6/17/2020 USP-NF 〈1092〉 the Dissolution Procedure: Development and Validation

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〈1092〉 THE DISSOLUTION PROCEDURE: DEVELOPMENT AND

VALIDATION
INTRODUCTION
Purpose
The Dissolution Procedure: Development and Validation〈1092〉 provides a comprehensive approach covering items to consider for
developing and validating dissolution procedures and the accompanying analytical procedures. It addresses the use of automation
throughout the test and provides guidance and criteria for validation. It also addresses the treatment of the data generated and the
interpretation of acceptance criteria for immediate- and modi ed-release solid oral dosage forms.

Scope
Chapter 〈1092〉 addresses the development and validation of dissolution procedures, with a focus on solid oral dosage forms.
Many of the concepts presented, however, may be applicable to other dosage forms and routes of administration. General
recommendations are given with the understanding that modi cations of the apparatus and procedures as given in USP general
chapters need to be justi ed.
The organization of 〈1092〉 follows the sequence of actions often performed in the development and validation of a dissolution

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test. The sections appear in the following sequence.
1. PRELIMINARY ASSESSMENT (FOR EARLY STAGES OF PRODUCT DEVELOPMENT/ DISSOLUTION METHOD DEVELOPMENT)
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1.1 Performing Filter Compatibility
1.2 Determining Solubility and Stability of Drug Substance in Various Media
1.3 Choosing a Medium and Volume
1.4 Choosing an Apparatus
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2. METHOD DEVELOPMENT

2.1 Deaeration
2.2 Sinkers
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2.3 Agitation
2.4 Study Design

2.4.1 Time Points

2.4.2 Observations
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2.4.3 Sampling
2.4.4 Cleaning

2.5 Data Handling

2.6 Dissolution Procedure Assessment
3. ANALYTICAL FINISH

3.1 Sample Processing

3.2 Filters
3.3 Centrifugation
3.4 Analytical Procedure
3.5 Spectrophotometric Analysis
3.6 HPLC
4. AUTOMATION

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4.1 Medium Preparation

4.2 Sample Introduction and Timing
4.3 Sampling and Filtration
4.4 Cleaning
4.5 Operating Software and Computation of Results
4.6 Common Deviations from the Compendia Procedures That May Require Validation
5. VALIDATION

5.1 Speci city/Placebo Interference

5.2 Linearity and Range
5.3 Accuracy/Recovery
5.4 Precision

5.4.1 Repeatability of Analysis

5.4.2 Intermediate Precision/Ruggedness
5.4.3 Reproducibility

5.5 Robustness
5.6 Stability of Standard and Sample Solutions
5.7 Considerations for Automation
6. ACCEPTANCE CRITERIA

6.1 Immediate-Release Dosage Forms

6.2 Delayed-Release Dosage Forms
6.3 Extended-Release Dosage Forms

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6.4 Multiple Dissolution Tests
6.5 Interpretation of Dissolution Results
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6.5.1 Immediate-Release Dosage Forms
6.5.2 Delayed-Release Dosage Forms
6.5.3 Extended-Release Dosage Forms

7. REFERENCES
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1. PRELIMINARY ASSESSMENT (FOR EARLY STAGES OF PRODUCT DEVELOPMENT/ DISSOLUTION METHOD

DEVELOPMENT)
Before method development can begin, it is important to characterize the molecule so that the lter, medium, volume of medium,
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and apparatus can be chosen properly in order to evaluate the performance of the dosage form.

1.1 Performing Filter Compatibility

Filtration is a key sample-preparation step in achieving accurate test results. The purpose of ltration is to remove undissolved drug
and excipients from the withdrawn solution. If not removed from the sample solution, particles of the drug will continue to dissolve
and can bias the results. Therefore, ltering the dissolution samples is usually necessary and should be done immediately if the lter
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is not positioned on the cannula.

Filtration also removes insoluble excipients that may otherwise interfere with the analytical nish. Selection of the proper lter
material is important and should be accomplished, and experimentally justi ed, early in the development of the dissolution
procedure. Important characteristics to consider when choosing a lter material are type, lter size, and pore size. The lter that is
selected based on evaluation during the early stages of dissolution procedure development may need to be reconsidered at a later
time point. Requali cation has to be considered after a change in composition of the drug product or changes in the quality of the
ingredients (e.g. particle size of microcrystalline cellulose).
Examples of lters used in dissolution testing can be cannula lters, lter disks or frits, lter tips, or syringe lters. The lter
material has to be compatible with the media and the drug. Common pore sizes range from 0.20 to 70 µm, however, lters of other
pore sizes can be used as needed. If the drug substance particle size is very small (e.g., micronized or nanoparticles), it can be
challenging to nd a lter pore size that excludes these small particles.
Adsorption of the drug(s) by the lter may occur and needs to be evaluated. Filter materials will interact with dissolution media to
affect the recovery of the individual solutes and must be considered on a case-by-case basis. Different lter materials exhibit different
drug-binding properties. Percentage of drug loss from the ltrate due to binding may be dependent on the drug concentration.
Therefore the adsorptive interference should be evaluated on sample solutions at different concentrations bracketing the expected
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concentration range. Where the drug adsorption is saturable, discarding an initial volume of ltrate may allow the collection of a
subsequent solution that approaches the original solution concentration. Alternative lter materials that minimize adsorptive
interference can usually be found. Prewetting of the lter with the medium may be necessary. In addition, it is important that
leachables from the lter do not interfere with the analytical procedure. This can be evaluated by analyzing the ltered dissolution
medium and comparing it with the un ltered medium.
The lter size should be based on the volume to be withdrawn and the amount of particles to be separated. Use of the correct lter
dimensions will improve throughput and recovery, and also reduce clogging. Use of a large lter for small-volume ltration can lead to
loss of sample through hold-up volume, whereas ltration through small lter sizes needs higher pressures and longer times, and the
lters can clog quickly.
Filters used for USP Apparatus 4 need special attention because they are integrated in the ow-through process. Undissolved
particles may deposit on the lters, creating resistance to the ow.
In the case of automated systems, selection of the lter with regard to material and pore size can be done in a similar manner to
manual ltration. Flow rate through the lter and clogging may be critical for lters used in automated systems. Experimental
veri cation that a lter is appropriate may be accomplished by comparing the responses for ltered and un ltered standard and
sample solutions. This is done by rst preparing a suitable standard solution and a sample solution. For example, prepare a typical
dissolution sample in a beaker and stir vigorously with a magnetic stirrer to dissolve the drug load completely. For standard
solutions, compare the results for ltered solutions (after discarding the appropriate volume) to those for the un ltered solutions. For
sample solutions, compare the results for ltered solutions (after discarding the appropriate volume) to those for centrifuged,
un ltered solutions.

1.2 Determining Solubility and Stability of Drug Substance in Various Media

Physical and chemical characteristics of the drug substance need to be determined as part of the process of selecting the proper
dissolution medium. When deciding the composition of the medium for dissolution testing, it is important to evaluate the in uence
of buffers, pH, and if needed, different surfactants on the solubility and stability of the drug substance. Solubility of the drug

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substance is usually evaluated by determining the saturation concentration of the drug in different media at 37° using the shake- ask
solubility method (equilibrium solubility). To level out potential ion effects between the drug and the buffers used in the media,
mixtures of hydrochloric acid and sodium hydroxide are used to perform solubility investigations; this is in addition to the typical
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buffer solutions. In certain cases, it may be necessary to evaluate the solubility of the drug at temperatures other than 37° (i.e., 25°).
The pH of the clear supernatant should be checked to determine whether the pH changes during the solubility test. Alternative
approaches for solubility determination may also be used.
Typical media for dissolution may include the following (not listed in order of preference): diluted hydrochloric acid, buffers
(phosphate or acetate) in the physiologic pH range of 1.2–7.5, simulated gastric or intestinal uid (with or without enzymes), and
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water. For some drugs, incompatibility of the drug with certain buffers or salts may in uence the choice of buffer. The molarity of the
buffers and acids used can in uence the solubilizing effect, and this factor may be evaluated.
Aqueous solutions (acidic or buffer solutions) may contain a percentage of a surfactant [e.g., sodium dodecyl sulfate (SDS),
polysorbate, or lauryldimethylamine oxide] to enhance the solubility of the drug. The surfactants selected for the solubility
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investigations should cover all common surfactant types, i.e., anionic, nonionic, and cationic. When a suitable surfactant has been
identi ed, different concentrations of that surfactant should be investigated to identify the lowest concentration needed to achieve
sink conditions. Typically, the surfactant concentration is above its critical micellar concentration (CMC). Table 1 shows a list of some
of the surfactants used in dissolution media. Approximate CMC values are provided with references when available. The list is not
comprehensive and is not intended to exclude surfactants that are not listed. Other substances, such as hydroxypropyl β-cyclodextrin,
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have been used as dissolution media additives to enhance dissolution of poorly soluble compounds. The U.S. Food and Drug
Administration (FDA) maintains a database of dissolution methods, including information on dissolution media that have been used
(1). Typically, the amount of surfactant added is su cient to achieve sink conditions in the desired volume of dissolution medium.
It is important to control the grade and purity of surfactants because use of different grades could affect the solubility of the drug.
For example, SDS is available in both a technical grade and a high-purity grade. Obtaining polysorbate 80 from different sources can
affect its suitability when performing high-performance liquid chromatography (HPLC) analysis.
There may be effects of counter-ions or pH on the solubility or solution stability of the surfactant solutions. For example, a
precipitate forms when the potassium salt for the phosphate buffer is used at a concentration of 0.5 M in combination with SDS. This
can be avoided by using the sodium phosphate salt when preparing media with SDS.

Table 1. Commonly Used Surfactants with Critical Micelle Concentrations

Surfactant CMC (% wt/volume) Reference

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Surfactant CMC (% wt/volume) Reference

Sodium dodecyl sulfate

(SDS), Sodium lauryl sulfate
(SLS) 0.18%–0.23% (2–4)

Taurocholic acid sodium salt 0.2% (3)

Cholic acid sodium salt 0.16% (3)

Desoxycholic acid sodium

Anionic salt 0.12% (3)

Cetyltrimethyl ammonium
bromide (CTAB,
Hexadecyltrimethylammoniu 0.033%–0.036% (0.92–1.0
m bromide) mM) (5,6)

Benzethonium chloride
Cationic (Hyamine 1622) 0.18% (4 mM) (2)

Polysorbate 20
(Polyoxyethylene (20)
sorbitan monolaurate, Tween
20) 0.07%–0.09% (3,7)

Polysorbate 80
(Polyoxyethylene (20)
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sorbitan monooleate, Tween
80) 0.02%–0.08% (3,7)

Caprylocaproyl polyoxyl-8
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glycerides (Labrasol) 0.01% (4)

Polyoxyl 35 castor oil

(Cremophor EL) 0.02% (8)
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Polyoxyethylene 23 lauryl
ether (Brij 35) 0.013% (9)

Nonionic Octoxinol (Triton X-100) 0.01%–0.03% (3,10)

Lauryldimethylamine N-oxide
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Zwitterion (LDAO) 0.023% (11)

Routinely, the dissolution medium is buffered; however, the use of puri ed water as the dissolution medium is suitable for
products with a dissolution behavior independent of the pH of the medium. There are several reasons why puri ed water may not be
preferred. The water quality can vary depending on its source, and the pH of the water is not as strictly controlled as the pH of buffer
solutions. Additionally, the pH can vary from day to day and can also change during the run, depending on the drug substance and
excipients. Use of an aqueous–organic solvent mixture as a dissolution medium is discouraged; however, with proper justi cation
this type of medium may be acceptable.
Investigations of the stability of the drug substance should be carried out, when needed, in the selected dissolution medium with
excipients present, at 37°. This elevated temperature has the potential to decrease solution stability (degradation). Stability should
allow for su cient time to complete or repeat the analytical procedure. Physical stability may be of concern when precipitation
occurs because of lower solubility at room or refrigerated temperature.

1.3 Choosing a Medium and Volume

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When developing a dissolution procedure, one goal is to have sink conditions, which are de ned as having a volume of medium at
least three times the volume required to form a saturated solution of drug substance. When sink conditions are present, it is more
likely that dissolution results will re ect the properties of the dosage form. A medium that fails to provide sink conditions may be
acceptable if it is appropriately justi ed. The composition and volume of dissolution medium are guided by the solubility
investigations. For example, the choice and concentration of a surfactant need to be justi ed from the solubility data and the
dissolution pro les.
The use of enzymes in the dissolution medium is permitted, in accordance with Dissolution 〈711〉, when dissolution failures
occur as a result of cross-linking with gelatin capsules or gelatin-coated products. A discussion of the phenomenon of cross-linking
and method development using enzymes can be found in Capsules– Dissolution Testing and Related Quality Attributes 〈1094〉.
Validation should be performed with the method using enzymes according to section 5. Validation.
Another option is to use media that follow more closely the composition of uids in the stomach and intestinal tract. These media
may contain physiological surface-active ingredients, such as taurocholates. The media also may contain emulsi ers (lecithin) and
components such as saline solution that increase osmolality. Also, the ionic strength or molarity of the buffer solutions may be
manipulated. The media are designed to represent the fed and fasted state in the stomach and small intestine. These media may be
very useful in modeling in vivo dissolution behavior of immediate-release (IR) dosage forms, in particular those containing lipophilic
drug substances, and may help in understanding the dissolution kinetics of the product related to the physiological make-up of the
digestive uids. Results of successful modeling of dissolution kinetics have been published, mainly for IR products. In the case of
extended-release dosage forms with reduced effect of the drug substance on dissolution behavior, the use of such media needs to
be evaluated differently. In vitro performance testing does not necessarily require media modeling the fasted and postprandial states
(12,13).
An acid stage is part of the testing of delayed-release products by Method A or Method B in 〈711〉. For drugs with acid solubility less
than 10% of the label claim or drugs that degrade in acid the usefulness of the acid stage in detecting a coating failure is
compromised. This would be handled on a case-by-case basis. Possible resolutions include the addition of surfactant to the acid
stage, or adjustment of the speci cations.

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During selection of the dissolution medium, care should be taken to ensure that the drug substance is suitably stable throughout
the analysis. In some cases, antioxidants such as ascorbic acid may be used in the dissolution medium to stabilize the drug. There
are occasions where such actions are not su cient. For compounds that rapidly degrade to form a stable degradant, monitoring the
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degradant alone or in combination with a drug substance may be more suitable than analyzing only the drug substance. In situ
spectroscopic techniques tend to be less affected by degradation when compared with HPLC analysis (including UHPLC and other
liquid chromatographic approaches).
For compendial Apparatus 1 (basket) and Apparatus 2 (paddle), the volume of the dissolution medium can vary from 500 to 1000
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mL. Usually, the volume needed for the dissolution test can be determined in order to maintain sink conditions. In some cases, the
volume can be increased to between 2 and 4 L, using larger vessels and depending on the concentration and sink conditions of the
drug; justi cation for this approach is expected. In practice, the volume of the dissolution medium is usually maintained within the
compendial range given above. Alternatively, it may be preferable to switch to other compendial apparatus, such as a reciprocating
cylinder (Apparatus 3), reciprocating holder (Apparatus 7), or ow-through cell (Apparatus 4). Certain applications may require low
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volumes of dissolution media (e.g., 100–200 mL) when the use of a paddle or basket is preferred. In these cases, an alternative,
noncompendial apparatus (e.g., small-volume apparatus) may be used.

1.4 Choosing an Apparatus

The choice of apparatus is based on knowledge of the formulation design and the practical aspects of dosage form performance in
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the in vitro test system. In general, a compendial apparatus should be selected.

For solid oral dosage forms, Apparatus 1 and Apparatus 2 are used most frequently. When Apparatus 1 or Apparatus 2 is not
appropriate, another o cial apparatus may be used. Apparatus 3 (reciprocating cylinder) has been found especially useful for
chewable tablets, soft gelatin capsules, delayed-release dosage forms, and nondisintegrating-type products, such as coated beads.
Apparatus 4 ( ow-through cell) may offer advantages for modi ed-release dosage forms and immediate-release dosage forms that
contain active ingredients with limited solubility. In addition, Apparatus 4 may have utility for multiple dosage form types such as soft
gelatin capsules, beaded products, suppositories, or depot dosage forms, as well as suspension-type extended-release dosage forms.
Apparatus 5 (paddle over disk) and Apparatus 6 (rotating cylinder) are useful for evaluating and testing transdermal dosage forms.
Apparatus 7 (reciprocating holder) has application to non-disintegrating, oral modi ed-release dosage forms, stents, and implants, as
well as transdermal dosage forms. For semisolid dosage forms, the generally used apparatus include the vertical diffusion cell,
immersion cell, and ow-through cell apparatus with the insert for topical dosage forms (see Semisolid Drug Products—Performance
Tests 〈1724〉).
Some changes can be made to the compendial apparatus; for example, a basket mesh size other than the typical 40-mesh basket
(e.g., 10-, 20-, or 80-mesh) may be used when the need is clearly documented by supporting data. Care must be taken that baskets are
uniform and meet the dimensional requirements speci ed in 〈711〉.

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A noncompendial apparatus may have some utility with proper justi cation, quali cation, and documentation of superiority over the
standard equipment. For example, a small-volume apparatus with mini paddles and baskets may be considered for low-dosage
strength products. A rotating bottle or dialysis tubes may have utility for microspheres and implants, peak vessels, and modi ed ow-
through cells for special dosage forms including powders and stents.

2. METHOD DEVELOPMENT
A properly designed test should yield data that are not highly variable, and should be free of signi cant stability problems. High
variability in the results can make it di cult to identify trends or effects of formulation changes. Sample size can affect the observed
variability. One guidance de nes dissolution results as highly variable if the relative standard deviation (RSD) is more than 20% at
time points of 10 min or less and more than 10% at later time points for a sample size of 12 (14). However, during method
development, smaller sample sizes may be used, and the analyst will need to make a judgment accordingly. Most dissolution results,
however, exhibit less variability. In the development of a dissolution procedure the source of the variability should be investigated,
and attempts should be made to reduce variability whenever possible. The two most likely causes are the formulation itself (e.g., drug
substance, excipients, or manufacturing process) or artifacts associated with the test procedure (e.g., coning, tablets sticking to the
vessel wall or basket screen). Visual observations are often helpful for understanding the source of the variability and whether the
dissolution test itself is contributing to the variability. Any time the dosage contents do not disperse freely throughout the vessel in a
uniform fashion, aberrant results can occur. Depending on the problem, the usual remedies include changing any of the following
factors: the apparatus type, speed of agitation, level of deaeration, sinker type, or composition of the medium.
Many causes of variability can be found in the formulation and manufacturing process. For example, poor content uniformity,
process inconsistencies, excipient interactions or interference, lm coating, capsule shell aging, and hardening or softening of the
dosage form on stability may be sources of variability and interferences.

2.1 Deaeration
The signi cance of deaeration of the dissolution medium should be determined because air bubbles can act as a barrier to the
dissolution process if present on the dosage unit or basket mesh and can adversely affect the reliability of the test results.

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Furthermore, bubbles can cause particles to cling to the apparatus and vessel walls. Bubbles on the dosage unit may increase
buoyancy, leading to an increase in the dissolution rate, or may decrease the available surface area, leading to a decrease in the
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dissolution rate. Poorly soluble drugs are most sensitive to interference from air bubbles; therefore, deaeration may be needed when
testing these types of products. A deaeration method is described as a footnote in the Procedure section of 〈711〉. Typical steps
include heating the medium, ltering, and drawing a vacuum for a short period of time. Other methods of deaeration are available and
are in routine use throughout the industry. Once a suitable deaeration process is identi ed, it should be documented as part of the
dissolution procedure. The extent of deaeration can be evaluated by measuring the total dissolved gas pressure or by measuring the
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concentration of dissolved oxygen in water. For example, an oxygen concentration below 6 mg/L has been found effective as a
marker for adequate deaeration of water for the Performance Veri cation Test with USP Prednisone Tablets RS.
Media containing surfactants usually are not deaerated because the process results in excessive foaming, and usually the effect of
dissolved air on the dissolution process is mitigated by the reduced surface tension of the medium. Sometimes, deaerating the
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medium before adding surfactants can be effective.

To determine whether deaeration of the medium is necessary, compare results from dissolution samples run in non-deaerated
medium and medium deaerated using a compendial technique, as described above. If no effect of deaeration is detected, this
experiment could serve as justi cation that deaeration is not required in the future. If there is an effect, however, then it is necessary
to carefully control this parameter, and it is prudent to characterize the robustness of the deaeration process. The dissolved gas
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content of deaerated media under atmospheric pressure is unstable and will tend toward saturation. Manipulations of the deaerated
medium such as stirring or pouring can increase the rate at which atmospheric gases are redissolved.

2.2 Sinkers
Sinkers are often used to adjust the buoyancy of dosage forms that would otherwise oat during testing with Apparatus 2. When
sinkers are used, a detailed description of the sinker must be provided in the written procedure. It may be useful to evaluate different
sinker types, recognizing that sinkers can signi cantly in uence the dissolution pro le of a dosage unit. When transferring the
procedure, the same sinkers should be used, or if a different design is used, it should be shown to produce equivalent results. There
are several types of commercially available sinkers. In 〈711〉, a harmonized sinker is described in Figure 2a.
A standard sinker can be made by using the appropriate length of wire and coiling it around a cylinder. For materials, use 316
stainless steel wire, typically 0.032 inch/20 gauge, or other inert material and wind the wire around cylinders of appropriate diameter
(e.g., cork borers) for an appropriate number of turns to t the capsule shell type. Sizes are shown in Table 2. The ends of the coil can
be curved to retain the capsule within the sinker when they are immersed. Because the ends of the wire may be rough, they may need
to be led. If the sinker is handmade, the sinker material and construction procedure instructions should be documented (e.g.,
dimension, design, number of coils); if a commercial sinker is used, the vendor part number should be reported if available.

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Table 2. Wire Sinkers Used With Common Capsule Shell Sizes

Capsule Shell Size Length of Wire (cm) Diameter Size (cm) Cork Bore Number

#0, elongated 12 0.8 4

#1 and #2 10 0.7 3

#3 and #4 8 0.55 2

Although sinkers are typically used to keep the dosage form at the bottom of the vessel, they can also be used to keep dosage
forms from sticking to the vessel (e.g., lm-coated tablets). The sinker should be appropriate to the dosage form; therefore, the same
sinker size may not be suitable for all dosage-form sizes. The sinker should not be too tight around the dosage form because this
may restrict interaction with the medium. Conversely, if wrapped too loosely, the dosage form may escape soon after the test begins.
The sinker should be small enough that the capsule does not change its orientation within the sinker. Care should be taken when
testing capsules that have some cross-linking present, to keep the sticky shell from attaching to the vessel bottom. In this case, the
harmonized sinker design provided in Figure 2a of 〈711〉 will be advantageous.

2.3 Agitation
For immediate-release capsule or tablet formulations, Apparatus 1 (baskets) at 50–100 rpm or Apparatus 2 (paddles) at 50 or 75
rpm are used commonly. Other agitation speeds are acceptable with appropriate justi cation. Rates outside 25–150 rpm for both the
paddle and the basket are usually not appropriate because of mixing inconsistencies that can be generated by stirring too slow or too
fast. Agitation rates between 25 and 50 rpm are generally acceptable for suspensions.
For dosage forms that exhibit coning (mounding) under the paddle at 50 rpm, the coning can be reduced by increasing the paddle
speed to 75 rpm, thus reducing the artifact and improving the data. If justi ed, 100 rpm may be used with Apparatus 2, especially for

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extended-release products. Decreasing or increasing the apparatus rotation speed may be justi ed if to achieve an in-vitro–in-vivo
correlation (IVIVC) the resulting pro les better re ect in vivo performance, or if the method results in better discrimination without
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adversely affecting method variability.
Apparatus 3 (reciprocating cylinder) can be used at dip rates ranging from 5 to 30 dips/min. The hydrodynamics are in uenced by
the cylinder's reciprocating motion and the resulting movement of the sample in the medium. The reciprocating motion of the cylinder
and screen may cause foaming if the medium contains surfactants. Addition of an anti-foaming agent such as simethicone or n-
octanol may be useful for avoiding foaming from surfactants.
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Apparatus 4 ( ow-through cell) is described in 〈711〉 with standard ow rates of 4, 8, and 16 mL/min. Other ow rates for Apparatus
4 can be used if justi ed and if within the capacity of the pump to conform with the requirements in 〈711〉. Agitation in Apparatus 4 is
not only related to the pump speed but can also be affected by cell diameter. At a set ow rate, as measured by volume, the 12-mm
cell will develop a greater linear uid velocity than is achieved in the 22.6-mm cell. Apparatus 4 can be con gured with the addition of
glass beads in the entry cone of the ow-through cell (packed column) or without glass beads (open column).
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The ow characteristics of the ow-through cell are discussed in the scienti c literature (15). The placement of the sample in the
ow-through cell will in uence the ow patterns that occur and thus should be a consideration in the attempt to reduce variability of
the results.

2.4 Study Design

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Selection of the agitation rate and other study design elements for the dosage form, whether immediate release or modi ed
release, should conform to the requirements and speci cations (i.e., apparatus, procedures, and interpretation) given in 〈711〉.

2.4.1 TIME POINTS

For immediate-release dosage forms, the duration of the dissolution procedure is typically 30–60 min; in most cases, a single
time point speci cation is adequate for pharmacopeial purposes. For method development, however, a su cient number of time
points should be selected to adequately characterize the ascending and plateau phases of the dissolution curve. Industrial and
regulatory concepts of product comparability and performance may require additional time points, which may also be required for
product registration or approval. According to the Biopharmaceutics Classi cation System referred to in several FDA Guidances,
highly soluble, highly permeable drugs formulated into very rapidly dissolving products need not be subjected to a pro le
comparison if they can be shown to release 85% or more of the drug substance within 15 min. For these types of products, a one-
point test or disintegration will su ce. However, most products do not fall into this category. Dissolution pro les of immediate-
release products typically show a gradual increase reaching 85%–100% at about 30–45 min. Thus, su cient dissolution time points
are chosen to characterize the performance for most immediate-release products. For some products, including suspensions, useful
information may be obtained from earlier points, e.g., 5–10 min. For slower-dissolving products, time points later than 60 min may

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be useful. Dissolution test times for compendial tests are usually established on the basis of an evaluation of the dissolution
pro le data.
The f2 similarity factor may not be useful when more than 85% is dissolved at 15 min. If the f2 similarity factor is to be used,
multiple time points for the dissolution test are required, with at least two time points with mean percent dissolved (typically for n =
12) below 85% dissolved and only one point above 85% for both products (16). Therefore, the addition of early time points may be
useful.
For testing an extended-release dosage form, at least three time points are chosen, to guard against dose dumping, to de ne the
in vitro release pro le, and to show that essentially complete release (>80%) of the drug is achieved. Additional sampling times may
be useful. Certain IVIVC criteria, such as level B correlation (according to In Vitro and In Vivo Evaluation of Dosage Forms 〈1088〉),
require the experimental determination of the time to dissolve 100% of the label claim. Selection of the nal time points is re ective
of the data from the drug release pro le that are generated during development. For products containing more than a single active
ingredient, determine the drug release for each active ingredient.
Delayed-release dosage forms usually require speci cations for at least two time points; therefore, it is important during
development to evaluate the entire dissolution pro le. In the case of enteric-coated dosage forms, the functionality of the coating is
usually proven by challenge in an acid medium, followed by a demonstration of dissolution in a higher-pH medium. Chapter 〈711〉
gives a standard buffer medium for that stage of testing but other media may be used if justi ed. The timing of the acid stage is
typically 2 h, and release in the buffer is similar to the timing for immediate-release forms. For delayed-release dosage forms that are
not enteric coated, setting of speci cations is different. Unlike delayed release, the onset of release is not determined by the
experimental design, which is the pH change; multivariate speci cations, therefore, may be needed to de ne time ranges and
corresponding percentage ranges.
So-called in nity points can be useful during development studies. To obtain an in nity point, the paddle or basket speed is
increased at the end of the run (after the last time point) for a sustained period (typically, 15–60 min), after which time an additional
sample is taken. Although there is no requirement for 100% dissolution in the pro le, the in nity point can be compared to content
uniformity data and may provide useful information about formulation characteristics during initial development or about method

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bias.

2.4.2 OBSERVATIONS
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Visual observations and recordings of product dissolution and disintegration behavior are useful because dissolution and
disintegration patterns can be indicative of variables in the formulation or manufacturing process. For visual observation, proper
lighting (with appropriate consideration of photo-degradation) of the vessel contents and clear visibility in the bath are essential.
Documenting observations by drawing sketches and taking photographs or videos can be instructive and helpful for those who are
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not able to observe the real-time dissolution test. Observations are especially useful during method development and formulation
optimization. It is important to record observations of all six vessels to determine if the observation is seen in all six vessels, or just
a few. If the test is performed to assist with formulation development, provide any unique observations to the formulator. Examples
of typical observations include, but are not limited to, the following:
1. Uneven distribution of particles throughout the vessel. This can occur when particles cling to the sides of the vessel, when
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there is coning or mounding directly under the apparatus (e.g., below the basket or paddle), when particles oat at the surface
of the medium, when lm-coated tablets stick to the vessel, and/or when off-center mounds are formed.
2. Air bubbles on the inside of the vessel or on the apparatus or dosage unit. Sheen on the apparatus is also a sign of air
bubbles. This observation would typically be made when assessing the need to deaerate the medium.
3. Dancing or spinning of the dosage unit, or the dosage unit being hit by the paddle.
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4. Adhesion of particles to the paddle or the inside of the basket, which may be observed upon removal of the stirring device at
the end of the run.
5. Pellicles or analogous formations, such as transparent sacs or rubbery, swollen masses surrounding the capsule contents.
6. Presence of large oating particles or chunks of the dosage unit, especially at the surface of the media.
7. Observation of the disintegration rate (e.g., percentage reduction in size of the dosage unit within a certain time frame).
8. Complex disintegration of the coating of modi ed or enteric-coated products, [e.g., the partial opening and splitting apart
(similar to a clamshell) or incomplete opening of the shell], accompanied by the release of air bubbles and excipients.
9. Whether the dosage form lands in the vessel center or off-center, and if off-center, whether it sticks there.
10. Time required for the complete dissolution of the capsule shell or for tablet disintegration.
Observations also help to document that the proper procedure has been followed, or more importantly, that a deviation has
occurred. Examples include the con rmation that a dosage form is actually in the vessel during the test or that more than one
dosage form are inadvertently in the same vessel, or that a lter from the autosampler has dropped into the vessel.

2.4.3 SAMPLING

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Manual: For manual sampling, use chemically inert devices (e.g., polymeric or glass syringes, and polymeric or stainless steel
cannula), a lter, and/or a lter holder. The sampling site must conform to speci cations in 〈711〉. When the agitation conditions are
very slow, e.g., a 50-rpm basket, care should be taken to sample consistently in the same location in the vessel because there may be
a concentration gradient; avoid sampling very close to the shaft or vessel wall. During method development, a decision should be
made regarding whether to replace the media after each time point. Replacement is not preferred because the dosage unit may be
disturbed during delivery of the media. However, replacement may be necessary if maintaining sink conditions is a challenge. With
replacement, the volume used in the calculations remains the same throughout the time points, but there is some drug substance
withdrawn with each sample that will need to be accounted for in the calculations.
Metal surfaces may interact with the sample. For example, adsorption onto metal surfaces may occur, or the metal surfaces may
release metal ions into aqueous media. The ions can then catalyze degradation reactions, leading to artifacts during the analytical
procedures. The surfaces of stirring elements and metal locks of syringes may be sources of interference to accurate sampling.
Autosampling: Autosampling is discussed in section 4. Automation.

2.4.4 CLEANING
Importance is placed on evaluation of the cleaning process between tests. Changes of dissolution medium and/or product
necessitate the need for cleaning. Residues on the vessels can affect the results (e.g., adsorbed residues may dissolve and alter
subsequent media properties or interfere with the sample analysis), and effective cleaning will return them to a suitable state.
Automated systems are discussed in section 4.4 Cleaning.

Change to read:
2.5 Data Handling
Dissolution rates are calculated from the change in drug concentration in the dissolution medium. For procedures in which the
volume of medium is xed, such as for Apparatus 1 and Apparatus 2 testing of immediate-release dosage forms with only one
sampling time, the concentration of the sample is multiplied by the medium volume to arrive at the mass of drug dissolved usually
expressed as percentage of label claim. When multiple time points are taken, the total amount of drug removed at earlier time points

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should be assessed and may be part of the calculation of the amount dissolved, if considered important. Similarly, if the medium
volume is not xed, for example when the sample volume is not replaced in testing extended-release products, the change in medium
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volume must be part of the calculation for successive sampling points. Dissolution tests performed with Apparatus 4 in the closed-
loop con guration with in situ detection provide a convenient control of the medium volume. For testing with Apparatus 4 in the open
con guration, the test time and ow rate will determine the volume of medium used in the dissolution calculations.
Dissolution results can be evaluated as either cumulative rates or fractional rates. Cumulative rates represent the sum of all drug
dissolution that occurs during an interval (Figure 1). Fractional rates are assessed at a speci c time point or during a portion of the
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total test time (Figure 2). Typically, the rate of release will be expressed as either mass or percentage of label claim per unit time. For
most compendial dissolution testing, the dissolution rate is expressed as a percentage of the label claim dissolved at the indicated
test time.
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Figure 1. An example of a plot of dissolution as a cumulative process. Concentration, C, is the amount of drug released per volume
of medium, and t represents time. This type of plot is readily observed in constant-volume dissolution systems, such as Apparatus 1
or Apparatus 2, or Apparatus 4 in closed-loop con guration.

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Figure 2. An example of a plot of the observed concentration of the sample taken for an interval that is negligibly small in relation to
the time of the overall dissolution process. This concentration is propostional to the instantaneous or fractional dissolution rate
(dc/dt). This type of plot is readily observed in continuous- ow dissolution systems, such as Apparatus 4 in open-loop con guration.

Cumulative dissolution pro les represent the total amount of drug dissolved from the formulation over time. When cumulative
dissolution is measured in a constant-volume system, no correction for the amount lost in sampling needs to be made. If sample is
removed from the system, the amount consumed in analysis must be accounted for in the calculation. Recirculated sampling with
Apparatus 1 or Apparatus 2, or with Apparatus 4 in the closed-loop con guration (Figure 3), are all examples of systems that will
produce cumulative dissolution rates. With Apparatus 4 in the open con guration (Figure 4), cumulative rates accounting for the total
amount of drug dissolved across the testing interval are obtained by collecting and analyzing the entire out ow from each individual
ow-through cell. With Apparatus 3 (Figure 5), the medium in each tube is sampled at the end of the programmed interval, and the
analyzed concentration represents the cumulative dissolution rate during that interval.

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Figure 3. Apparatus 4 in the closed-loop con guration.

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Figure 4. Apparatus 4 in the open-loop con guration. The sample can be collected in fractions, as shown at the top. The medium
can be changed by using successive reservoirs.

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Figure 5. The progression that is possible for one reciprocating cylinder from Apparatus 3. The reciprocating cylinder can move
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from vessel to vessel. This feature facilitates changing the dissolution medium and testing for different intervals in successive
tubes.

Fractional dissolution rates are typically measured for a discrete interval. A series of such rates will produce a step function as the
dissolution pro le. At any time, the cumulative dissolution rate from this type of pro le is the sum of the preceding intervals. This
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type of pro le is represented by Apparatus 3 using multiple tubes or Apparatus 4 in the open-loop con guration where the total
out ow is collected and analyzed for successive intervals.
A number of algebraic and numerical methods exist for transforming cumulative and fractional dissolution results. The difference
in amount released for successive time points can be calculated, and the average release rate is determined by the formula:

Result = (M2 − M1)/(t2 − t1)

M = mass or percentage of label claim

t = time
As the difference of t2 from t1 is reduced, the average rate can be considered to approach an instantaneous rate. Sampling
considerations and physical constraints on measurement of the mass transfer at the medium interface of the dosage form make the
measurement of true instantaneous dissolution impractical for routine determination in the laboratory. Fractional dissolution is
measured for intervals where the difference between t2 and t1 is small, relative to the total test time. The design of Apparatus 4 in the
open con guration permits a direct measurement of the fractional dissolution over small time intervals. For example, if a 4-mL

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fraction of out ow for Apparatus 4 running 16 mL/min is sampled, either by in situ detection or o ine, the amount of drug detected
represents the dissolution occurring in a 15-s interval.
Pooled dissolution has been used in a number of monographs. The pooled dissolution procedure produces an average release
rate for the units tested by combining equal volumes from each vessel or cell and performing analysis of only the one resulting
solution. Because this approach uses only the average release rate for comparison with the acceptance table, the pooled dissolution
procedure has been viewed as reducing the amount of data available from the dissolution test and, thus, reducing its value. However,
it should be noted that the pooling of equal sample volumes is equivalent, from a calculation standpoint, to determining the arithmetic
mean of the individual sample results.
The use of the f2 similarity factor in the comparison of dissolution pro les is discussed in ▲Assessment of Solid Oral Drug Product
Performance and Interchangeability, Bioavailability, Bioequivalence, and Dissolution 〈1090〉▲ (CN 1-May-2019).
For the purpose of correlation with in vivo data, parameters of mathematical models are obtained by tting to dissolution data to
establish a continuous functional relationship called IVIVC (see 〈1088〉).

2.6 Dissolution Procedure Assessment

The dissolution procedure requires an apparatus, a dissolution medium, and test conditions that together provide a method that
is sensitive to changes in critical quality attributes, yet su ciently rugged and reproducible for day-to-day operation. The method
should be able to be transferred between laboratories.
The ideal dissolution procedure will not contribute an unacceptable degree of variability and will provide a pro le with adequate
points below 85% dissolved. If 85% dissolved occurs before 15 min, then f2 comparisons may not be appropriate.
There are many ways to challenge the sensitivity of the method. One option is to compare dissolution pro les of formulations that
are intentionally manufactured with meaningful variations for the most relevant critical manufacturing variable, for example, ±10%–
20% change to the ranges of these variables. Similarly, samples that have been stressed may be used to demonstrate sensitivity to
changes on stability. This concept may be used to establish the factors that are most signi cant in their in uence on the dissolution
rate. These studies can focus on either the dissolution parameters (e.g., media concentration, agitation rate, and deaeration) or the

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product attributes (e.g., excipient ratios, particle size, compression). The ultimate goal is to understand the release mechanisms and
determine whether the dissolution procedure can show change in the critical quality attributes of a drug product.
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3. ANALYTICAL FINISH
The dissolution step has been described as an involved sample preparation. The sample handling and analytical procedure that
are used to determine the amount of drug substance dissolved during the dissolution procedure are termed the “analytical nish.”
Although spectrophotometric determinations and HPLC are used most commonly and are discussed in this chapter, any suitable
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analytical technology may be used. Section 5. Validation describes criteria for the methods.

3.1 Sample Processing

After the samples are withdrawn from the dissolution medium, they may require additional processing to make them suitable for
the analytical methodology used to determine the amount released. For example, ltration may be used to remove undissolved
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particulate matter, or samples may need to be protected from exposure to light or may need refrigerated storage. In addition, samples
may have to be diluted to a level that is within the linear range of the method. With analysis by HPLC, dilution of the sample with
mobile phase may be necessary to reduce the effect on the separation of injecting dissolution medium. Other types of treatment
may be necessary depending on the product formulation, such as the inactivation or elimination of interference caused by
components of the formulation by the addition of appropriate reagents. However, separation may not be possible or needed in all
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cases. In some cases, in situ measurements obtained with methods such as ber optics or electrochemical determination may be
useful.

3.2 Filters
The topic of ltration is discussed in section 1.1 Performing Filter Compatibility.

3.3 Centrifugation
Centrifugation of samples is not preferred, for several reasons: dissolution can continue to occur until the solids are removed, a
concentration gradient may form in the supernatant, and energy imparted may lead to increased dissolution of the drug substance
particles. Possible exceptions, when centrifugation could be preferred, might include the use with compounds that adsorb onto all
common lters, or situations when the potential lter leachables and extractables might interfere in the quantitative step of the
dissolution test (e.g., when uorescence procedures are used in quantitation). Centrifugation may prove useful during method
development for evaluating the suitability of the lter material.

3.4 Analytical Procedure

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The usual assay for a dissolution sample employs either a spectrophotometric procedure or a liquid chromatographic procedure.
Spectrophotometric determination may be direct or may provide the detection for HPLC. Spectrophotometric determination is used
often because results can be obtained faster, the analysis is simpler, it is easier to automate, and fewer solvents are needed. The use
of direct spectrophotometric determination typically requires con rmation of speci city. HPLC is preferred for a number of reasons
such as providing a wide dynamic range that reduces the need to dilute some samples while also providing sensitivity in the analysis
of dilute samples, and greater selectivity when excipients or multiple drugs in the formulation present a signi cant interference.
Modern HPLC systems employ autosamplers that provide speed and simplicity advantages comparable to spectrophotometric
analysis.

3.5 Spectrophotometric Analysis

Direct spectrophotometric analysis may be performed on samples that are manually introduced to the cuvette. Alternatively,
samples may be automatically introduced into the spectrophotometer using autosippers and ow cells. Routine performance checks,
cleaning, and maintenance, as described in the standard operating procedures or metrology documents, help to ensure reliable
operation of these instruments. Cells with path lengths ranging from 0.02 cm to 1 cm are typically used, and longer path-length
cuvettes can be used to increase the range for quanti cation of dilute samples. Cell alignment and air bubbles could be sources of
error. The shorter path-length cells are used to avoid diluting the sample; in all cases, however, acceptable linearity and standard error
need to be demonstrated.
The choice of wavelength for the determination should be based on the spectrum of the drug in solution. In some cases, where the
drug substance can degrade in the dissolution medium (e.g., dosage forms containing aspirin), it is useful to carry out the
measurements at the isosbestic point. Excipients can also have effects, but performing analysis at multiple wavelengths can
minimize their effects. The contribution of the absorbance from an excipient at the analytical wavelength can sometimes be
determined by ratio from its absorbance at a wavelength where the absorbance of the drug substance is minimal.
Using a validated analytical nish, standard solutions are typically prepared in dissolution media and analyzed at just one
concentration, either at 100% of the dosage strength or the selected Q value because linearity of the analytical nish has been

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established. Prior to validation, dissolution pro le analysis, or analysis of products of various strengths, requires using multiple
standard solutions covering the expected range of concentration. A typical media blank, standard, and sample may be analyzed in a
sequence that brackets the sample with standards and blanks, especially at the beginning and end of the analysis. The standard and
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sample solutions should both be prepared in the dissolution medium in the linear concentration range and measured at the same
wavelength. However, small amounts of an organic solvent may be used in the preparation of the standard, provided that the accuracy
criteria can be met during validation.
The absorptivity is calculated by dividing the mean standard absorbance by the concentration, in mg/mL, divided by the cell path
length in cm. A rearrangement of the Beer-Lambert expression gives the absorptivity, a, as:
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a = A/bc

A = absorbance
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b = path length (cm)

c = concentration (mg/mL)
Typical units for absorptivity that are used for dissolution testing are in terms of AU · mL/mg, where AU is absorbance unit.
Historical data may be used to provide an acceptable absorptivity range for the analyte (using the appropriate path-length cell). This
value may be useful in troubleshooting aberrant data.
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Fiber optics as a sampling and determinative method, with proper validation, are an option.

3.6 HPLC
For HPLC analysis, the effect on the chromatogram of peaks resulting from injection of dissolution media require enumeration. A
large solvent disturbance may affect accuracy and precision of response if it is poorly resolved from the peak of interest. This is even
more important if large injector volumes (>100 µL) are needed. System suitability tests may evaluate peak shape; separation of the
main peak from solvent disturbance and from closely eluting peaks; and injection precision. At a minimum, the precision is critical.
Ideally, the standard solutions should be diluted with the dissolution media at a concentration within the linear range of the
method, e.g., 100%, or the selected Q value of the dosage strength. However, organic solvent may be used in the preparation of the
standard, provided that the accuracy criteria can be met during validation. In some cases, the sample may be diluted with mobile
phase to improve the peak shape. The standard and sample solutions should both be prepared in the linear concentration range and
measured at the same wavelength.

4. AUTOMATION
Automated dissolution systems may be con gured in various ways and degrees. The elements of test preparation, initiation,
sampling and timing, and cleaning all can be automated. Fully automated systems are available, as are systems where individual

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steps, such as media preparation or sampling, are automated. This section will discuss operational steps that can be automated. The
level of complexity for automation depends on whether the instrument con guration is open or closed loop and also whether the
analytical device is coupled online or o ine. Online analysis returns the sample aliquot to the test system, as in the case of
spectrophotometry with ow-through cuvettes. O ine analysis removes the sample aliquot from the dissolution medium for
subsequent analysis, typically by HPLC, where the analysis consumes the sample. The decision on the con guration usually depends
on the number of samples to be processed and the time required for their analysis.
Automation may require deviations from the pharmacopeial speci cations of the instruments, such as incorporation of an
integrated outlet on the bottom of the vessel for cleaning and replacement of medium.
Operational steps that are not part of the compendial procedure should be validated. Deviations from the standard procedure
described in 〈711〉, such as use of sampling probes or ber-optic probes, should be validated against the standard procedure.

4.1 Medium Preparation

Automated media preparation generally is accomplished by diluting concentrates. Automated media preparation systems typically
dispense the volume of medium into the vessel by monitoring either the weight or volume. Chemical and physical stability of the
concentrates as well as homogeneity of the dilutions over the intended period of use are important issues and should be understood.
Concentrates of buffer solutions and surfactants may have stability issues, such as chemical degradation and pH change. Physical
instability may manifest as precipitation, re-crystallization, or phase separation and should be prevented.
If deaeration of the medium is required, the level of deaeration should be speci ed.
The concentration of the dissolved oxygen can be used to evaluate the e ciency of deaeration procedures discussed in section 2.1
Deaeration.

4.2 Sample Introduction and Timing

Samples should be inserted in the vessel in a reproducible way. Automated sample introduction and aliquot withdrawal provide an
advantage over manual sampling because the automated techniques can reduce the variability in the vessel-to-vessel timing of the
test intervals. However, automated sample handling may impose timing limitations that need to be considered. The pharmacopeial

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tolerance of ±2% of the speci ed dissolution test time may be di cult to meet for early time points.

4.3 Sampling and Filtration

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Autosampling is a useful alternative to manual sampling, especially if the test includes several time points. The transfer and
ltration of sample solutions from the dissolution instrument to the analytical unit may be undertaken via tube connections or via
robotic devices operated in a stepwise procedure. Sample volumes may be removed from the dissolution medium and not returned
(consumptive sampling), or the sample volume may be returned to the dissolution medium (recirculated sampling).
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There are many brands of autosamplers, including semi-automated and fully automated systems. Routine performance checks,
cleaning, and maintenance, as described in the pertinent standard operating procedures or metrology documents, help to ensure
reliable operation of these devices.
Sampling probes may or may not remain in the vessel throughout the entire run. Sampling probes or ber-optic probes can disturb
the hydrodynamics of the vessel; therefore, adequate validation should be performed to ensure that the probes are not causing a
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signi cant change in the dissolution rate. If lters are used that are different from those used for manual sampling, then these
different lters should also be evaluated separately. The position of the pharmacopeial sampling zone for Apparatus 1 and Apparatus
2 is midway from the top of the stirring element to the medium surface and depends on the medium volume. Sampling probes should
pull the sample from the sampling zone. Instruments for which the sampling occurs through the hollow shaft should be designed with
a means to adjust the depth of the inlet aperture to allow conformance with this requirement. The programmed sampling volume
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depends on the dead volume of the tubing, cuvettes, and other devices and has to be adjusted accordingly.
A recirculated sampling alignment can be operated either by discharging the tubing contents into the vessel after each sampling or
by allowing the tubing to remain lled with solution in the intervals between sampling points. In the latter case, the dead volume and
carryover effects are important considerations.
The need for sample volume replacement should be considered. In consumptive sampling with multiple sampling time points, the
withdrawn volume may be replaced with an equal volume of fresh medium. The sampling volume may be critical if, in total, it exceeds
1% of the stated volume of dissolution medium required by the procedure. If it can be shown that replacement of the medium is not
necessary, the volume change must be part of the calculation of results. See section 2.5 Data Handling.
Carryover may occur when subsequent samples are affected by residues or conditions of previous samples; the effect of the rst
sample or condition “carries over” to the second. In liquid handling, residues of liquids previously in the sample solution may
contaminate subsequent sample solutions. Dissolution media containing surfactants or lipids may present problems. Carryover may
occur for successive samples taken over a multiple time-point test, as well as at the beginning of a new test due to the cleaning
solution. This topic is discussed in section 4.4 Cleaning.
Interaction of dissolved drug substance with the sampling and transfer devices is an important consideration. When adsorption of
the dissolved drug substance occurs, it most often involves surfaces of the dissolution apparatus or sampling lters and tubing.

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Adsorption may be pH dependent in the case of charged, dissolved drug substance. Adsorption of the dissolved drug to the parts of
the sampling device should be assessed using a typical sample solution ( dissolution sample from the product or drug substance
with formulation matrix) with known concentration. The typical design is a cross-validation with aliquots of the same sample solution
passing and bypassing the sampling device (including the sampling probe, lter, tubing, valves, and pump). There is no general
recommendation that may give preference to any kind of material or equipment construction (e.g., glass or speci c polymers). See
section 5.7 Considerations for Automation for more information.
In addition to the information in section 2.4.3 Sampling, connections of pumps and tubing may be sources of contamination in
automated systems. Interferences with the spectroscopic analytical procedures, which are commonly used for dissolution testing,
are less of a concern. However, interferences must be evaluated if the product under investigation contains low-dose metal salts, as
do some dietary supplements.
Liquid transfer usually is undertaken via polymeric tubing. Inert materials such as polytetra uoroethylene (PTFE) sometimes
cannot be used because of their mechanical properties. Where exible tubes are required, for example in peristaltic pumps or for
coiling in a small radius, polypropylene (PP) or high-density polyethylene (HDPE) may be the preferred materials. Depending on the
type of polymer and its crystallinity and density, leaching of constituents, mainly plasticizers, may occur. Leachables can interfere
with the analytical procedure. The concentration leached to the sample solution usually depends on the surface, the temperature, the
exposure time, the hydrodynamic conditions, and the composition of the media.

4.4 Cleaning
In addition to the information in section 2.4.4 Cleaning, automated systems have speci c cleaning issues. For example, evaluation
of the effectiveness of purging and rinsing between sampling times and within-run condition of the tubing is recommended. Also it is
important to evaluate the cleaning process between tests.

4.5 Operating Software and Computation of Results

The software systems for data evaluation and instrument operation must be validated as per 21 CFR 11 (17).

4.6 Common Deviations from the Compendial Procedures That May Require Validation

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Some common areas of deviation from compendial procedures include the following:
Sample introduction relative to start of spindle rotation
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Residence time and positioning of sampling probes
Recirculated versus consumptive sampling
Sample volume replacement in consumptive sampling.
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5. VALIDATION
The validation topics described in this section are typical but not all-inclusive and can be viewed in the context of Validation of
Compendial Procedures 〈1225〉, as well as the International Conference on Harmonization (ICH) document, Validation of Analytical
Procedures (18). Validation for both parts of the dissolution procedure, the analytical nish and the dissolution step, will be
discussed in this section. The dissolution step is the release of the drug in the dissolution medium and sampling. The analytical
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nish is de ned in section 3. Analytical Finish. Validation of the analytical nish will evaluate the attributes, linearity and range,
precision, speci city, accuracy/recovery, robustness, and stability of the sample and standard solutions. Validation of the dissolution
step will include evaluation of precision and robustness of the dissolution sample preparation. Validation of the analytical nish is
performed either using a standard solution or spiked placebo or by the method of standard addition (spiked drug product as
described in Accuracy in 〈1225〉), as speci ed in the sections below. Validation of the dissolution step requires the use of a well-
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characterized dosage form (e.g., having tight content uniformity and uniform performance). Depending on the parameter of interest,
validation of the sample handling and analytical procedure can be performed in situ, e.g., within the dissolution vessel. The validation
parameters addressed and the extent of the validation may vary, depending on the phase of development or the intended use for the
data.
The acceptance criteria are presented as guidelines only, and may differ for some products. Manufacturers should document the
appropriate acceptance criteria for their products in pertinent Standard Operating Procedures (SOPs) or in validation protocols. Other
considerations may be important for special dosage forms. Validation studies should be performed across the range of pro le time
points. For products containing more than a single active ingredient, the dissolution procedure needs to be validated for each active
ingredient. It is expected that investigations into lter suitability and the potential for glass adsorption will have been undertaken
already (see 1.1 Performing Filter Compatibility). Validation of these assessments may occur during spiked recovery experiments.

5.1 Speci city/Placebo Interference

It is necessary to demonstrate that the results are not unduly affected by placebo constituents, other active drugs, or degradants.
The placebo consists of all the excipients and coatings, with inks and capsule shells included if appropriate, without the active
ingredient. Placebo interference can be evaluated by using a spiked placebo that is prepared by weighing samples of the placebo

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blend, dissolving or dispersing them in dissolution medium at concentrations that would be encountered during testing, and adding a
known amount of the drug in solution. It may be preferable to perform this experiment at 37°, comparing the solution to a standard
solution at the concentration expected to be encountered during testing, by using the formula:

Result = (AP/AS) × CS × (V/L) × 100

AP = absorbance of the placebo

AS = absorbance of the standard
CS = concentration of the standard (mg/mL)
V = volume of the medium (mL)
L = label claim (mg)
The interference should not exceed 2%. Note that for extended-release products, a placebo version of the nished dosage form
may be more appropriate than blends because this placebo formulation will release the various excipients in a manner more nearly
re ecting the product than will a simple blend of the excipients. In this case, it may be appropriate to evaluate potential interference at
multiple sampling points in the release pro le, with worst-case interference expected at the later sampling points.
The blank is the dissolution medium without dissolved sample, and it is treated in the same manner as the sample. The effect of
the absorbance of the blank at the analytical wavelength should be evaluated. In most cases, the absorbance of the dissolution
medium blank may not exceed 1% of the standard solution at the concentration used for analysis. Values >1% should be evaluated on
a case-by-case basis.
If the placebo interference exceeds 2%, modi cation of the method may be necessary. Possible modi cations include choosing
another wavelength, subtracting baseline using a longer wavelength, transforming absorbance values (e.g., rst derivative), and using
an alternative analytical technique such as HPLC. Other means for minimizing the placebo interference would be acceptable with
appropriate justi cation. When other active drug substances or signi cant levels of degradants are present, it is necessary to show

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that these do not signi cantly affect the results. One procedure for doing this is to measure the matrix in the presence and absence of
the other active drug substance or degradant: any interference should not exceed 2%. Similar approaches may be used if other
techniques are used for the analytical nish.
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5.2 Linearity and Range
Linearity is typically established by preparing solutions of the drug substance, ranging in concentration from less than the lowest
expected concentration to more than the highest concentration during release. The solutions may be prepared either using either a
standard solution or spiked solution or by the method of standard addition. A minimum of ve concentrations is normally used (see
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〈1225〉). Typically, solutions are made from a common stock if possible. The concentration range may not exceed the linearity limits
of the method, including the instrumentation. Organic solvents may be used to enhance drug solubility for the preparation of the
linearity standard solutions. However, no more than 5% (v/v) of organic solvent should be present in the nal solution unless
validated. Linearity is typically calculated by using an appropriate least-squares regression program. Typically, a square of the
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correlation coe cient (r2 ≥ 0.98) demonstrates linearity. In addition, the y-intercept must not be importantly different from zero.
The range of the procedure is the interval between the upper and lower concentrations of the drug substance (including these
levels) that has been demonstrated to have a suitable level of precision, accuracy, and linearity using the procedure as written.

5.3 Accuracy/Recovery
Accuracy/recovery is typically established by preparing multiple samples containing the drug substance and any other constituents
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present in the dosage form (e.g., excipients, coating materials, capsule shell) ranging in concentration from less than the lowest
expected concentration to more than the highest concentration during release. Accuracy/recovery may be done in conjunction with
linearity determination. The method of standard addition can also be used. Before this activity, it is expected that lter assessment
will already have been performed, and adsorption of drug onto the glass has also been investigated and ruled out.
Individual solutions may be directly prepared in the dissolution medium. Alternatively, to enhance drug solubility it may be
appropriate to prepare a stock solution by dissolving the drug substance in a small amount of organic solvent (typically not exceeding
5% organic solvent in the nal dissolution media) and diluting to the nal concentration with dissolution medium. An amount of
stock solution equivalent to the targeted label claim may be used instead of the drug substance powder. Similarly, for very low
strengths, it may be more appropriate to prepare a stock solution than to attempt to weigh very small amounts.
The measured recovery is typically 95%–105% of the amount added. Bracketing or matrixing of multiple strengths may be useful. A
special case for validation is the Acid Stage procedure described in 〈711〉, Delayed-Release Dosage Forms. The limit of NMT 10%
needs to be validated. Recovery experiments for drugs that have low solubility in acidic media may be challenging or impossible to
perform and may need to be addressed on a case-by-case basis. If the compound degrades in acid, the validation experiment must
address this fact.

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5.4 Precision

5.4.1 REPEATABILITY OF ANALYSIS

For the analytical nish, repeatability is evaluated by obtaining replicate measurements of standard and/or spiked
placebo/standard addition solutions. It can be determined by calculating the RSD of the multiple injections or spectrophotometric
readings for each standard solution, or by using the accuracy or linearity data. ICH guidance, Validation of Analytical Procedures:
Methodology, recommends that repeatability should be assessed using a minimum of nine determinations covering the speci ed
range for the procedure (i.e., three concentrations and three replicates of each concentration) or using a minimum of six
determinations at 100% of the test concentration. A typical acceptance criterion is an RSD of <2%. The demonstration of the
repeatability for the dissolution step is conducted by performing the dissolution step on separate units of a well-characterized
dosage form or equivalent composite.

5.4.2 INTERMEDIATE PRECISION/RUGGEDNESS

Assuming that the major contributor to the variance is from the dissolution step, intermediate precision may be evaluated to
determine the effects of random events on the precision of the dissolution procedure. This evaluation is typically done later in the
development of the drug product and is required for full method validation. For many analytical procedures intermediate precision is
typically assessed by determination of contributions to variance and, possibly, by a comparison of means. The use of an
experimental matrix design is encouraged for evaluation of intermediate precision because interaction effects may be observed
more clearly relative to a single variable experiment. In dissolution testing, a ruggedness approach that compares means alone is
often taken to investigate the factors that contribute to intermediate precision. The ruggedness can be evaluated across the range of
product strengths. Typical variations to be studied include different days, analysts, and equipment. If possible, ruggedness can be
evaluated using a drug product lot if well characterized, for example, by having tight content uniformity and uniform performance,
but if this type of lot is not available, a premeasured placebo with active ingredients may be used to investigate the intermediate
precision. The use of such a spiked placebo would additionally support the assessment of the contribution of the analytical nish to
the observed variability of results.

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The dissolution procedure on the same lot of well-characterized dosage form may be run by at least two different analysts from
the same laboratory, with each analyst preparing the standard solutions and the medium and following the de ned
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extraction/quanti cation procedure. Typically, the analysts use different dissolution baths, spectrophotometers or HPLC equipment
(including columns), and autosamplers, and they perform the test on different days. Full pro les are assessed where relevant to the
product. This procedure may not be necessary at each strength; instead, bracketing with high and low strengths may be acceptable.
Acceptance criteria for intermediate precision or for ruggedness are predetermined. A typical acceptance criterion for ruggedness
is that the difference in the mean value for dissolution results between any two conditions, using the same strength, does not
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exceed an absolute 10% at time points with <85% dissolved and does not exceed 5% for time points >85%. Acceptance criteria may
be product speci c, and other statistical tests and limits may be used.

5.4.3 REPRODUCIBILITY
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Reproducibility follows the general concepts of intermediate precision, but is performed by two different analysts at different labs.

5.5 Robustness
Evaluation of robustness, which assesses the effect of making small, deliberate changes to the dissolution conditions, typically is
done later in development of the drug product and is a requirement for full method validation. It is performed using a well-
characterized lot of drug product, for example having tight content uniformity and uniform performance. The number of replicates
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(typically 3 or 6) is dependent on the intermediate precision. All pro le points should be evaluated.
Selection of parameters to be varied depends on the dissolution procedure and analysis type. The parameters may include
medium composition (e.g., buffer or surfactant concentration, pH, deaeration), volume, agitation rate, sampling time, and
temperature. Statistical analysis of the data generated will help determine the extent to which the parameters must be controlled in
the method. The robustness assessment is well suited to Design of Experiments (DoE) methodologies to e ciently investigate the
impact of the individual parameters and/or their interaction.
Robustness of analytical nish is referenced in 〈1225〉. HPLC analysis parameters may include mobile phase composition
(percentage organic, buffer concentration, pH), ow rate, wavelength, column temperature, and multiple columns (of the same type).
For spectrophotometric analysis, the wavelength may be varied.

5.6 Stability of Standard and Sample Solutions

The standard solution is stored under conditions that ensure stability. The stability of the standard solution is analyzed over a
speci ed period of time (for at least the time of the entire dissolution procedure), using a freshly prepared standard solution at each
time interval for comparison. The acceptable range for standard solution stability is in uenced by the concentration and is typically
between 98% and 102% at the expected nal concentration.

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The sample solution is typically stored at room temperature. The sample is analyzed over a speci ed period of time, using the
original sample solution response for comparison. The typical acceptable range for sample solution stability may be between 98%
and 102%, compared with the initial analysis of the sample solutions. If the solution is not stable, aspects to consider include
temperature (refrigeration may be needed), light protection, and container material (plastic or glass).
The procedure may state that the standards and samples need to be analyzed within a time period demonstrating acceptable
standard and sample solution stability.

5.7 Considerations for Automation

Automated methods offer opportunities for increased precision and reproducibility; however, bias may be introduced. In particular,
the sampling probe and the sample lines warrant attention as places where inaccuracies may occur. Deviations from the procedure
described in 〈711〉, such as resident sampling probes, sampling through the stirring element shaft (hollow-shaft sampling), or ber-
optic probes, should be validated. Other aspects of automation validation may include carryover of residual drug, effect of an in-
residence probe, adsorption of drug, and cleaning and/or rinse cycles. Validation is performed using the automated dissolution
system including materials. Therefore, any change in materials will require demonstration of suitability based on the validation
attributes that are impacted by the change.
Manual and automated procedures should be compared to evaluate the interchangeability of the procedures. This is done by
performing two automated runs at each dosage concentration, using all sampling points, compared to manually sampled runs of the
same samples. The effect of the in-resident probe cannot be determined by sampling both ways from the same vessel. Results
should be consistent with the requirements for intermediate precision if the procedures are to be considered interchangeable. The
difference in the mean value for dissolution results between any two conditions using the same strength should not exceed an
absolute 10% at time points with <85% dissolved nor exceed 5% for time points >85%. Acceptance criteria may be product speci c,
and other statistical tests and limits may be used.
Revalidation may be necessary when the automated system is used with different formulations because of the interaction with
excipients. Dissolution media containing surfactants or lipids may require additional validation efforts.

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6. ACCEPTANCE CRITERIA
The acceptance criteria should be consistent with historical release or stability data. There is an expectation that acceptable
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batches will have results that fall within the acceptance criteria and that all manufactured batches should have similar dissolution
behavior, thus highlighting the importance of having a method that is not highly variable. The acceptance criteria and time point(s),
therefore, should discriminate between an acceptable and an unacceptable batch. In addition, the dissolution test results are viewed
as a link to the pivotal clinical trial batches. When changes in dissolution rate have been shown to affect bioavailability signi cantly,
the dissolution test and acceptance criterion should distinguish batches with unacceptable bioavailability (19). Likewise, when
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changes in the formulation and manufacturing process signi cantly affect dissolution and such changes are not controlled by
another aspect of the speci cation, the dissolution test and criteria should distinguish these changes.

6.1 Immediate-Release Dosage Forms

Although release and stability data are collected during dosage form development, it is common to record the entire dissolution
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pro le or the amount of drug dissolved at speci ed intervals, such as 10, 20, 30, 40, 50, and 60 min or 15, 30, 45, and 60 min. At
registration, dissolution for an immediate-release tablet usually becomes a single-point test. The acceptance criterion and test time
are established by evaluating the dissolution pro le data. The acceptance criterion for a dissolution test is a function of Q, which is
expressed as a percentage of label claim of drug dissolved at a speci ed time. Typical Q values are in the range of 75%–80%
dissolved. Q values in excess of 80% are not generally used because allowance needs to be made for assay and content uniformity
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ranges.

6.2 Delayed-Release Dosage Forms

The discussion about dissolution of delayed-release dosage forms in 〈711〉 focuses on enteric-coated dosage forms, which is the
most common delayed-release dosage form. A dissolution test for a delayed-release tablet or capsule is a two-part test, and each
part has acceptance criteria. First, the dosage forms are exposed to an acid medium, followed by exposure to a buffer medium. To
ensure that the enteric coating performs properly, a “NMT” acceptance criterion is indicated in 〈711〉 for the acid stage. The medium
used for an acid stage is usually 0.1 N HCl, and the duration of this stage is typically 2 h. The dosage forms are then exposed to a
buffer medium, usually 0.05 M phosphate buffer at pH 6.8, but other buffers and pH targets may be used if justi ed. The duration of
the buffer stage is usually 45 min for compendial tests, but this duration may vary, depending on the drug product. As with immediate-
release dosage forms, a Q value and time point are determined by evaluating the entire dissolution pro le.

6.3 Extended-Release Dosage Forms

A dissolution test for an extended-release dosage form is generally similar to that used for an immediate- or delayed-release drug
product, except that the duration of the test is longer, and at least three time points are speci ed for pharmacopeial purposes (20).

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Additional sampling times may be required for drug approval purposes. An early time point, usually 1–2 h, is chosen to show that
dose dumping is not probable. An intermediate time point is chosen to de ne the in vitro release pro le of the dosage form, and a
nal time point is chosen to show essentially complete release of the drug (20). The time points for the test should be determined by
evaluating the dissolution pro le across the desired test duration. Often, additional time points are obtained during dosage form
development to aid with selecting the appropriate time points for the speci cation or monograph.
As with an immediate- or delayed-release drug product, the acceptance criteria and time points for an extended-release drug
product should discriminate between an acceptable and an unacceptable batch. The acceptance criteria for the rst stage of testing
(L1) should be established on the basis of available batch data (19,20). If human bioavailability data are available for formulations
exhibiting different release rates, then an in vitro/in vivo relationship may be used to establish acceptance criteria (19,20). Acceptance
criteria for the second (L2) and third (L3) stages are derived from the L1 criteria using Acceptance Table 2 in 〈711〉.

6.4 Multiple Dissolution Tests

Typically, monographs for extended-release dosage forms contain multiple dissolution tests representing speci c products. In
accordance with General Notices, 4.10.10 Applicability of Test Procedures, the appropriate test, if not Test 1, is indicated on the
product labeling. For example, the USP monograph for Oxycodone Hydrochloride Extended-Release Tablets (21) lists two dissolution
tests, each of which has either three or four time points. If the Tablets are analyzed using Test 2 and the dissolution results comply
with the criteria provided in the monograph, the labeling for Tablets can indicate that the Tablets meet USP Dissolution Test 2.
Multiple dissolution tests also can be found in monographs for immediate- and delayed-release dosage forms. For example, the USP
monographs for Levothyroxine Sodium Tablets and Pantoprazole Sodium Delayed-Release Tablets provide four dissolution tests
(22,23).

6.5 Interpretation of Dissolution Results

The Interpretation section of 〈711〉 discusses immediate-, delayed-, and extended-release dosage forms. The discussion for each of
these release patterns is expanded here with examples to assist with applying the criteria during the various stages of testing.

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Understanding how these criteria are applied will assist in setting appropriate acceptance criteria.

6.5.1 IMMEDIATE-RELEASE DOSAGE FORMS

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Once the Q value is established, the dissolution test is a staged test of three levels. In the rst level of testing called S1, six
dosage forms are tested. Each dosage form must be Q + 5% (absolute percentage points) dissolved at a speci ed time. For
example, the time and tolerances in a monograph would be:
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Time: 30 min
Tolerances: NLT 80% (Q) of the labeled amount of “drug substance” is dissolved.
If the Q value for a 200-mg label claim (LC) immediate-release tablet is speci ed as 80% and the time point is 30 min, then NLT
85% LC (170 mg) of the drug substance in each tablet must be dissolved at 30 min.
If this criterion is not met, then 6 additional tablets are tested at level 2 (S2). To pass the S2 acceptance criteria, the average of all
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12 tablets must be equal to or greater than Q (80% LC; 160 mg in the above example), and no tablet has less than Q – 15% (65% LC;
130 mg in the above example).
If these criteria are not met, then level 3 or S3 testing must be performed by testing 12 additional tablets. To pass S3, the average
of all 24 tablets must be equal to or greater than Q (80% LC; 160 mg in the above example). Two additional criteria must be met as
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well: 1) no more than 2 tablets are less than Q – 15% (65% LC; 130 mg in the above example), and 2) no tablet is less than Q – 25%
dissolved (55% LC; 110 mg in the above example.)

6.5.2 DELAYED-RELEASE DOSAGE FORMS

An aliquot of the acid medium from each vessel is analyzed at the end of the acid stage. For the acid stage, the acceptance
criteria have three levels. Level 1 (A1) testing is passed if no individual value exceeds 10% dissolved. If the A1 criteria are not met,
then the dissolution test is performed on 6 additional dosage forms for level 2 (A2) testing. Level A2 criteria are passed if the
average of all 12 dosage forms in the acid stage is NMT 10% dissolved and if no individual dosage form is more than 25% dissolved.
Level 3 testing is performed if the A2 criteria are not met. The A3 criteria are passed if the average of all 24 dosage forms in the acid
stage is NMT 10% dissolved and if no individual tablet is more than 25% dissolved. For the special case in which the solubility of the
drug in an acidic medium because of conversion to the free acid is too low to support an acceptance criterion of not more than 10%
the drug product should be exposed to the acid stage for the de ned duration and then exposed to the buffered medium. Alternate
acceptance criteria for the acid stage based on drug solubility may be justi ed.

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For delayed-release dosage forms, the total percentage dissolved is determined by adding the measured amounts in the acid and
buffer phases for each individual dosage form. These calculated values are then compared to staged acceptance criteria (B1, B2, and
B3) that are based on a Q value. The B1, B2, and B3 criteria are identical to those for the immediate release S1, S2, and S3 criteria.

6.5.3 EXTENDED-RELEASE DOSAGE FORMS

In the following hypothetical example, which is used to describe the criteria for an extended-release dosage form, the time points
are 1, 4, and 8 h. The acceptance range for each time point is as follows:
Between 24% and 44% LC drug substance dissolved at 1 h
Between 56% and 76% LC drug substance dissolved at 4 h
NLT 85% LC drug substance dissolved at 8 h.
Acceptance ranges are often expressed in tabular form in the USP–NF (see Table 3):

Table 3. L1 Criteria

Time (h) Amount Dissolved

1 24%–44%

4 56%–76%

8 NLT 85%

Six tablets are analyzed at Level 1 (L1); acceptance criteria are met if no individual value lies outside each of the stated ranges,
and no individual value is less than the percentage speci ed for the nal time point. If the L1 criteria are not met, then 6 additional

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tablets are analyzed at level 2 (L2). The L2 criteria are met if these three conditions are met:
1. The average value of the 12 tablets lies within each of the stated ranges and is NLT the stated range of the nal time point.
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2. None of the 12 tablets is >10% of the labeled content outside each of the stated ranges.
3. None of the 12 tablets is >10% of the labeled content below the stated amount at the nal test time.
For the above example, the L2 acceptance criteria for the 12 tablets (see Table 4) are as follows:

Table 4. L2 Criteria
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1h 4h 8h

Average 24%–44% 56%–76% NLT 85%

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Individual tablets 14%–54% 46%–86% NLT 75%

If the L2 criteria are not met, then 12 additional tablets are tested at level 3 (L3). The L3 criteria are met if these ve conditions are
met:
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1. The average value of the 24 tablets lies within each of the stated ranges and is NLT the stated range of the nal time point.

2. NMT 2 of the 24 tablets are >10% of labeled content outside each of the stated ranges.

3. NMT 2 of the 24 tablets are >10% of the labeled content below the stated amount at the nal test time.

4. None of the 24 tablets is >20% of the labeled content outside each of the stated ranges.

5. None of the 24 tablets is >20% of the labeled content below the stated amount at the nal test time.

The L3 acceptance criteria for the 24 tablets in the above example are summarized in Table 5:

Table 5. L3 Criteria

1h 4h 8h

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1h 4h 8h

Average 24%–44% 56%–76% NLT 85%

NMT 2 tablets are outside the NMT 2 tablets are outside the
range of 14%–54%, and no range of 46%–86%, and no NMT 2 tablets release <75%
individual tablet is outside the individual tablet is outside the and no individual tablet
Individual Tablets range of 4%–64% range of 36%–96% releases <65%

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23. USP. USP 36–NF 31, Pantoprazole Sodium Delayed-Release Tablets. Rockville, MD: USP; 2013:4682–4686.

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6/17/2020 USP-NF 〈1092〉 the Dissolution Procedure: Development and Validation

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<1092> THE DISSOLUTION PROCEDURE Margareth R.C. Marques GCDF2015 General Chapters-Dosage
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