76-0
delta-decalactone 705-86-2
4-vinylguaiacol 7786-61-0
Amyl salicylate 2050-08-0
Cyclohexyl formate 4351-54-6
Dimethylbenzylcarbinyl acetate 151-05-3
Geranyl propionate 105-90-8
Terpinyl acetate 80-26-2
isopropyl 3-methylbutanoate 32665-23-9
isopropyl 2-methylbutanoate 66576-71-4
EP 2 292 585 A1
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(continued)
Name CAS #
3-Hexenyl 3-methylbutanoate 10032-11-8
Isoamyl 2-methylbutyrate 27625-35-0
3-Octyl acetate 4864-61-3.
Benzyl isobutyrate 103-28-6
Cis-3-hexenyl butyrate 16491-36-4
Cis-3-hexenyl lactate 61931-81-5
Citronellyl butyrate 141-16-2
Citronellyl propionate 141-14-0
Isoamyl hexanoate 2198-61-0
1,3,5-Undecatriene 16356-11-9
1-Benzyloxy-2-methoxy-4-propenyl benzene 120-11-6
1-Octen-3-yl acetate 198242
2-Acetyl-3-ethyl pyrazine 32974-92-8
2-Isopropyl-4-methyl thiazole 15679-13-7
-2-Methyl-2-pentenoic acid 3142-72-1
2-sec-butyl thiazole 18277-27-5
4,5-Dimethyl thiazole 3581-91-7
4- (2,6,6-Trimethyl-2-cyclohexen-1-yl)butan-2-one 31499-72-6
4-(2,6,6-Trimethyl cyclohexa-1,3-clienyl)but-2-en-4-one 23696-85-7
Acetaldehyde phenethyl propyl acetal 7493-57-4
Acetaldehyde ethyl cis-3-hexenyl acetal 28069-74-1
Acetone propylene glycol acetal 1193-11-9
Acetyl isoeugenol 93-29-8
2-Acetyl-5-methyl furan 1193-79-9
Allyl cyclohexylbutyrate 7493-65-4
Alpha, alpha-dimethylphenethyl butyrate 10094-34-5
Alpha, alpha-dimethyl phenethyl formate 10058-43-2
Alpha, beta-santalol 11031-45-1
Alpha-amyl cinnamaldehyde dimethyl acetal 91-87-2
Alpha-fenchyl acetate 13851-11-1
Alpha-furfuryl pentanoate 36701-01-6
Alpha-ionol 25312-34-9
6-Methyl-alpha-ionone 79-69-6
Alpha-methyl-p-isopropylphenylpropanaldehyde 103-95-7
Alpha-n-amyl-beta-phenylacryl acetate 7493-78-9
Alpha-piperitone 6091-50-5
Alpha-n-amyl-beta-phenyl acryl isovalerate 7493-80-3
6-Amyl-alpha-pyrone 27593-23-3
EP 2 292 585 A1
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(continued)
Name CAS #
Anisyl formate 122-91-8
Benzylcarbinyl 2-methyl butyrate 24817-51-4
Benzylcarbinyl 3-phenyl propenoate 103-53-7
Benzylcarbinyl alpha-toluate 102-20-5
Benzylcarbinyl butyrate 103-52-6
Benzylcarbinyl caproate 6290-37-5
Benzylcarbinyl formate 104-62-1
Benzylcarbinyl isobutyrate 103-48-0
Benzylcarbinyl salicylate 87-22-9
Benzylcarbinyl tiglate 55719-85-2
Benzyl dipropyl ketone 7492-37-7
Benzyl tiglate 37526-88-8
Beta-homocyclocitral 472-66-2
Beta-ionol 22029-76-1
3-Phenylpropyl propanoate 122-74-7
Bois de rose oxide 7392-19-0
Butyl 2-methyl butyrate 15706-73-7
Butyl cinnamate 538-65-8
ortho-sec-Butyl cyclohexanone 14765-30-1
isobutyl cis-2-methyl-2-butenoate 7779-81-9
5-n-Butyl-delta-valerolactone 3301-94-8
Campholenic aldehyde 4501-58-0
Cedran-8-yl acetate 77-54-3
Cinnamyl isovalerate 140-27-2
Cis-3-hexenyl benzoate 25152-85-6
Cis-3-hexenyl caproate 31501-11-8
Cis-3-hexenyl formate 33467-73-1
Cis-3-hexenyl isobutyrate 41519-23-7
Cis-3-hexenyl phenylacetate 42436-07-7
Cis-3-hexenyl propionate 33467-74-2
Cis-3-hexenyl tiglate 67883-79-8
Cis-3-hexenyl valerate 35852-46-1
cis-4-Hepten-1-ol 6191-71-5
Cis-5-octen-1-ol 64275-73-6
Citral dimethyl acetal 7549-37-3
Citronellyl isobutyrate 97-89-2
Citronellyl isovalerate 68922-10-1
Citronellyl valerate 7540-53-6
EP 2 292 585 A1
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(continued)
Name CAS #
Citroxide 7416-35-5
Cocal 21834-92-4
p-Cresyl alpha-toluate 101-94-0
p-Cresyl isovalerate 55066-56-3
Dehydro-beta-cyclocitral 116-26-7
8,8-Diethoxy-2,6-dimethyl-2-octanol 7779-94-4
5,7-Dihydro-2-methyl thieno(3,4-d)pyrimidine 36267-71-7
2,5-Dihydro-4,5-dimethyl-2-(2-methyl propyl)thiazole 65894-83-9
Dihydrojasmone 1128-08-1
Dihydroxyacetophenone 28631-86-9
1,1-Dimethoxy-3,7-dimethyl-7-octanol 141-92-4
3,7-Dimethyl-1,6-octadien-3-yl benzoate 126-64-7
3,7-Dimethyl-1,6-octadien-3-yl butyrate 78-36-4
3,7-Dimethyl-1,6-octadien-3-yl isobutyrate 78-35-3
3,7-Dimethyl-1,6-octadien-3-yl propanoate 144-39-8
cis-3,7-Dimethyl-2,6-octadien-1-yl 2-methyl propanoate 2345-24-6
2,4-Dimethyl-3-cyclohexene-1-carboxaldehyde 68039-49-6
2,6-Dimethyl-5-hepten-1-al 106-72-9
trans, cis-2,6-Dodecadien-1-al 21662-13-5
Eglantal 26643-91-4
Ethyl E-2-hexenoate 27829-72-7
Ethyl tiglate 5837-78-5
Ethyl trans-4-decenoate 76649-16-6
5-Ethyl-4-hydroxy-2-methyl-3 [2H] furanone 27538-09-6
2-Ethyl-4-methyl thiazole 15679-12-6
2,6,10-Trimethyl-2,6,10-pentadecatrien-14-one 762-29-8
Guaiacyl phenyl acetate 4112-89-4
3-Hepten-2-one 1119-44-4
trans-2-Hexen-1-ol 2305-21-7
Trans-2-hexenyl butyrate 53398-83-7
Hexyl phenylacetate 5421-17-0
Hexyl propionate 2445-76-3
Hydroxycitronellol 107-74-4
Isobutyl 2-butenoate 589-66-2
Isobutyl salicylate 87-19-4
Isodihydro lavandulal 35158-25-9
Isoeugenyl phenyl acetate 120-24-1
isopropyl alpha-methylcrotonate 1733-25-1
EP 2 292 585 A1
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(continued)
Name CAS #
p-Menth-1-en-8-yl propionate 80-27-3
Menthalactone 13341-72-5
3-Methoxy-p-cymene 1076-56-8
Methyl 4-methyl pentanoate 2412-80-8
alpha-Methyl benzyl formate 7775-38-4
2-Methylbutyl 2-methylbutanoate 2445-78-5
Methyl e-2-octenoate 2396-85-2
p-Methyl hydratropaldehyde 99-72-9
3-(5-Methyl-2-furyl) butanal 317 04-80-0
Nerol oxide 1786-08-9
trans,cis-2,6-Nonadien-1-ol 7786-44-9
trans-2-Octen-1-yl acetate 3913-80-2
3-Octen-2-one 1669-44-9
2-Phenyl-2-butenal 4411-89-6
2-Propionylthiazole . 43039-98-1
1-Hydroxy-2-butanone 5077-67-8
2-Butanone, 3-hydroxy-, (+-)- 52217-02-4
Thiazole, 2,5-dimethyl- 4175-66-0
Butanethioic acid, S-methyl ester 2432-51-1
2,4-Hexadienoic acid, methyl ester, (E,E)- 689-89-4
Benzeneacetaldehyde, 4-methyl- 104-09-6
Bicyclo [4.1.0]hept-3-ene, 3,7,7-trimethyl-, (1S)- 498-15-7
Ethyl 3-hexenoate 2396-83-0
1H-Pyrrole, 1-(2-furanylmethyl)- 1438-94-4
6-Octenal, 3,7-dimethyl-, (R)- 2385-77-5
Ethanethioic acid, S-(2-furanylmethyl) ester 13678-68-7
6-Octen-1-ol, 3,7-dimethyl-, (R) - 1117-61-9
6-Octen-1-ol, 3,7-dimethyl-, (S) - 7540-51-4
DL-Tetrohydrofurfuryl propionate 637-65-0
Benzenepentanol 10521-91-2
Cyclohexaneethanol, acetate 21722-83-8
Benzyl isobutyl ketone 5349-62-2
Butanoic acid, 3-oxo-, phenylmethyl ester 5396-89-4
1,2-Ethanediamine, N,N-bis(phenylmethyl)- 140-28-3
2-Ethyl-3-hydroxy-4-pyrone 1110651
Dicyclohexyl disulfide 2550-40-5
Tetrahydrofurfuryl butyrate 2217-33-6
Thujone 546-80-5
EP 2 292 585 A1
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(continued)
Name CAS #
Benzyl alcohol, alpha-methyl-, butyrate 3460-44-4
Citronellyl tiglate 24717-85-9
Lactitol 585-86-4
Nonivamide 2444-46-4
2-Acetoxy-3-butanone 4906-24-5
3-Acetyl-2,5-dimethylthiophene 230378
3-Acetyl-2-5dimethylfuran 10599-70-9
4-Acetyl-6-t-butyl-1,1-dimethylindan 13171-00-1
Allyl 2-furoate 4208-49-5
Allyl sorbate 7493-75-6
Allyl thiopropionate 41820-22-8
Allyl tiglate 7493-71-2
Amylcyclohexyl acetate 67874-72-0
Benzaldehyde glyceryl acetal 1319-88-6
Benzaldehyde propylene glycol acetal 2568-25-4
Bornyl isovalerate 76-50-6
1,3-Butanedithiol 24330-52-7
2,3-Butanedithiol 4532-64-3
Butyl cinnamic aldehyde 7492-44-6
Cinnamyl benzoate 5320-75-2
Citral ethylene glycol acetal 66408-78-4
Citronellyloxyacetaldehyde 7492-67-3
Citronellyl phenylacetate 139-70-8
Cyclohexyl isovalerate 7774-44-9
Decalactone 5579-78-2
2,5-Dimethyl-4-methoxy-3(2H)-furanone 4077-47-8
6,10-Dimethyl-9-undecen-2-one 4433-36-7
2-Ethoxythiazole 15679-19-3
Ethyl 2-mercaptopropionate 19788-49-9
Ethyl 2-methyl-4-pentenoate 53399-81-8
Ethyl 3-(2-furyl)propanoate 94278-27-0
Ethyl cyclohexanepropionate 10094-36-7
Ethyl (p-tolyloxy)acetate 67028-40-4
3-Ethyl-2-hydroxy-2-cyclopenten-1-one 21835-01-8
Ethylene brassylate 105-95-3
2-Ethylfenchol 18368-91-7
Furfuryl 3-methylbutanoate 13678-60-9
Furfuryl butyrate 623-21-2
EP 2 292 585 A1
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(continued)
Name CAS #
Furfuryl isopropyl sulfide 1883-78-9
Furfuryl methyl sulfide 1438-91-1
Furfuryl propionate 623-19-8
Furfuryl thiopropionate 59020-85-8
Geranyl acetoacetate 10032-00-5
Geranyl benzoate 94-48-4
Geranyl isovalerate 109-20-6
delta-Hexalactone 823-22-3
trans-3-Hexenal 69112-21-6
cis-3-Hexenyl anthranilate 65405-76-7
trans-2-Hexenyl propionate 53398-80-4
5-(cis-3-Hexenyl) dihydro-5-methyl-2(3H)furanone 70851-61-5
Hexyl 2-formate 39251-86-0
Hexyl crotonate 19089-92-0
Hexyl formate 629-33-4
Isoamyl 3-(2-furyl)propionate 7779-67-1
Isoamyl pyruvate 7779-72-8
Isobutyl furylpropionate 105-01-1
Isohexenyl cyclohexenyl carboxaldehyde 37677-14-8
p-Isopropyl phenylacetaldehyde 4395-92-0
Linalyl cinnamate 78-37-5
Linalyl formate 115-99-1
Linalyl isovalerate 1118-27-0
Linalyl phenylacetate 7143-69-3
Maltol isobutyrate 65416-14-0
Methyl 2-methylpentanoate 2177-77-7
Methyl 3-hydroxyhexanoate 21188-58-9
Methyl 3-nonenoate 13481-87-3
Methyl furfuryl disulfide 57500-00-2
Methyl p-tert-butylphenylacetate 3549-23-3
3-Methyl-1,2-cyclohexanedione 3008-43-3
alpha-Methylanisalacetone 104-27-8
2-Methylbutyl isovalerate 2445-77-4
4-Methylnonanoic acid 45019-28-1
4-Methyloctanoic acid 54947-74-9
2-Methyltetrahydrothiophen-3-one 13679-85-1
3-(Methylthio)butanal 16630-52-7
4-(Methylthio)butanol 20582-85-8
EP 2 292 585 A1
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(continued)
Name CAS #
4-Methylthio-2-butanone 34047-39-7
4-Methylthio-4-methyl-2-pentanone 23550-40-5
Neryl butyrate 999-40-6
Neryl formate 2142-94-1
Neryl isovalerate 3915-83-1
Octahydrocoumarin 4430-31-3
Phenethyl 2- furoate 7149-32-8
1-Phenyl-2-pentanol 705-73-7
Phenylacetaldehyde diisobutylacetal 68345-22-2
Phenylacetaldehyde glyceryl acetal 29895-73-6
2-(3-Phenylpropyl)pyridine 2110-18-1
Propyl phenylacetate 4606-15-9
Pyrazineethanethiol 35250-53-4
Ethyl 2-methyl pentanoate 39255-32-8
Methyl 2,4-decadienoate 4493-42-9
alpha-Isomethyl ionone 127-51-5
5-Methyl hexanoic acid 628-46-6
Ethyl 3-methyl pentanoate 5870-68-8
Ethyl 2-methyl-3,4-pentadienoate 60523-21-9
3-Nonen-2-one 14309-57-0-
5-Methyl-3-hexen-2-one 5166-53-0
Maltol propionate 68555-63-5
2-Methyl-3-(2-furyl) acrolein 874-66-8
Ethyl 3(2-furyl)propanoate 10031-90-0
2-Phenyl-3-(2-furyl)-propenal 557568-60-2
4-Methyl-2-pentyl-1,3-dioxolane 1599-49-1
2-Ethyl-4,5-dimethyl oxazole 53833-30-0,
isobornyl isovalerate 7779-73-9
Theophylline-7-acetic acid 652-37-9
Ethyl trans-2-octenoate 7367-82-0
DL-Arginine 7200-25-1
Allyl Crotonate 20474-93-5
2-Methoxystyrene 612-15-7
Magnesium Fumarate 7704-71-4
2-Propionylpyrrole 1073-26-3
2-methyl-1,3-dithiolane 5616-51-3
2-ethyl-5-methyl pyrazine 13360-64-0
2-methyl-3-(dimercaptomethyl)-furan 65505-17-1
EP 2 292 585 A1
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(continued)
Name CAS #
Magnesium gluconate 3632-91-5
Manganese gluconate 6485-39-8
Erythritol 149-32-6
D-Arabinose 28697-53-2
D-Galactose 59-23-4
D-(+)-Mannose 3458-28-4
Sorbitol 50-70-4
Aspartame 22839-47-0
Cyclamic Acid 100-88-9
Dulcin 150-69-6
Glucose-1-phosphate Dipotassium Salt 29732-59-0
L-(+)-Arabinose 87-72-9
Fructose-6-Phosphate 643-13-0
D-Maltose Monohydrate . 6363-53-7
Ribose 24259-59-4
Fructose 1,6-Diphosphate Disodium Salt 26177-85-5
Saccharin sodium, dihydrate 6155-57-3
1,2-Benzisothiazol-3(2H)-one 1,1-dioxide, calcium salt 6485-34-3
1,2-Benzisothiazolin-3-one 1,1-dioxide, potassium salt 10332-51-1
zeranol 26538-44-3
beta-D-fructopyranose 7660-25-5
D-fructose 1,6-bisphosphate 488-69-7
Ribose 5-phosphate 4300-28-1
Arabinose 147-81-9
Saccharin, sodium salt hydrate 82385-42-0
Maltitol 585-88-6
D-Fructose 1-phosphate 15978-08-2
D-Sorbitol 6-phosphate 108392-12-
alpha-D-Xylose 31178-70-8
Inositol 1-phosphate 573-35-3
Table 10
Name CAS #
Sodium Metabisulfite 7681-57-4
sodium hydrogen phosphate 7558-79-4
sodium Phosphate Monobasic 7558-80-7
Sodium thiosulfate 7772-98-71
Orthoboric acid 10043-35-3
EP 2 292 585 A1
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(continued)
Name CAS #
Diethanolamine 111-42-2
Benzaldehyde 100-52-7
Sorbic acid 110-44-1
L-(+)-Tartaric Acid 87-69-4
D-mannitol 69-65-8
Butyl paraben 94-26-8
Thymol 89-83-8
Methyl salicylate 119-36-8
Citric acid 77-92-9
Creatinine 60-27-5
Vitamin C 50-81-7
Benzoic Acid 65-85-0
Methyl 4-hydroxybenzoate 99-76-3
m-Cresol 108-39-4
p-Cresol 106-44-5
Aspirin 50-78-2
Phenol 109-95-2
Sucrose 57-50-1
Potassium citrate, monohydrate 1534146
Sodium acetate 127-09-3
Lactic acid 50-21-5
Propionic acid, sodium salt 65-85
Benzyl alcohol 100-51-6
Phenethyl alcohol 60-12-8
Cholesterol 57-88-5
D-Glucose 50-99-7
Sorbitol 50-70-4
Aspartame 22839-47-0
Saccharin 81-07-2
2,6-Di-tert-Butyl-p-Cresol 128-37-0
4-Chloro-3-methylphenol 59-50-7
glycerin 56-81-5
Propyl paraben 94-13-3
fumaric acid 110-17-8
dabco 280-57-9
p-Phenylenediamine 106-50-3
Anethole 4180-23-8
propyl gallate. 121-79-9
EP 2 292 585 A1
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(continued)
Name CAS #
L-monosodium glutamate 142-47-2
Butylated hydroxyanisole 25013-16-5
Cyclohexanol, 5-methyl-2-(1-methylethyl)-, (1alpha,2beta,5alpha)- 89-78-1
alpha-Thioglycerol 96-27-5
Sodium dehydroacetate 4418-26-2
Ethyl 4-hydroxybenzoate 120-47-8
Ethyl Vanillin 121-32-4
Triacetin 102-76-1
Potassium sorbate 590-00-1
Triethyl citrate 77-93-0
(S)-(+)-Arginine 74-79-3
Glycine 56-40-6.
(S)-(-)-Histidine 71-00-1
(S)-(+)-Lysine 56-87-1
Quinone 106-51-4
Naphthalene, 2-ethoxy- 93-18-5
Methanesulfonic Acid 75-75-2
DL-Tartaric Acid 133-37-9
Cyclamic acid 100-88-9
(S)-(-)-Phenylalanine 63-91-2
(S)-(-)-Tyrosine 60-18-4
Carvone 99-49-0
Ethyl butyrate 105-54-4
6-Methyl-5-hepten-2-one 110-93-0
Ethyl acetoacetate 141-97-9
Methyl benzoate 93-58-3
Phenylacetic Acid 103-82-2
Adipic acid 124-04-9
Ethyl benzoate 93-89-0
Benzyl benzoate 120-51-4
Pyruvic acid 127-17-3
Succinic acid 110-15-6
Indole 120-72-9
Methyl anthranilate 134-20-3
Diethyl malonate 105-53-3
Niacin 59-67-6
Meso-inositol 87-89-8
4-Aminobenzoic acid 150-13-0
EP 2 292 585 A1
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(continued)
Name CAS #
Anisole 100-66-3
Urea 57-13-6
Pyrrolidine 123-75-1
Cyclopentanone 120-92-3
Acetic anhydride 108-24-7
Benzophenone 119-61-9
D-(-)-Fructose 57-48-7
D-(+)-Xylose 58-86-6
o-Methoxybenzoic Acid 579-75-9
linalool 78-70-6
ethyl isovalerate 108-64-5
1,1-Azobisformamide 123-77-3
5-Methylcoumarin 92-48-8
acetoin 513-86-0
alpha-Phellandrene 99-83-2
Cymene 99-87-6
Diethyl Succinate 106-65-0
p-Anisaldehyde 123-11-5
Phenyl ether 101-84-8
Tetrahydro-2-furanmethanol 97-99-4
Valeric Acid 109-52-4
3,4-xylenol 95-65-8
1,1-diethoxyethane 105-57-7
ethyl butyraldehyde 97-96-1
Ethyl crotonate 623-70-1
ethyl isobutyrate 97-62-1
methyl isovalerate 556-24-1
methyl propionate 554-12-1
methyl valeraldehyde 123-15-9
4-(2,6,6-Trimethyl-2-cyclohexen-1-yl)-3-buten-2-one 127-41-3
4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-one 14901-07-6
Maleic acid 110-16-7
3-Methylbutanoic acid 503-74-2
L-Glutamic Acid 56-86-0
D-limonene 5989-27-5
1-Phenyl-1-propanol 93-54-9
2-Hydroxyacetophenone 118-93-4
2,4-Dihydroxybenzoic Acid 89-86-1
EP 2 292 585 A1
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(continued)
Name CAS #
2-Phenyl-1-propanol 1123-85-9
3-Phenylpropionic Acid 501-52-0
4-Ethoxyphenol 622-62-8
Alpha-Terpineol 98-55-5
Benzaldehyde Dimethylacetal 1125-88-8
Benzyl Ether 103-50-4
Benzyl Formate 104-57-4
Benzyl Salicylate 118-58-1
Cinnamyl Alcohol . 104-54-1
D-(+)-Glucono-1,5-lactone 4253-68-3
D-Isoascorbic Acid 89-65-6
2,3-Naphthalenediol 92-44-4
Diethyl Succinate 123-25-1
Ethyl 2-Aminobenzoate 87-25-2
Ethyl Cinnamate 103-36-6
Ethyl Phenylacetate 101-97-3
Ethyl Salicylate 118-61-6
gamma-Valerolactone 10B-29-2
Hydroquinone Dimethyl Ether 150-78-7
Isocaproic Acid 646-07-1
Isoeugenol 97-54-1
Isopropyl Benzoate 939-48-0
L-(+)-Isoleucine 73-32-5
L-Malic acid 97-67-6
L-2-Aminopropionic Acid 56-41-7
L-Carnitine 541-15-1
L-Glutamine 56-85-9
L-Hydroxyproline 51-35-4
L-Proline 147-85-3
L-Serine 56-45-1
L-Threonine 72-19-5
L-Valine 72-18-4
Phenoxyacetic Acid 122-59-8
Veratrole 91-16-7
2-Ethylbutyric acid 88-09-5
2-Methylpyrazine 109-08-0
o-methoxybenzaldehyde 135-02-4
L-Leucine 61-90-5
EP 2 292 585 A1
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(continued)
Name CAS #
L-Asparagine 70-47-3
propiophenone 93-55-0
5-isopropyl-2-methyl-phenol 499-75-2
Xylitol 87-99-0
ethyl 4-oxopentanoate 539-88-8
methyl cinnamate 103-26-4
cumic alcohol 536-60-7
methyl 2-naphthyl ketone 93-08-3
1-methyl-4-(1-methylethyl)-1,4-Cyclohexadiene 99-85-4
en - ethylene diamine
Caffeine 58-08-2
5-methylfurfural 620-02-0
furfuryl acetate 623-17-6
terpinen-4-ol 10482-56-1
phenylethanal 122-78-1
4-Methoxyacetophenone 100-06-1
D-Fenchone 4695-62-9
1-Methoxy-4-methylbenzene 104-93-8
o-methylanisole 578-58-5
Acetylacetaldehyde dimethyl acetal 5436-21-5
p-methylacetophenone 122-00-9
Methyl phenylacetate 101-41-7
4-Ethoxybenzaldehyde 10031-82-0
p-tolyl acetate 140-33-6
2,6-Dimethoxyphenol 91-10-1
Methyl 2-methoxybenzoate 606-45-1
alpha-methylcinnamaldehyde 101-39-3
2-methoxycinnamaldehyde 60125-24-8
Potassium bicarbonate 298-14-6
piperonyl acetate 326-61-4
2,3-hexanedione 3848-24-6
furfural acetone 623-15-4
trans beta-(2-furyl)acrolein 623-30-3
carveol 99-48-9
Methyl nicotinate 93-60-7
Ethyl benzoylacetate 94-02-0
Methyl 4-methoxybenzoate 121-98-2
Levulinic acid 123-76-2
EP 2 292 585 A1
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(continued)
Name CAS #
m-Dimethoxybenzene 151-10-0
2-acetylpyridine 1122-62-9
tetramethyl-pyrazine 1124-11-4
2,3-dimethyl-pyrazine 5910-89-4
trimethyl-pyrazine 14667-55-1
2-ethyl-3-methyl-pyrazine 15707-23-0
5-Methyl-3H-furan-2-one 591-12-8
2-Methoxy-4-methylphenol 93-51-6
piperazine 110-85-0
2-Methoxy-4-propylphenol 2785-87-7
Naphthalene, 2-(2-methylpropoxy)- 2173-57-1
2-Acetyl-1-methylpyrrole 932-16-1
3,3-Dimethylacrylic acid 541-47-9
Ethyl sorbate 2396-84-1
4-(4-Hydroxyphenyl)-2-butanone 5471-51-2
4-Methoxyphenylacetone 122-84-9
(-)-Myrtenal 564-94-3
3-Phenylpropionaldehyde 104-53-0
1-Phenylethyl propionate 120-45-6
2-Methyltetrahydrofuran-3-one 3185-00-9
Cinnamyl acetate 103-54-8
Styrallyl acetate 93-92-5
Ethyl 4-methoxybenzoate 94-30-4
Benzyl Propionate 122-63-4
Phenylpyruvate 156-06-9
furaneol 3658-77-3
methyl 2-methylbutanoate 868-57-5
Benzeneacetaldehyde, alpha-methyl- 93-53-8
Dimethyl anthranilate 85-91-6
1,1-Dimethoxy-2 -phenylpropane 90-87-9
4-hexanolide 695-06-7
Dimethylbenzylcarbinyl acetate 151-05-3
Benzyl isobutyrate 103-28-6
Acetyl isoeugenol 93-29-8
2-Acetyl-5-methyl furan 1193-79-9
Alpha-methyl-p-isopropylphenylpropanaldehyde 103-95-7
Benzylcarbinyl formate 104-62-1
p-Cresyl alpha-toluate 101-94-0
EP 2 292 585 A1
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(continued)
Name CAS #
Potassium bisulfate 7646-93-7
Potassium carbonate 584-08-7
Potassium chloride 7447-40-7
Potassium hydroxide 1310-58-3
Ethyl tiglate 5837-78-5
Nerol oxide 1786-08-9
DL-Tetrohydrofurfuryl propionate 637-65-0
Benzaldehyde propylene glycol acetal 2568-25-4
2-Methyl-3- (2-furyl) acrolein 874-66-8
vanillin 121-33-5
Cholic acid 81-25-4
R-Carvone 6485-40-1
Potassium nitrate 7757-79-1
Potassium permanganate 7722-64-7
Potassium persulfate 7727-21-1
Potassium phosphate, dibasic 2139900
Potassium Phosphate Monobasic 7778-77-0
Potassium sulfate 7778-80-5
Sodium bicarbonate 144-55-8
Sodium bisulfite 7631-90-5
Sodium carbonate 497-19-8
Sodium chloride 7647-14-5
Sodium dithionite 7775-14-6
Sodium hydroxide 1310-73-2
Sodium nitrite 7632-00-0
Sodium Pyrophosphate 7722-88-5
Sodium sulfate 7757-82-6
Sodium sulfite 7757-83-7
Sodium thiocyanate 540-72-7
Calcium Carbonate 471-34-1
Calcium chloride 10043-52-4
Calcium gluconate 299-28-5
Calcium hydroxide 1305-62-0
Calcium phosphate, dibasic 7757-93-9
Calcium sulfate 7778-18-9
N-Methyl-D-glucamine 6284-40-8
Calcium oxide 1305-78-8
Calcium Phosphate Monobasic 7758-23-8
EP 2 292 585 A1
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(continued)
Name CAS #
Magnesium chloride hexahydrate 7791-18-6
Magnesium sulfate 7487-88-9
Magnesium Sulfate Heptahydrate 10034-99-8
Aluminum chloride hexahydrate 7784-13-6
aluminum nitrate nonahydrate 7784-27-2
Aluminum potassium sulfate, dodecahydrate 7784-24-9
Aluminum sulfate, octadecahydrate 7784-31-8
(S)-(-)-Cysteine 52-90-4
p-Toluenesulfonic Acid 104-15-4
Potassium bitartrate 868-14-4
DL-aspartic acid 617-45-8
p-Dimethylaminobenzaldehyde 100-10-7
Sodium salicylate 54-21-7
Benzoin 119-53-9
Sodium dodecyl sulfate 151-21-3
L-Menthol 2216-51-5
Tiron 149-45-1
Riboflavin 83-88-5
Sodium Acetate Trihydrate 6131-90-4
Disodium Succinate Hexahydrate 6106-21-4
Disodium ethylenediaminetetraacetate dihydrate 6381-92-6
sodium citrate, dihydrate 1545B01
Sodium potassium tartrate, tetrahydrate 6381-59-5
L-(+)-Arginine monohydrochloride 1119-34-2
Ethylenediamine dihydrochloride 333-1B-6
Sodium formate 141-53-7
Sodium acetate 127-09-3
Potassium acetate 127-08-2
Ammonium citrate 3012-65-5
Ammonium bicarbonate 1066-33-7
Ammonium chloride 12125-02-9
Ammonium nitrate 6484-52-2
Ammonium persulfate 7727-54-0
Ammonium sulfate 7783-20-2
Zinc chloride 7646-85-7
Sulfuric acid, zinc salt (1:1), heptahydrate 7446-20-0
Sodium Tripolyphosphate 7758-29-4
ammonium benzoate 1863-63-4
EP 2 292 585 A1
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(continued)
Name CAS #
ammonium bisulfite 10192-30-0
1,5-Naphthalenedisulfonic Acid Disodium Salt 1655-29-4
4-Hydroxybenzoic Acid 99-96-7
Diphenylacetic Acid 117-34-0
Glutaric Acid 110-94-1
L-(-)-Fucose 2438-80-4
L-Cysteine Hydrochloride 52-89-1
L-Histidine Hydrochloride Monohydrate 1880304
o-Toluic Acid 118-90-1
Pivalic Acid 75-98-9
Pyruvic Acid Sodium Salt 113-24-6
Potassium bromide 2139626
Sodium Dithionate Dihydrate 7631-94-9
Sodium Malonate 141-95-7
Trisodium Citrate 68-04-2
Potassium Sodium Tartrate 304-59-6
Potassium Citrate 866-84-2
D-Maltose Monohydrate 6363-53-7
Cyclohexaamylose 10016-20-3
Dodecyl sulfate, lithium salt 2044-56-6
Manganese chloride 2145076
methyl-urea 598-50-5
beta-Cyclodextrin 7585-39-9
Triphosphoric acid, pentapotassium salt 13845-36- 8
lycine ethyl ester Hydrochloride 623-33-6
L-Histidine methyl ester dihydrochloride 7389-87-9
L-Leucine methyl ester hydrochloride 7517-19-3
D-Lysine hydrochloride 7274-88-6
2-Naphthalenesulfonic acid sodium salt 532-02-5
calcium nitrate tetrahydrate 13477-34-4
Vitamin B1 59-43-8
Zinc Acetate Dihydrate 5570-45-6
Potassium fluoride 7789-23-3
Potassium iodate 2139718
Potassium iodide 7681-11-0
Potassium thiocyanate 333-20-0
Sodium bromide 7547-15-6
Sodium fluoride 7681-49-4
EP 2 292 585 A1
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(continued)
Name CAS #
Sodium iodide 7681-82-5
Sodium nitrate 7631-99-4
Calcium acetate 5743-26-0
Trichloroacetic acid 76-03-9
Ammonium acetate 631-61-8
Ammonium fluoride 12125-01-8
DL-malic acid 617-48-1
t-Butyl Alcohol 75-65-0
beta-Alanine 107-95-9
(S)-(-)-Tryptophan 73-22-3
Malonic acid 141-82-2
Phenethylamine 64-04-0
Salicylylaldehyde 90-02-8
Sodium benzoate 532-32-1
Mandelic acid 90-64-2
Calcium pantothenate 137-08-6
Chloroacetic Acid 79-11-8
Ethanol Amine 141-43-5
Salicylic acid 69-72-7
Saccharin sodium 128-44-9
Thiamine hydrochloride 67-03-8
2, 2-Oxybisethanol 111-46-6
Resorcinol 108-46-3
2-Amino-2-(hydroxymethyl)-1,3-propanediol 77-86-1
2,5-Dimethylphenol 95-87-4
Ammonium Phosphate Monobasic 7722-76-1
1,3-Butanediol 107-88-0
Glycolic Acid 79-14-1
Sodium Gluconate 527-07-1
Terephthalic Acid 100-21-0
L-Ascorbic Acid Sodium Salt 134-03-2
3-Acetyl-6-methyl-2,4-pyrandione 520-45-6
Calcium Acetate 62-54-4
Nicotinamide 98-92-0
1-Hydroxy-2-naphthoic Acid 86-48-6
2-Isopropylphenol 88-69-7
4-Aminosalicylic Acid 65-49-6
Calcium Glycerophosphate 27214-00-2
EP 2 292 585 A1
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55
(continued)
Name CAS #
Erythorbic Acid Sodium Salt 7378-23-6
Gluconid Acid Potassium Salt 299-27-4
Orotic Acid 65-86-1
p-Anise Alcohol . 105-13-5
Potassium Benzoate 582-25-2
Taurine 107-35-7
Thiamine Nitrate 532-43-4
3,3,5-Trimethyl-1-cyclohexanol 116-02-9
tert-Butylhydroquinone 1948-33-0
Sulfosalicylic acid 97-05-2
Gallic acid 149-91-7
L-borneol 464-45-9
Isoborneol 124-76-5
2,5-Dihydroxybenzoic acid, Gentisic acid 490-79-9
5-hydroxy-6-methyl-3,4-pyridinedimethanol 65-23-6
Naphthalene-2-sulfonic acid 120-18-3
Ethanesulfonic acid, 2-hydxoxy-, monosodium salt 1562-00-1
Pamoic acid 130-85-8
2,4-Dimethylphenol 105-67-9
3,5-Dihydroxyacetophenone 51863-60-6
Eugenol 97-53-0
n-Butyric Acid 107-92-6
Hydroquinone 123-31-9
Propionic Acid 79-09-4
meta-Phenylenediamine 108-45-2
Oxalic Acid 144-62-7
n-Hexanoic Acid 142-62-1
2-Furancarboxylic Acid 88-14-2
4-Nitroacetanilide 104-04-1
D-(-)-Tartaric Acid 147-71-7
p-Acetamidobenzoic Acid 556-08-1
Galactaric acid 526-99-8
D-glucuronate 1700908
Lactobionic acid 96-82-2
p-Formylacetanilide 122-85-0
2-Mercaptobenzoic acid 147-93-3
Propanoic acid, 2-hydroxy-, calcium salt (2:1) (S)- 28305-25-1
D(+)-10-Camphorsulfonic acid 3144-16-9
EP 2 292 585 A1
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(continued)
Name CAS #
3-Cyclopentylpropionic acid 140-77-2
1R-(-)-Camphorsulfonic acid 35963-20-3
DL-Lysine 70-54-2
Cinnamic acid 621-82-9
Triethanolamine . 102-71-6
Acetic Acid 64-29-7
Dichloroacetic Acid 79-43-6
Diethylamine 109-89-7
Diethylaminoethanol 100-37-8
N-(2-Hydroxyethyl)Morpholine 622-40-2
Octanoic Acid 124-07-2
isobutyric acid 79-31-2
Anisic Acid 100-09-4
Betaine 107-43-7
Enanthoic Acid 111-14-8
Hippuric Acid 495-69-2
Tiglic Acid 80-59-1
Cyclohexanecarboxylic acid 98-89-5
m-Methoxybenzoic acid 586-38-9
D-(+)-Camphoric acid 124-83-4
N-(2-Hydroxyethyl)pyrrolidine 2955-88-6
Name CAS #
Sodium Metabisulfite 7681-57-4
sodium hydrogen phosphate 7558-79-4
Sodium Phosphate Monobasic 7558-80-7
Sodium thiosulfate 7772-98-71
Orthoboric acid 10043-35-3
Diethanolamine 111-42-2
Benzaldehyde 100-52-7
Sorbic acid 110-44-1
L-(+)-Tartaric Acid 87-69-4
D-mannitol 69-65-8
Butyl paraben 94-26-8
Thymol 89-83-8
Methyl salicylate 119-36-8
Citric acid 77-92-9
Creatinine 60-27-5
Vitamin C 50-81-7
EP 2 292 585 A1
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(continued)
Name CAS #
Benzoic Acid 65-85-0
Methyl, 4-hydroxybenzoate 99-76-3
m-Cresol 108-39-4
p-Cresol 106-44-5
Aspirin 50-78-2
Phenol 108-95-2
Sucrose 57-50-1
Potassium citrate, monohydrate 1534146
Sodium acetate 127-09-3
Lactic acid 50-21-5
Propionic acid, sodium salt 65-85
Benzyl alcohol 100-51-6
Phenethyl alcohol 60-12-8
Cholesterol 57-88-5
D-Glucose 50-99-7
Sorbitol 50-70-4
Aspartame 22839-47-0
Saccharin 81-07-2
2,6-Di-tert-Butyl-p-Cresol 128-37-0
4-Chloro-3-methylphenol 59-50-7
glycerin 56-81-5
Propyl paraben 94-13-3
fumaric acid 110-17-8
dabco 250-57-9
p-Phenylenediamine , 106-50-3
Anethole 4180-23-B
propyl gallate 121-79-9
L-monosodium glutamate 142-47-2
Butylated hydroxyanisole 25013-16-5
Cyclohexanol, 5-methyl-2-(1-methylethyl)-, (1alpha,2beta,5alpha)- 89-78-1
alpha-Thioglycerol 96-27-5
Sodium dehydroacetate 4418-26-2
Ethyl 4-hydroxybenzoate 120-47-8
Ethyl Vanillin 121-32-4
Triacetin 102-76-1
Potassium sorbate 590-00-1
Triethyl citrate 77-93-0
(S)-(+)-Arginine 74-79-3
EP 2 292 585 A1
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(continued)
Name CAS #
Glycine 56-40-6
(S)-(-)-Histidine 71-00-1
(S)-(+)-Lysine 56-87-1
Quinone 106-51-4
Naphthalene, 2-ethoxy- 93-18-5
Methanesulfonic Acid 75-75-2
DL-Tartaric Acid 133-37-9
Cyclamic acid 100-88-9
(S)-(-)-Phenylalanine 63-91-2
(S)-(-)-Tyrosine 60-18-4
Carvone 99-49-0
Ethyl butyrate 105-54-4
6-Methyl-5-hepten-2-one 110-93-0
Ethyl acetoacetate 141-97-9
Methyl benzoate 93-58-3
Phenylacetic Acid 103-82-2
Adipic acid 124-04-9
Ethyl benzoate 93-89-0
Benzyl benzoate 120-51-4
Pyruvic acid 127-17-3
Succinic acid 110-15-6
Indole 120-72-9
Methyl anthranilate 134-20-3
Diethyl malonate 105-53-3
Niacin 59-67-6
Meso-inositol 87-89-8
4-Aminobenzoic acid 150-13-0
Anisole 100-66-3
Urea 57-13-6
Pyrrolidine 123-75-1
Cyclopentanone 120-92-3
Acetic anhydride 108-24-7
Benzophenone 119-61-9
D- (-)-Fructose 57-48-7
D-(+)-Xylose 58-86-6
o-Methoxybenzoic Acid 579-75-9
linalool 78-70-6
ethyl isovalerate 108-64-5
EP 2 292 585 A1
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(continued)
Name CAS #
1,1-Azobisformamide 123-77-3
6-Methylcoumarin 92-48-8
acetoin 513-86-0
alpha-Phellandrene 99-83-2
Cymene 99-87-6
Dimethyl Succinate 106-65-0
p-Anisaldehyde 123-11-5
Phenyl ether 101-84-8
Tetrahydro-2-furanmethanol 97-99-4
Valeric Acid 109-52-4
3,4-xylenol 95-65-8
1,1-diethoxyethane 105-57-7
ethyl butyraldehyde 97-96-1
Ethyl crotonate 623-70-1
ethyl isobutyrate 97-62-1
methyl isovalerate 556-24-1
methyl propionate 554-12-1
methyl valeraldehyde 123-15-9
4-(2,6,6-Trimethyl-2-cyclohexen-1-yl)-3-buten-2-one 127-41-3
4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-one 14901-07-6
Maleic acid 110-16-7
3-Methylbutanoic acid 503-74-2
L-Glutamic Acid 56-86-0
D-limonene 5989-27-5
1-Phenyl-1-propanol 93-54-9
2-Hydroxyacetophenone 118-93-4
2,4-Dihydroxybenzoic Acid 89-86-1
2-Phenyl-1-propanol 1123-85-9
3-Phenylpropionic Acid 501-52-0
4-Ethoxyphenol 622-62-8
Alpha-Terpineol 98-55-5
Benzaldehyde Dimethylacetal 1125-88-8
Benzyl Ether 103-50-4
Benzyl Formate 104-57-4
Benzyl Salicylate 118-58-1
Cinnamyl Alcohol 104-54-1
D-(+)-Glucono-1,5-lactone 4253-68-3
D-Isoascorbic Acid 89-65-6
EP 2 292 585 A1
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(continued)
Name CAS #
2,3-Naphthalenediol 92-44-4
Diethyl Succinate 123-25-1
Ethyl 2-Aminobenzoate 87-25-2
Ethyl Cinnamate 103-36-6
Ethyl Phenylacetate 101-97-3
Ethyl Salicylate 118-61-6
gamma-Valerolactone 108-29-2
Hydroquinone Dimethyl Ether 150-78-7
Isocaproic Acid 646-07-1
Isoeugenol 97-54-1
Isopropyl Benzoate 939-48-0
L-(+)-Isoleucine 73-32-5
L-Malic acid 97-67-6
L-2-Aminopropionic Acid 56-41-7
L-Carnitine 541-15-1
L-Glutamine 56-85-9
L-Hydroxyproline 51-35-4
L-Proline 147-85-3
L-Serine 56-45-1
L-Threonine 72-19-5
L-Valine 72-18-4
Phenoxyacetic Acid 122-59-8
Veratrole 91-16-7
2-Ethylbutyric acid 88-09-5
2-Methylpyrazine 109-08-0
o-methoxybenzaldehyde 135-02-4
L-Leucine 61-90-5
L-Asparagine 70-47-3
propiophenone 93-55-0
5-isopropyl-2-methyl-phenol 499-75-2
Xylitol 87-99-0
ethyl 4-oxopentanoate 539-88-8
methyl cinnamate 103-26-4
cumic alcohol 536-60-7
methyl 2-naphthyl ketone 93-08-3
1-methyl-4-(1-methylethyl)-1,4-Cyclohexadiene 99-85-4
en - ethylene diamine
Caffeine 58-08-2
EP 2 292 585 A1
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(continued)
Name CAS #
5-methylfurfural 620-02-0
furfuryl acetate 623-17-6
terpinen-4-ol 10482-56-1
phenylethanal 122-78-1
4-Methoxyacetophenone 100-06-1
D-Fenchone 4695-62-9
1-Methoxy-4-methylbenzene 104-93-8
o-methylanisole 578-58-5
Acetylacetaldehyde dimethyl acetal 5436-21-5
p-methylacetophenone 122-00-9
Methyl phenylacetate 101-41-7
44-Ethoxybenzaldehyde 10031-82-0
p-tolyl acetate 140-39-6
2,6-Dimethoxyphenol 91-10-1
Methyl 2-methoxybenzoate 606-45-1
alpha-methylcinnamaldehyde 101-39-3
2-methoxycinnamaldehyde 60125-24-8
Potassium bicarbonate 298-14-6
piperonyl acetate 326-61-4
2,3-hexanedione 3848-24-6
furfural acetone 623-15-4
trans beta-(2-furyl)acrolein 623-30-3
carveol 99-48-9
Methyl nicotinate 93-60-7
Ethyl benzoylacetate 94-02-0
Methyl 4-methoxybenzoate 121-98-2
Levulinic acid 123-76-2
m-Dimethoxybenzene 151-10-0
2-acetylpyridine 1122-62-9
tetramethyl-pyrazine 1124-11-4
2,3-dimethyl-pyrazine 5910-89-4
trimethyl-pyrazine 14667-55-1
2-ethyl-3-methyl-pyrazine 15707-23-0
5-Methyl-3H-furan-2-one 591-12-8
2-Methoxy-4-methylphenol 93-51-6
piperazine 110-85-0
2-Methoxy-4-propylphenol 2785-87-7
Naphthalene, 2-(2-methylpropoxy)- 2173-57-1
EP 2 292 585 A1
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(continued)
Name CAS #
2-Acetyl-1-methylpyrrole 932-16-1
3,3-Dimethylacrylic acid 541-47-9
Ethyl sorbate 2396-84-1
4-(4-Hydroxyphenyl)-2-butanone 5471-51-2
4-Methoxyphenylacetone 122-84-9
(-)-Myrtenal 564-94-3
3-Phenylpropionaldehyde 104-53-0
1-Phenylethyl propionate 120-45-6
2-Methyltetrahydrofuran-3-one 3188-00-9
Cinnamyl acetate 103-54-8
Styrallyl acetate 93-92-5
Ethyl 4-methoxybenzoate 94-30-4
Benzyl propionate 122-63-4
Phenylpyruvate 156-06-9
furaneol 3658-77-3
methyl 2-methylbutanoate 868-57-5
Benzeneacetaldehyde, alpha-methyl- 93-53-8
Dimethyl anthranilate 85-91-6
1,1-Dimethoxy-2-phenylpropane 90-87-9
4-hexanolide 695-06-7
Dimethylbenzylcarbinyl acetate 151-05-3
Benzyl isobutyrate 103-28-6
Acetyl isoeugenol 93-29-8
2-Acetyl-5-methyl furan 1193-79-9
Alpha-methyl-p-isopropylphenylpropanaldehyde 103-95-7
Benzylcarbinyl formate 104-62-1
P-Cresyl alpha-toluate 101-94-0
Potassium bisulfate 7646-93-7
Potassium carbonate 584-08-7
Potassium chloride 7447-40-7
Potassium hydroxide 1310-58-3
Ethyl tiglate 5837-78-5
Nerol oxide 1786-08-9
DL-Tetrohydrofurfuryl propionate 637-65-0
Benzaldehyde propylene glycol acetal 2568-25-4
2-Methyl-3-(2-furyl) acrolein 874-66-8
vanillin 121-33-5
Cholic acid 81-25-4
EP 2 292 585 A1
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(continued)
Name CAS #
R-Carvone 6485-40-1
Potassium nitrate 7757-79-1
Potassium permanganate 7722-64-7
Potassium persulfate 7727-21-1
Potassium phosphate, dibasic 2139900
Potassium Phosphate Monobasic 7778-77-0
Potassium sulfate 7778-80-5
Sodium bicarbonate 144-55-8
Sodium bisulfite 7631-90-5
Sodium carbonate 497-19-8
Sodium chloride 7647-14-5
Sodium dithionite 7775-14-6
Sodium hydroxide 1310-73-2
Sodium nitrite 7632-00-0
Sodium Pyrophosphate 7722-88-5
Sodium sulfate 7757-82-6
Sodium sulfite 7757-83-7
Sodium thiocyanate 540-72-7
Calcium Carbonate 471-34-1
Calcium chloride 10043-52-4
Calcium gluconate 299-28-5
Calcium hydroxide 1305-62-0
Calcium phosphate, dibasic 7757-93-9
Calcium sulfate 7778-18-9
N-Methyl-D-glucamine 6284-40-8
Calcium oxide 1305-78-8
Calcium Phosphate Monobasic 7758-23-8
Magnesium chloride hexahydrate 7791-18-6
Magnesium sulfate 7487-88-9
Magnesium Sulfate Heptahydrate 10034-99-8
Aluminum chloride hexahydrate 7784-13-6
aluminum nitrate nonahydrate 7784-27-2
Aluminum potassium sulfate, dodecahydrate 7784-24-9
Aluminum sulfate, octadecahydrate 7784-31-8
(s)-(-)-cysteine 52-90-4
p-Toluenesulfonic Acid 104-15-4
Potassium bitartrate 868-14-4
DL-aspartic acid 617-45-8
EP 2 292 585 A1
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(continued)
Name CAS #
p-Dimethylaminobenzaldehyde 100-10-7
Sodium salicylate 54-21-7
Benzoin 119-53-9
Sodium dodecyl sulfate 151-21-3
L-Menthol 2216-51-5
Tiron 149-45-1
Riboflavin 83-88-5
Sodium Acetate Trihydrate 6131-90-4
Disodium Succinate Hexahydrate 6106-21-4
Disodium ethylenediaminetetraacetate dihydrate 6381-92-6
sodium citrate, dihydrate 1545801
Sodium potassium tartrate, tetrahydrate 6381-59-5
L-(+)-Arginine monohydrochloride 1119-34-2
Ethylenediamine dihydrochloride 333-18-6
Sodium formate 141-53-7
Sodium acetate 127-09-3
Potassium acetate 127-08-2
Ammonium citrate 3012-65-5
Ammonium bicarbonate 1066-33-7
Ammonium chloride 12125-02-9
Ammonium nitrate 6484-52-2
Ammonium persulfate 7727-54-0
Ammonium sulfate 7783-20-2
Zinc chloride 7646-85-7
Sulfuric acid, zinc salt (1:1), heptahydrate 7446-20-0
Sodium Tripolyphosphate 7758-29-4
ammonium benzoate 1863-63-4
ammonium bisulfite 10192-30-0
1,5-Naphthalenedisulfonic Acid Disodium Salt 1655-29-4
4-Hydroxybenzoic Acid 99-96-7
Diphenylacetic Acid 117-34-0
Glutaric Acid 110-94-1
L-(-)-Fucose 2438-80-4
L-Cysteine Hydrochloride 52-89-1
L-Histidine Hydrochloride Monohydrate 1880304
o-Toluic Acid 118-90-1
Pivalic Acid 75-98-9
Pyruvic Acid Sodium Salt 113-24-6
EP 2 292 585 A1
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(continued)
Name CAS #
Potassium bromide 2139626
Sodium Dithionate Dihydrate 7631-94-9
Sodium Malonate 141-95-7
Trisodium Citrate 68-04-2
Potassium Sodium Tartrate 304-59-6
Potassium Citrate 866-84-2
D-Maltose Monohydrate 6363-53-7
Cyclohexaamylose 10016-20-3
Dodecyl sulfate, lithium salt 2044-56-6
Manganese chloride 2145076
methyl-urea 598-50-5
beta-Cyclodextrin 7585-39-9
Triphosphoric acid, pentapotassium salt 13845-36-8
Glycine ethyl ester hydrochloride 623-33-6
L-Histidine methyl ester dihydrochloride 7389-87-9
L-Leucine methyl ester hydrochloride 7517-19-3
D-Lysine hydrochloride 7274-88-6
2-Naphthalenesulfonic acid sodium salt 532-02-5
calcium nitrate tetrahydrate 13477-34-4
Vitamin B1 59-43-8
Zinc Acetate Dihydrate 5970-45-6
Potassium fluoride 7789-23-3
Potassium iodate 2139718
Potassium iodide 7681-11-0
Potassium thiocyanate 333-20-0
Sodium bromide 7647-15-6
Sodium fluoride 7681-49-4
Sodium iodide 7681-82-5
Sodium nitrate 7631-99-4
Calcium acetate 5743-26-0
Trichloroacetic acid 76-03-9
Ammonium acetate 631-61-8
Ammonium fluoride 12125-01-8
DL-malic acid 617-48-1
t-Butyl Alcohol 75-65-0
beta-Alanine 107-95-9
(S)-(-)-Tryptophan 73-22-3
Malonic acid 141-82-2
EP 2 292 585 A1
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(continued)
Name CAS #
Phenethylamine 64-04-0
Salicylylaldehyde 90-02-8
Sodium benzoate 532-32-1
Mandelic acid 90-64-2
Calcium pantothenate 137-08-6
Chloroacetic Acid 79-11-8
Ethanol Amine 141-43-5
Salicylic acid 69-72-7
Saccharin sodium 128-44-9
Thiamine hydrochloride 67-03-8
2,2-Oxybisethanol 111-46-6
Resorcinol 108-46-3
2-Amino-2-(hydroxymethyl)-1,3-propanediol 77-86-1
2,5-Dimethylphenol 95-87-4
Ammonium Phosphate Monobasic 7722-76-1
1,3-Butanediol 107-88-0
Glycolic Acid 79-14-1
Sodium Gluconate 527-07-1
Terephthalic Acid 100-21-0
L-Ascorbic Acid Sodium Salt 134-03-2
3-Acetyl-6-methyl-2,4-pyrandione 520-45-6
Calcium Acetate 62-54-4
Nicotinamide 98-92-0
1-Hydroxy-2-naphthoic Acid 86-48-6
2-Isopropylphenol 88-69-7
4-Aminosalicylic Acid 65-49-6
Calcium Glycerophosphate 27214-00-2
Erythorbic Acid Sodium Salt 7378-23-6
Gluconic Acid Potassium Salt 299-27-4
Orotic Acid 65-86-1
p-Anise Alcohol 105-13-5
Potassium Benzoate 582-25-2
Taurine 107-35-7
Thiamine Nitrate 532-43-4
3,3,5-Trimethyl-1-cyclohexanol 116-02-9
tert-Butylhydroquinone 1948-33-0
Sulfosalicylic acid 97-05-2
Gallic acid 149-91-7
EP 2 292 585 A1
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55
(continued)
Name CAS #
L-borneol 464-45-9
Isoborneol 124-76-5
2,5-Dihydroxybenzoic acid, Gentisic acid 490-79-9
5-hydroxy-6-methyl-3,4-pyridinedimethanol 65-23-6
Naphthalene-2-sulfonic acid 120-18-3
Ethanesulfonic acid, 2-hydroxy-, monosodium salt 1562-00-1
Pamoic acid 130-85-8
2,4-Dimethylphenol 105-67-9
3,5-Dihydroxyacetophenone 51863-60-6
Eugenol 97-53-0
n-Butyric Acid 107-92-6
Hydroquinone 123-31-9
Propionic Acid 79-09-4
meta-Phenylenediamine 108-45-2
Oxalic Acid 144-62-7
n-Hexanoic Acid 142-62-1
2-Furancarboxylic Acid 88-14-2
4 -Nitroacetanilide 104-04-1
D- (-) -Tartaric Acid 147-71-7
p-Acetamidobenzoic Acid 556-08-1
Galactaric acid 526-99-8
D-glucuronate 1700908
Lactobionic acid 96-82-2
p-Formylacetanilide 122-85-0
2-Mercaptobenzoic acid 147-93-3
Propanoic acid, 2-hydroxy-, calcium salt (2:1), (S)- 28305-25-1
D(+)-10-Camphorsulfonic acid 3144-16-9
3-Cyclopentylpropionic acid 140-77-2
1R-(-)-Camphorsulfonic acid 35963-20-3
DL-Lysine 70-54-2
Cinnamic acid 621-82-9
Triethanolamine 102-71-6
Acetic Acid 64-19-7
Dichloroacetic Acid 79-43-6
Diethylamine 109-89-7
Diethylaminoethanol 100-37-8
N-(2-Hydroxyethyl)Morpholine 622-40-2
Octanoic Acid 124-07-2
EP 2 292 585 A1
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(continued)
Name CAS #
isobutyric acid 79-31-2
Anisic Acid 100-09-4
Betaine 107-43-7
Enanthoic Acid 111-14-8
Hippuric Acid 495-69-2
Tiglic Acid 80-59-1
Cyclohexanecarboxylic acid 98-89-5
m-Methoxybenzoic acid 586-38-9
D-(+)-Cainphoric acid 124-83-4
N-(2-Hydroxyethyl)pyrrolidine 2955-88-6
Name CAS #
Sodium Metabisulfite 7681-57-4
sodium hydrogen phosphate 7558-79-4
Sodium Phosphate Monobasic 7558-80-7
Sodium thiosulfate 7772-98-71
Orthoboric acid 10043-35-3
Diethanolamine 111-42-2
Benzaldehyde 100-52-7
Sorbic acid 110-44-1
L-(+)-Tartaric Acid 87-69-4
D-mannitol 69-65-8
Butyl paraben 94-26-8
Thymol 89-83-8
Methyl salicylate 119-36-8
Citric acid 77-92-9
Creatinine 60-27-5
Vitamin C 50-81-7
Benzoic Acid 65-85-0
Methyl 4-hydroxybenzoate 99-76-3
m-Cresol 108-39-4
p-Cresol 106-44-5
Aspirin 50-78-2
Phenol 108-95-2
Sucrose 57-50-1
Potassium citrate, monohydrate 1534146
Sodium acetate 127-09-3
Lactic acid 50-21-5
Propionic acid, sodium salt 65-85
EP 2 292 585 A1
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(continued)
Name CAS #
Benzyl alcohol 100-51-6
Phenethyl alcohol 60-12-8
Cholesterol 57-88-5
D-Glucose 50-99-7
Sorbitol 50-70-4
Aspartame 22839-47-0
Saccharin 81-07-2
2,6-Di-tert-Butyl-p-Cresol 128-37-0
4-Chloro-3-methylphenol 59-50-7
glycerin 56-81-5
Propyl paraben 94-13-3
fumaric acid 110-17-8
dabco 280-57-9
p-Phenylenediamine 106-50-3
Anethole 4180-23-8
propyl gallate 121-79-9
L-monosodium glutamate 142-47-2
Butylated hydroxyanisole 25013-16-5
Cyclohexanol, 5-methyl-2-(1-methylethyl)-, (1alpha,2beta,5alpha)- 89-78-1
alpha-Thioglycerol 96-27-5
Sodium dehydroacetate 4418-26-2
Ethyl 4-hydroxybenzoate 120-47-8
Ethyl Vanillin 121-32-4
Triacetin 102-76-1
Potassium sorbate 590-00-1
Triethyl citrate 77-93-0
(S)-(+)-Arginine 74-79-3
Glycine 56-40-6
(S)-(-)-Histidine 71-00-1
(S)-(+)-Lysine 56-87-1
Quinone 106-51-4
Naphthalene, 2-ethoxy- 93-18-5
Methanesulfonic Acid 75- 75-2
DL-Tartaric Acid 133 -37-9
Cyclamic acid 100-88-9
(S)-(-)-Phenylalanine 63- 91-2
(S)-(-)-Tyrosine 60- 18-4
Carvone 99- 49-0
EP 2 292 585 A1
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(continued)
Name CAS #
Ethyl butyrate 105-54-4
6-Methyl-5-hepten-2-one 110-93-0
Ethyl acetoacetate 141-97-9
Methyl benzoate 93-58-3
Phenylacetic Acid 103-82-2
Adipic acid 124-04-9
Ethyl benzoate 93-89-0
Benzyl benzoate 120-51-4
Pyruvic acid 127-17-3
Succinic acid 110-15-6
Indole 120-72-9
Methyl anthranilate 134-20-3
Diethyl malonate 105-53-3
Niacin 59-67-6
Meso-inositol 87-89-8
4-Aminobenzoic acid 150-13-0
Anisole 100-66-3
Urea 57-13-6
Pyrrolidine 123-75-1
Cyclopentanone 120-92-3
Acetic anhydride 108-24-7
Benzophenone 119-61-9
D-(-)-Fructose 57-48-7
D-(+)-Xylose 58-86-6
o-Methoxybenzoic Acid 579-75-9
linalool 78-70-6
ethyl isovalerate 108-64-5
1,1-Azobisformamide 123-77-3
6-Methylcoumarin 92-48-8
acetoin 513-86-0
alpha-Phellandrene 99-83-2
Cymene 99-87-6
Dimethyl Succinate 106-65-0
p-Anisaldehyde 123-11-5
Phenyl ether 101-84-8
Tetrahydro-2-furanmethanol 97-99-4
Valeric Acid 109-52-4
3,4-xylenol 95-65-8
EP 2 292 585 A1
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(continued)
Name CAS #
1,1-diethoxyethane 105-57-7
ethyl butyraldehyde 97-96-1
Ethyl crotonate 623-70-1
ethyl isobutyrate 97-62-1
methyl isovalerate 556-24-1
methyl propionate 554-12-1
methyl valeraldehyde 123-15-9
4-(2,6,6-Trimethyl-2-cyclohexen-1-yl)-3-buten-2-one 127-41-3
4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-one 14901-07-6
Maleic acid 110-16-7
3-Methylbutanoic acid 503-74-2
L-Glutamic Acid 56-86-0
D-limonene 5989-27-5
1-Phenyl-1-propanol 93-54-9
2-Hydroxyacetophenone 118-93-4
2,4-Dihydroxybenzoic Acid 89-86-1
2-Phenyl-1-propanol 1123-85-9
3-Phenylpropionic Acid 501-52-0
4-Ethoxyphenol 622-62-8
Alpha-Terpineol 98-55-5
Benzaldehyde Dimethylacetal 1125-88-8
Benzyl Ether 103-50-4
Benzyl Formate 104-57-4
Benzyl Salicylate 118-58-1
Cinnamyl Alcohol 104-54-1
D-(+)-Glucono-1,5-lactone 4253-68-3
D-Isoascorbic Acid 89-65-6
2,3-Naphthalenediol 92-44-4
Diethyl Succinate 123-25-1
Ethyl 2-Aminobenzoate 87-25-2
Ethyl Cinnamate 103-36-6
Ethyl Phenylacetate 101-97-3
Ethyl Salicylate 118-61-6
gamma-Valerolactone 108-29-2
Hydroquinone Dimethyl Ether 150-78-7
Isocaproic Acid 646-07-1
Isoeugenol 97-54-1
Isopropyl Benzoate 939-48-0
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(continued)
Name CAS #
L-(+)-Isoleucine 73-32-5
L-Malic acid 97-67-6
L-2-Aminopropionic Acid 56-41-7
L-Carnitine 541-15-1
L-Glutamine 56-85-9
L-Hydroxyproline 51-35-4
L-Proline 147-85-3
L-Serine 56-45-1
L-Threonine 72-19-5
L-Valine 72-18-4
Phenoxyacetic Acid 122-59-8
Veratrole 91-16-7
2-Ethylbutyric acid 88-09-5
2-Methylpyrazine 109-08-0
o-methoxybenzaldehyde 135-02-4
L-Leucine 61-90-5
L-Asparagine 70-47-3 ,
propiophenone 93-55-0
5-isopropyl-2-methyl-phenol 499-75-2
Xylitol 87-99-0
ethyl 4-oxopentanoate 539-88-8
methyl cinnamate 103-26-4
cumic alcohol 536-60-7
methyl 2-naphthyl ketone 93-08-3
1-methyl-4-(1-methylethyl)-1,4-Cyclohexadiene 99-85-4
en - ethylene diamine
Caffeine 58-08-2
5-methylfurfural 620-02-0
furfuryl acetate 623-17-6
terpinen-4-ol 10482-56-1
phenylethanal 122-78-1
4-Methoxyacetophenone 100-06-1
D-Fenchone 4695-62-9
1-Methoxy-4-methylbenzene 104-93-8
o-methylanisole 578-58-5
Acetylacetaldehyde dimethyl acetal 5436-21-5
p-methylacetophenone 122-00-9
Methyl phenylacetate 101-41-7
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(continued)
Name CAS #
4-Ethoxybenzaldehyde 10031-82-0
p-tolyl acetate 140-39-6
2,6-Dimethoxyphenol 91-10-1
Methyl 2-methoxybenzoate 606-45-1
alpha-methylcinnamaldehyde 101-39-3
2-methoxycinnamaldehyde 60125-24-8
Potassium bicarbonate 298-14-6
piperonyl acetate 326-61-4
2,3-hexanedione 3848-24-6
furfural acetone 623-15-4
trans beta-(2-furyl)acrolein 623-30-3
carveol 99-48-9
Methyl nicotinate 93-60-7
Ethyl benzoylacetate 94-02-0
Methyl 4-methoxybenzoate 121-98-2
Levulinic acid 123-76-2
m-Dimethoxybenzene 151-10-0
2-acetylpyridine 1122-62-9
tetramethyl-pyrazine 1124-11-4
2,3-dimethyl-pyrazine 5910-89-4
trimethyl-pyrazine 14667-55-1
2-ethyl-3-methyl-pyrazine 15707-23-0
5-Methyl-3H-furan-2-one 591-12-8
2-Methoxy-4-methylphenol 93-51-6
piperazine 110-85-0
2-Methoxy-4-propylphenol 2785-87-7
Naphthalene, 2-(2-methylpropoxy)- 2173-57-1
2-Acetyl-1-methylpyrrole 932-16-1
3,3-Dimethylacrylic acid 541-47-9
Ethyl sorbate 2396-84-1
4-(4-Hydroxyphenyl)-2-butanone 5471-51-2
4-Methoxyphenylacetone 122-84-9
(-)-Myrtenal 564-94-3
3-Phanylpropionaldehyde 104-53-0
1-Phenylethyl propionate 120-45-6
2-Methyltetrahydrofuran-3-one 3188-00-9
Cinnamyl acetate 103-54-8
Styrallyl acetate 93-92-5
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(continued)
Name CAS #
Ethyl 4-methoxybenzoate 94-30-4
Benzyl propionate 122-63-4
Phenylpyruvate 156-06-9
furaneol 3658-77-3
methyl 2-methylbutanoate 868-57-5
Benzeneacetaldehyde, alpha-methyl- 93-53-8
Dimethyl anthranilate 85-91-6
1,1-Dimethoxy-2-phenylpropane 90-87-9
4-hexanolide 695-06-7
Dimethylbenzylcarbinyl acetate 151-05-3
Benzyl isobutyrate 103-28-6
Acetyl isoeugenol 93-29-8
2-Acetyl-5-methyl furan 1193-79-9
Alpha-methyl-p-isopropylphenylpropanaldehyde 103-95-7
Benzylcarbinyl formate 104-62-1
p-cresyl alpha-toluate 101-54-0
Potassium bisulfate 7646-93-7
Potassium carbonate 584-08-7
Potassium chloride 7447-40-7
Potassium hydroxide 1310-58-3
Ethyl tiglate 5837-78-5
Nerol oxide 1786-08-9
DL-Tetrohydrofurfuryl propionate 637-65-0
Benzaldehyde propylene glycol acetal 2568-25-4
2-Methyl-3-(2-furyl) acrolein 874-66-8
vanillin 121-33-5
Cholic acid 81-25-4
R-Carvone 6485-40-1
Potassium nitrate 7757-79-1
Potassium permanganate 7722-64-7
Potassium persulfate 7727-21-1
Potassium phosphate, dibasic 2139900
Potassium Phosphate Monobasic 7778-77-0
Potassium sulfate 7778-80-5
Sodium bicarbonate 144-55-8
Sodium bisulfite 7631-90-5
Sodium carbonate 497-19-8
Sodium chloride 7647-14-5
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(continued)
Name CAS #
Sodium dithionite 7775-14-6
Sodium hydroxide 1310-73-2
Sodium nitrite 7632-00-0
Sodium Pyrophosphate 7722-85-5
Sodium sulfate 7757-82-6
Sodium sulfite 7757-83-7
Sodium thiocyanate 540-72-7
Calcium Carbonate 471-34-1
Calcium chloride 10043-52-4
Calcium gluconate 299-28-5
Calcium hydroxide 1305-62-0
Calcium phosphate, dibasic 7757-93-9
Calcium sulfate 7778-18-9
N-Methyl-D-glucamine 6284-40-8
Calcium oxide 1305-78-8
Calcium Phosphate Monobasic 7758-23-8
Magnesium chloride hexahydrate 7791-18-6
Magnesium sulfate 7487-88-9
Magnesium Sulfate Heptahydrate 10034-99-8
Aluminum chloride hexahydrate 7784-13-6
aluminum nitrate nonahydrate 7784-27-2
Aluminum potassium sulfate, dodecahydrate 7784-24-9
Aluminum sulfate, octadecahydrate 7784-31-8
(S)-(-)-Cysteine 52-90-4
p-Toluenesulfonic Acid 104-15-4
Potassium bitartrate 868-14-4
DL-aspartic acid 617-45-8
p-Dimethylaminobenzaldehyde 100-10-7
Sodium salicylate 54-21-7
Benzoin 119-53-9
Sodium dodecyl sulfate 151-21-3
L-Menthol 2216-51-5
Tiron 149-45-1
Riboflavin 83-83-5
Sodium Acetate Trihydrate 6131-90-4
Disodium Succinate Hexahydrate 6106-21-4
Disodium ethylenediaminetetraacetate dihydrate 6381-92-6
sodium citrate, dihydrate 1545801
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(continued)
Name CAS #
Sodium potassium tartrate, tetrahydrate 6381-59-5
L- (+)-Arginine monohydrochloride 1119-34-2
Ethylenediamine dihydrochloride 333-18-6
Sodium formate 141-53-7
Sodium acetate 127-09-3
Potassium acetate 127-08-2
Ammonium citrate 3012-65-5
Ammonium bicarbonate 1066-33-7
Ammonium chloride 12125-02-9
Ammonium nitrate 6484-52-2
Ammonium persulfate 7727-54-0
Ammonium sulfate 7783-20-2
Zinc chloride 7646-85-7
Sulfuric acid, zinc salt (1:1), heptahydrate 7446-20-0
Sodium Tripolyphosphate 7758-29-4
ammonium benzoate 1363-63-4
ammonium bisulfite 10192-30-0
1,5-Naphthalenedisulfonic Acid Disodium Salt 1655-29-4
4-Hydroxybenzoic Acid 99-96-7
Diphenylacetic Acid 117-34-0
Glutaric Acid 110-94-1
L-(-)-Fucose 2438-80-4
L-Cysteine Hydrochloride 52-89-1
L-Histidine Hydrochloride Monohydrate 1880304
o-Toluic Acid 118-90-1
Pivalic Acid 75-98-9
Pyruvic Acid Sodium Salt 113-24-6
Potassium bromide 2139626
Sodium Dithionate Dihydrate 7631-94-9
Sodium Malonate 141-95-7
Trisodium Citrate 68-04-2
Potassium Sodium Tartrate 304-59-6
Potassium Citrate 866-84-2
D-Maltose Monohydrate 6363-53-7
Cyclohexaamylose 10016-20-3
Dodecyl sulfate, lithium salt 2044-56-6
Manganese chloride 2145076
methyl-urea 598-50-5
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(continued)
Name CAS #
beta-Cyclodextrin 7585-39-9
Triphosphoric acid, pentapotassium salt 1384S-35-8
Glycine ethyl ester hydrochloride 623-33-6
L-Histidine methyl ester dihydrochloride 7389-87-9
L-Leucine methyl ester hydrochloride 7517-19-3
D-Lysine hydrochloride 7274-88-6
2-Naphthalenesulfonic acid sodium salt 532-02-5
calcium nitrate tetrahydrate 13477-34-4
Vitamin B1 59-43-8
Zinc Acetate Dihydrate 5970-45-6
Potassium fluoride 7789-23-3
Potassium iodate 2139718
potassium iodide 7681-11-0
Potassium thiocyanate 333-20-0
Sodium bromide 7647-15-6
Sodium fluoride 7681-49-4
Sodium iodide 7681-82-5
Sodium nitrate 7631-99-4
Calcium acetate 5743-26-0
Trichloroacetic acid 76-03-9
Ammonium acetate 631-61-8
Ammonium fluoride 12125-01-8
DL-malic acid 617-48-1
t-Butyl Alcohol 75-65-0
beta-Alanine 107-95-9
(S)-(-)-Tryptophan 73-22-3
Malonic acid 141-82-2
Phenethylamine 64-04-0
Salicylylaldehyde 90-02-8
Sodium benzoate 532-32-1
Mandelic acid 90-64-2
Calcium pantothenate 137-08-6
Chloroacetic Acid 79-11-8
Ethanol Amine 141-43-5
Salicylic acid 69-72-7
Saccharin sodium 128-44-9
Thiamine hydrochloride 67-03-8
2,2-Oxybisethanol 111-46-6
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(continued)
Name CAS #
Resorcinol 108-46-3
2-Amino-2-(hydroxymethyl)-1,3-propanediol _ 77-86-1
2,5-Dimethylphenol 95-87-4
Ammonium Phosphate Monobasic 7722-76-1
1,3-Butanediol 107-88-0
Glycolic Acid 79-14-1
Sodium Gluconate 527-07-1
Terephthalic Acid 100-21-0
L-Ascorbic Acid Sodium Salt 134-03-2
3-Acetyl-6-methyl-2,4-pyrandione 520-45-6
Calcium Acetate 62-54-4
Nicotinamide 98-92-0
1-Hydroxy-2-naphthoic Acid 86-48-6
2-Isopropy-lphenol 88-69-7
4-Aminosalicylic Acid 65-49-6
Calcium Glycerophosphate 27214-00-2
Erythorbic Acid Sodium Salt 7378-23-6
Gluconic Acid Potassium Salt 299-27-4
Orotic Acid 65-86-1
p-Anise Alcohol 105-13-5
Potassium Benzoate 582-25-2
Taurine 107-35-7
Thiamine Nitrate 532-43-4
3,3,5-Trimethyl-1-cyclohexanol 116-02-9
tart-Butylhydroquinone 1948-33-0
Sulfosalicylic acid 97-05-2
Gallic acid 149-91-7
L-borneol 464-45-9
Isoborneol 124-76-5
v2,5-Dihydroxybenzoic acid, Gentisic acid 490-79-9
5-hydroxy-6-methyl-3,4-pyridinedimethanol 65-23-6
Naphthalene-2-sulfonic acid 120-18-3
Ethanesulfonic acid, 2-hydroxy-, monosodium salt 1562-00-1
Pamoic acid 130-85-8
2,4-Dimethylphenol 105-67-9
3,5-Dihydroxyacetophenone 51863-60-6
Eugenol 97-53-0
n-Butyric Acid 107-92-6
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(continued)
Name CAS #
Hydroquinone 123-31-9
Propionic Acid 79-09-4
meta-Phenylenediamine 108-45-2
Oxalic Acid 144-62-7
n-Hexanoac Acid 142-62-1
2-Furancarboxylic Acid 88-14-2
4-Nitroacetanilide 104-04-1
D-(-)-Tartaric Acid 147-71-7
p-Acetamidobenzoic Acid 556-08-1
Galactaric acid 526-99-8
D-glucuronate 1700908
Lactobionic acid 96-82-2
p-Formylacetanilide 122-85-0
2-Mercaptobenzoic acid 147-93-3
Propanoic acid, 2-hydroxy-, calcium salt (2:1), (S) - 28305-25-1
D(+)-10-Camphorsulfonic acid 3144-16-9
3-Cyclopentylpropionic acid 140-77-2
1R-(-)-Camphorsulfonic acid 35963-20-3
DL-Lysine 70-54-2
Cinnamic acid 621-82-9
Triethanolamine 102-71-6
Acetic Acid 64-19-7
Dichloroacetic Acid 79-43-6
Diethylamine 109-89-7
Diethylaminoethanol 100-37-8
N-(2-Hydroxyethyl)Morpholine 622-40-2
Octanoic Acid 124-07-2
isobutyric acid 79-31-2
Anisic Acid 100-09-4
Betaine 107-43-7
Enanthoic Acid 111-14-8
Hippuric Acid 495-69-2
Tiglic Acid 80-59-1
Cyclohexanecarboxylic acid 98-89-5
m-Methoxybenzoic acid 586-38-9
D- (+) -Camphoric acid 124-83-4
N- (2-Hydroxyethyl)pyrrolidine 2955-88-6
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[0225] Further aspects of the invention refer to:
1. A method of screening a chemical substance for possible solid forms, said method comprising the steps of:
preparing a first sample comprising a chemical substance in a first solvent; preparing a second sample comprising
the chemical substance in a second solvent; sonicating the first and second samples; and solidifying the chemical
substance from the first and second samples.
2. The method of aspect 1, wherein the solidifying step and the sonicating step at least partially overlap.
3. The method of aspect 1, wherein at least one of said solvents is selected from the group consisting of acetone,
acetonitrile, chloroform, dioxane, ethanol, ethyl acetate, heptane, butanone, methanol, nitromethane, tetrahydro-
furan, toluene, water, dichloromethane, diethyl ether, isopropyl ether, cyclohexane, methylcyclohexane, isopropyl
alcohol, isopropyl acetate, trimethylpentane, n-octane, trichloroethane, trifluoroethanol, pyridine, propanol, butanol,
tetrachloroethylene, chlorobenzene, xylene, dibutyl ether, methyl-tert-butyl ether, tetrachloroethane, p-cymene,
dimethyl sulfoxide, formamide, and dimethylformamide.
4. The method of aspect 1, wherein the first solvent comprises a mixture of solvents.
5. The method of aspect 4, wherein the second solvent comprises a mixture of solvents.
6. The method of aspect 1, wherein at least one of the samples is a solution having a viscosity greater than about
10 cPoise before the solution is sonicated.
7. The method of aspect 1, wherein the samples are provided by preparing a solution from an amorphous solid
comprising the chemical substance.
8. The method of aspect 7, wherein the solvent is sonicated while the amorphous solid is added to the solvent.
9. The method of aspect 1, wherein at least one of the samples is an emulsion comprising two or more substantially
immiscible solvents and the chemical substance.
10. The method of aspect 1, wherein at least one of the samples is a slurry comprising a solvent and the chemical
substance.
11. The method of aspect 1, comprising providing a plurality of subsamples of said first sample, and wherein a first
portion of the subsamples are subjected to relatively slow evaporation, and a second portion of the subsamples are
subjected to relatively fast evaporation.
12. The method of aspect 1, wherein the solidifying step comprises evaporating a solvent from the samples, and
the method comprises sonicating at least one of the samples until the solvent is substantially completely evaporated.
13. The method of aspect 1, comprising the step of evaporating a solvent from at least one of the samples during
the sonicating step.
14. The method of aspect 1, comprising the step of evaporating a solvent from at least one of the samples after the
sonicating step.
15. The method of aspect 1, comprising the step of cooling at least one of the samples before the sonicating step.
16. The method of aspect 1, comprising the step of cooling at least one of the samples during the sonicating step.
17. The method of aspect 1, comprising the step of cooling at least one of the samples after the sonicating step.
18. The method of aspect 1, comprising the step of crash-cooling at least one of the samples before the sonicating
step.
19. The method of aspect 1, wherein at least one of the samples is sonicated by at least one ultrasound pulse.
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20. The method of aspect 1, wherein at least one of the samples is sonicated by a series of at least 5 ultrasound pulses.
21. The method of aspect 1, wherein at least one of the samples is sonicated by sonicating at least once for about
5 minutes.
22. The method of aspect 1, wherein the sonication is substantially continuous during the solidification step.
23. The method of aspect 1, wherein the solidification comprises generating at least one solid solvate of the chemical
substance.
24. The method of aspect 1, wherein the solidification comprises generating at least one solid hydrate of the chemical
substance.
25. The method of aspect 1, wherein the first sample and the second sample are placed in a well plate.
26. The method of aspect 25, wherein the solidified chemical substances are analyzed in the well plate by x-ray
diffraction.
27. The method of aspect 1, wherein the solidified chemical substances are analyzed by transmission x-ray diffraction.
28. The method of aspect 1, wherein the solidified chemical substances are analyzed by Raman spectroscopy.
29. The method of aspect 1, wherein the first sample and the second sample are sonicated in a well plate.
30. The method of aspect 1, further comprising the step of determining whether one or more solid forms were
generated using an analytical method selected from the group consisting of visual analysis, microscopic analysis,
thermal analysis, diffraction analysis, and spectroscopic analysis.
31. The method of aspect 1, further comprising the step of determining whether one or more solid forms were
generated using x-ray diffraction analysis.
32. The method of aspect 1, further comprising the step of determining whether one or more solid forms were
generated using Raman spectroscopic analysis.
33. A method of crystallizing a chemical substance, said method comprising the steps of: forming an emulsion
comprising two or more substantially immiscible solvents and the chemical substance by applying ultrasound to a
mixture of said solvents and the chemical substance; and crystallizing the chemical substance from the emulsion.
34. The method of aspect 33, further comprising the steps of adding an antisolvent to the emulsion, and thereafter
further sonicating the emulsion.
35. The method of aspect 33, wherein the chemical substance is substantially soluble in one of said immiscible
solvents and substantially insoluble in another of said immiscible solvents.
36. A method of crystallizing a chemical substance, said method comprising the steps of: providing a sample of the
chemical substance in a solvent; sonicating the sample at a predetermined supersaturation level; and crystallizing
the chemical substance from the sample.
37. The method of aspect 36, wherein the sonicating and crystallizing steps at least partially overlap.
38. The method of aspect 36, wherein the sample is cooled before sonicating.
39. The method of aspect 36, wherein the solvent is evaporated after sonicating.
40. The method of aspect 36, wherein the predetermined supersaturation level is selected to generate a relatively
stable form of the chemical substance.
41. The method of aspect 36, wherein the predetermined supersaturation level is selected to generate a solvate of
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the chemical substance.
42. The method of aspect 36, further comprising adding an additional solvent to the sample.
43. The method of aspect 36, wherein the sample is a solution having a viscosity greater than about 10 cPoise
before the solution is sonicated.
44. The method of aspect 36, wherein the sample has a metastable zone, and the metastable zone has a width of
at least about 1 C.
45. The method of aspect 36, wherein the sample has a metastable zone, and the metastable zone has a width that
is reduced by at least about 1 C through sonicating the sample.
46. The method of aspect 36, wherein the forming step comprises forming a solution or suspension from a solvent
and an amorphous solid comprising the chemical substance.
47. A method of screening a chemical substance for possible solid forms, said method comprising the steps of:
providing a chemical substance in a plurality of samples; sonicating at least one of the samples, wherein at least
one other sample is unsonicated; solidifying the samples of the chemical substance; and determining whether one
or more solid forms of the chemical substance were generated.
48. A method of generating the most stable form of a chemical substance, said method comprising the steps of:
providing a sample of the chemical substance in a solvent; sonicating the sample at a predetermined supersaturation
level; and crystallizing the chemical substance from the sample; wherein the crystallized chemical substance is the
most stable solid form of the chemical substance relative to known solid forms of the chemical substance.
49. A method of generating a solid form of a chemical substance from a metastable solution, said method comprising
the steps of: forming a metastable solution of the chemical substance in a solvent; sonicating the metastable solution;
and crystallizing the chemical substance from the solution.
50. A method of obtaining a substantially pure solid form of a chemical substance, said method comprising the steps
of: providing a sample of the chemical substance in a solvent; sonicating the sample at a predetermined supersat-
uration level; and crystallizing the chemical substance from the sample; wherein a substantially pure solid form of
the chemical substance is crystallized.
51. A method of preparing a solvate of a chemical substance, said method comprising the steps of: providing a
sample comprising the chemical substance and a solvent; sonicating the sample; and generating a solid from the
sample, wherein the solid comprises a solvate of the chemical substance and the solvent.
52. A method of screening for possible cocrystals comprising an active agent, said method comprising the steps of:
providing a plurality of samples, each sample comprising the active agent and one or more guests, wherein the
plurality of samples contains the same or different guests; sonicating the samples; crystallizing the active agent and
the guest from the samples ; and determining whether a cocrystal was generated in one or more of the samples.
53. The screening method of aspect 52, wherein at least one sample contains a different guest than at least one
other sample.
54. The screening method of aspect 52, wherein each sample contains a different guest.
55. The screening method of aspect 52, wherein the sonicating step and the crystallizing step at least partially overlap.
56. The screening method of aspect 52, wherein the samples are placed in a well plate and sonicated in the well plate.
57. The screening method of aspect 52, wherein the samples are supersaturated with respect to at least one of the
active agent and the guest before the sonicating step.
58. The method of aspect 52, wherein at least some of the samples comprise more than one solvent.
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59. The method of aspect 52, wherein the samples are sonicated by at least one ultrasound pulse.
60. The method of aspect 52, wherein at least one of the samples is sonicated by a series of ultrasound pulses,
each pulse having a duration of from about 0.1 second to about 10 seconds.
61. The method of aspect 52, wherein at least one of the samples is sonicated at least once for at least about 1 minute.
62. The method of aspect 52, wherein at least one of the samples is sonicated at least once for at least about 5 minutes.
63. The method of aspect 52, further comprising the step of determining whether a cocrystal was generated using
an analytical method selected from the group consisting of visual analysis, microscopic analysis, thermal analysis,
diffraction analysis, and spectroscopic analysis.
64. The method of aspect 52, further comprising the step of determining whether a cocrystal was generated using
x-ray diffraction analysis.
65. The method of aspect 52, further comprising the step of determining whether a cocrystal was generated using
Raman spectroscopic analysis.
66. The method of aspect 52, wherein at least one new solid state phase is formed by the crystallizing step.
67. The method of aspect 52, further comprising crystallizing at least one unsonicated sample that is substantially
the same as at least one sonicated sample.
68. A method of preparing a cocrystal comprising an active agent and a guest, said method comprising the steps
of: providing a sample of an active agent and a guest; sonicating the sample; and crystallizing a cocrystal from the
sample, the cocrystal comprising the active agent and the guest.
69. The method of aspect 68 wherein the active agent is an active pharmaceutical ingredient.
70. The method of aspect 68, wherein the active agent is provided as a salt in the sample.
71. The method of aspect 70, wherein the salt comprises chloride.
72. The method of aspect 68, wherein the guest is a salt.
73. The method of aspect 68, wherein the guest is an organic acid.
74. The method of aspect 68, wherein the active agent is not a salt.
75. The method of aspect 68, wherein the active agent is neutral or zwitterionic.
76. The method of aspect 68, wherein the sample comprises a solvent selected from the group consisting of acetone,
acetonitrile, chloroform, 1, 4-dioxane, ethanol, ethyl acetate, heptane, 2-butanone, methanol, nitromethane, tetrahy-
drofuran, toluene, water, dichloromethane, diethyl ether, isopropyl ether, cyclohexane, methylcyclohexane, isopropyl
alcohol, trimethylpentane, n-octane, trichloroethane, trifluoroethanol, pyridine, 1-butanol, tetrachloroethylene, chlo-
robenzene, xylene, dibutyl ether, tetrachloroethane, p-cymene, dimethyl sulfoxide, formamide, and dimethylforma-
mide.
77. The method of aspect 68, wherein the sample comprises more than one solvent.
78. The method of aspect 68, wherein the sample comprises more than one guest.
79. The method of aspect 68, wherein at least one of the samples is sonicated by at least one ultrasound pulse.
80. The method of aspect 68, wherein at least one of the samples is sonicated by a series of ultrasound pulses,
each pulse having a duration of from about 0.1 second to about 10 seconds.
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81. The method of aspect 68, wherein at least one of the samples is sonicated at least once for at least about 1 minute.
82. The method of aspect 68, wherein at least one of the samples is sonicated at least once for at least about 5 minutes.
83. The method of aspect 68, wherein the sonication is substantially continuous during the crystallization step.
84. A method of cocrystallizing two or more components, said method comprising the steps of: (a) determining a
concentration for two or more components in a sample effective for cocrystallization of the components; (b) preparing
the sample comprising the components, said sample having an effective concentration of the components; (c)
sonicating the sample; and (d) generating a cocrystal from the sample, the cocrystal comprising the components.
85. The method of aspect 84, wherein the components comprise an active agent and a guest.
86. A method for speeding the cocrystallization of an active agent and a guest comprising: providing a sample in
an effective volume; sonicating the sample; cocrystallizing said active agent and said guest from the sample; wherein
the rate of cocrystallization is increased by at least 25%.
87. The method of aspect 84, wherein the sample is a metastable solution.
88. A method for screening for possible salts comprising an ionizable active agent, said method comprises: providing
a plurality of samples comprising an ionizable active agent and one or more counterions, wherein the plurality of
samples contains the same or different counterions; sonicating the samples; forming one or more crystallized salt
compounds from the samples, said crystallized salt compounds comprising the ionizable active agent and the
counterions.
89. The method of aspect 88, wherein at least one sample contains a different counterion than at least one other
sample.
90. The method of aspect 88, wherein the plurality of samples comprises a plurality of sets, and the sets differ in
having different counterions, and the samples within each set have the same counterion.
Claims
1. A cocrystal of fluoxetine hydrochloride and benzoic acid.
2. The cocrystal of claim 1, wherein the fluoxetine hydrochloride and benzoic acid are in about a 1:1 molar ratio.
3. The cocrystal of claim 1, wherein the cocrystal is prepared by sonicating a solution of fluoxetine hydrochloride and
benzoic acid in acetonitrile.
4. A method of making a cocrystal of fluoxetine hydrochloride and benzoic acid, comprising: sonicating a solution of
fluoxetine hydrochloride and benzoic acid in acetonitrile.
5. The method of claim 4, wherein the fluoxetine hydrochloride and benzoic acid are in about a 1:1 molar ratio.
6. The method of claim 4, wherein the solution contains about 200 mg/mL of a mixture of fluoxetine hydrochloride and
benzoic acid.
7. The method of claim 4, wherein the solution contains between 35 mg/mL to 100 mg/mL of a mixture of fluoxetine
hydrochloride and benzoic acid.
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REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the readers convenience only. It does not form part of the European
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excluded and the EPO disclaims all liability in this regard.
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