A

Project work
On

COMPARE MARKETED PREPARATION OF SOLID

AND SEMISOLID DOSAGE FORM

Submitted for
Partial fulfilment of the requirement for the award of degree of

BACHELOR OF PHARMACY

Session 2024-25

SITA RAM KASHYAP COLLEGE OF

PHARMACY, RAHOD, JANJGIR-CHAMPA (C.G.)
 SITA RAM KASHYAP COLLAGE OF PHARMACY,
RAHOD, JANJGIR-CHAMPA (C.G.)
(Affiliated by CSVTU Bhilai C.G.)

FORWARDING CERTIFICATE

This is to certify that Mr. ANADIRANJAN SHARMA S/o SHRI ASHOK SHARMA
student of B. Pharm. 7th semester, SITARAM KASHYAP COLLAGE OF PHARMACY,
RAHOD, JANJGIR- CHAMPA (C.G.) has submitted his PROJECT entitled " Compare
Marketed Preparation Of Solid And Semisolid Dosage Form” for the Partial fulfilment of
the requirement for the award of degree of Bachelor of Pharmacy (practice school).He has
completed his project under the supervision of Miss SARITA PAIKRA. (Assi. Prof. SRKCOP).
His work is original, satisfactory and has not submitted anywhere else for the award of any
degree.

I here recommend this project for the award of the degree of B. pharmacy (practice school)
during the academic year 2021-2025

I hereby forward his project work in B. Pharm. during the academic session 2024-2025.

Date :- Forwarded By

PRINCIPAL SRKCOP, RAHOD

 SITA RAM KASHYAP COLLEGE OF PHARMACY,
RAHOD, JANJGIR-CHAMPA (C.G.)
(Affiliated by CSVTU Bhilai C.G.)

CERTIFICATE
This is to certify that Mr. ANADIRANJAN SHARMA student of B. pharm 7th
semester, SITARAM KASHYAP COLLAGE OF PHARMACY, RAHOD,
JANJGIR -CHAMPA (C.G.) has submitted project entitled for " Compare
Marketed Preparation Of Solid And Semisolid Dosage Form, for the partial fulfilment
of the requirement for the degree of Bachelor of Pharmacy. He has completed his
project under my supervision.

I hereby recommend this project work for the Award of Degree

of Bachelor of Pharmacy during the academic session 2021-2025.

Date:- Supervisor

Miss Sarita Paikra

(Assis. Prof. SRKCOP)

 SITA RAM KASHYAP COLLAGE OF PHARMACY,
RAHOD, JANJGIR-CHAMPA (C.G.)
(Affiliated by CSVTU Bhilai C.G.)

DECLARATION

I hereby declare that the project entitled " Compare Marketed Preparation Of Solid
And Semisolid Dosage Form " was done by me and the entire work was under the
esteemed supervision of Miss SARITA PAIKRA. (Assi. Prof. SRKCOP) for the
submission of project for the partial fulfilment of the requirement for the Degree
of Bachelor of Pharmacy.

I further declare that I have not submitted this project/practice school

previously for award of any degree or diploma anywhere else.

Name Anadiranjan Sharma

Date: - LOMASH
B. Pharm. (7th sem.)

Enroll.no. CB2510

SRKCOP, RAHOD, C.G.

 ACKNOWLEDGMENT

First of all, thanks to the Supreme Power of the Almighty god for the shiners of testing let my
research work to complete the research successfully a great pleasure to acknowledge my
deepest thanks and gratitude to everyone who appraised me throughout the course of the work.
I wish to extend my sincere and heartfelt ligation to work all the personages who have helped
me in this endeavour Without your support and encouragement, I would not have completed
my work.

I would like to express my special thanks in my guide Miss. SARITA PAIKRA, (assis. Prof.
SRKCOP), Sitaram Kashyap college of Pharmacy, Rahod, C.G. for his supervision, guidance
and support from the total duration of this research as well as giving me the golden opportunity
to do this wonderful project throughout the work which also helped me in doing a lot of
research and I came to know about so many new things Thank you sir, you made me believe in
me. I am indebted to you for giving me the time, space and suggestions for making me to
complete my project within time.

I also thank my cooperative Asst. Prof Dr. Jwala Patel, Mr. Kishan lal Bharti for their constant
efforts and support throughout my project work.

My deepest gratitude goes to my family who stood with me at all the time and whose support
enabled me to stand confidently against all difficult time.

My Sincere thanks to all

 Index

S.no Index Page no.

INTRODUCTION
1. 01-02
2. LITERATURE REVIEW
03-04
3. MATERIAL AND METHODS
05-15
4. CONCLUSION
16
5. REFERENCES 17-22
INTRODUCTION
Interest in Lipid Based Drug Delivery (LBDD) has developed over the past decade fuelled by
a better understanding of the multiple roles lipids may play in enhancing oral bioavailability.
Moreover, the emergence of novel excipients with acceptable regulatory and safety profiles
coupled with advances in formulation technologies have greatly improved the potential for
successful lipid based formulations. With the growing interest in this field, there is an
increasing need for guidelines in excipient selection and characterization; material handling,
formulation design, and processing techniques to obtain effective and patient-compliant dosage
forms. The aim of this review is to present the recent approaches in selecting the most
appropriate lipid system(s); methods for characterization of their behavior in vitro and in vivo;
and the current formulation and processing techniques to obtain various solid dosage forms.

Depending on the choice of excipient(s) and formulation techniques, it is possible to obtain a

variety of systems including physical mixtures, liquid/solid solutions, solid dispersions, and
Self-Micro or Self-Nano Emulsifying Drug Delivery Systems (SMEDDS/SNEDDS). These
systems may then be incorporated into capsules directly, or transformed into granules, pellets,
and powders for dry filled capsules as well as tablet preparations. The latter are possible by
innovative adaptations of conventional equipment with relative ease and process simplicity,
using methods like melt granulation, adsorption on solid support, spray cooling, melt-
extrusion/spheronization.

A prerequisite to formulating with lipids is the ability to differentiate among the classes of
lipids in relation to their physical–chemical properties and the mechanism of absorption
enhancement. Appropriate selection of lipid excipients and formulation strategies at the earliest
stages of drug development can lead to considerable savings in cost and time to reach market.
This necessitates a review of the current definitions and classifications for oral lipid-based
excipients and methods for characterizing their chemical, physical and biochemical behavior.

This review thus begins with definition of the lipid classes, rationale for excipient selection,
methods for characterization of their behavior in vitro and in vivo, followed by an overview of
current formulation and processing techniques to obtain various solid dosage forms.

In drug discovery, about 40% of new drug candidates display low solubility in water, which
leads to poor bioavailability, high intrasubject/intersubject variability and lack of dose
proportionality. Furthermore, oral delivery of numerous drugs is hindered owing to their high
hydrophobicity 1, 2. Therefore, producing suitable formulations is very important to improve
the solubility and bioavailability of such drugs.

One of the most popular and commercially viable formulation approaches for solving these
problems is self-emulsifying drug delivery systems (SEDDS). SEDDS have been shown to be
reasonably successful in improving the oral bioavailability of poorly water-soluble and
lipophilic drugs [3]. Traditional preparation of SEDDS involves dissolution of drugs in oils and
their blending with suitable solubilizing agents. However, SE formulations are normally
prepared as liquids that produce some disadvantages, for example, high production costs, low
stability and portability, low drug loading and few choices of dosage forms. Irreversible
drugs/excipients precipitation may also be problematic [4]. More importantly, the large
quantity (30–60%) of surfactants in the formulations can induce gastrointestinal (GI) irritation.

To address these problems, S-SEDDS have been investigated, as alternative approaches. Such
systems require the solidification of liquid self-emulsifying (SE) ingredients into
powders/nanoparticles to create various solid dosage forms (SE tablets 5, 6 and SE pellets 7,
8, and so on). Thus, S-SEDDS combine the advantages of SEDDS (i.e. enhanced solubility and
bioavailability) with those of solid dosage forms (e.g. low production cost, convenience of
process control, high stability and reproducibility, better patient compliance.).

To date, there have been some studies that mainly focus on the preparation and characterization
of a single, solid SE dosage form, yet relatively few that introduce S-SEDDS in a systemic
way, especially with respect to dosage form development and preparation techniques.
LITERATURE REVIEW
1. Michael E. Herbig et al (2001) reported that During the past decades, progress has been
made in the understanding of the design and characterization of semi-solid dosage
forms. Furthermore, knowledge of driving forces for skin penetration and the influence
of the formulation vehicle in this process has grown.

2. Dirk-Heinrich Evers et al (2002) reported that The characterization of semi-solid

formulations is discussed with a special focus on modern rheological approaches and
analytical methods for investigating and optimizing the chemical stability of active
ingredients in consideration of applicable guidelines. In conclusion, the combination of
a good understanding of scientific principles combined with early consideration of
regulatory requirements for product quality are enablers for the successful development
of innovative and robust semi-solid formulations for topical application.

3. Sascha Gorissen et al (2002) reported that More than many other dosage forms, topical
formulations can directly influence the wellbeing of the patient. They may provide
instant relief–or discomfort. Effects on the skin, like hydration and trans-epithelial water
loss, may persist for several hours.

4. Melanie Köllmer et al (2003) reported that Topical semi-solid formulations, especially

when emulsion-based, are often systems of high complexity, requiring sophisticated
approaches for the characterization of chemical, physical, and microbial stability.

5. Herbig et al (2003) reported that The rheological characterization of semi-solid

formulations provides an important source of information on various aspects relevant to
the systematic development and characterization of semi-solid formulations

6. M.E. Evers et al (2003) reported that An approach to rational formulation design based
on a systematic formulation design around the specific physicochemical properties of
an API can help to combine the requirements for quality with innovative formulation
approaches and optimization of aesthetic appeal and performance of formulations.
7. D.-H. Gorissen et al (2003) reported that, a reason for that may be the strong impact of
aspects of product quality in the strategy and risk management of topical development
projects in combination with increased risks of physical and chemical instability as
compared to peroral dosage forms.

8. S. Köllmer et al (2003) reported that A further aspect of importance for the

understanding of topical formulations and their rational design is the understanding of
partitioning or distribution between different phases of a formulation, most importantly,
between the water and oil phases of emulsion-type systems.

9. B. Michniak et al (2003) reported that The individual guidelines and their specific
requirements should not be discussed within the scope of this article, but their
consequences for product development shall be briefly outlined. Quality, according to
ICH Q6, is “the suitability of either a drug substance or drug product for its intended
use.

10. Bozena Kohn et al (2003) reported that One attribute that is always specified is the assay of
the active ingredient(s) (API). The standard limit is 95–105% of the declared concentration in
Europe and 90–110% in the US.
MATERIALS AND METHOD

SOLID SELF-EMULSIFYING DRUG DELIVERY SYSTEM

SEDDS can exist in either liquid or solid states. SEDDS are usually, however, limited to liquid dosage
forms, because many excipients used in SEDDS are not solids at room temperature. Given the
advantages of solid dosage forms, S-SEDDS have been extensively exploited in recent years, as they
frequently represent more effective alternatives to conventional liquid SEDDS. From the perspective
of dosage forms, S-SEDDS mean solid dosage forms with self-emulsification properties. S-SEDDS focus
on the incorporation of liquid/semisolid SE ingredients into powders/nanoarticles by different
solidification techniques (e.g. adsorptions to solid carriers, spray drying, melt extrusion, nanoparticle
technology, and so on). Such powders/nanoparticles, which refer to SE nanoparticles [14]/dry
emulsions/solid dispersions, are usually further processed into other solid SE dosage forms, or,
alternatively, filled into capsules (i.e. SE capsules). SE capsules also include those capsules into which
liquid/semisolid SEDDS are directly filled without any solidifying excipient. To some extent, S-SEDDS
are combinations of SEDDS and solid dosage forms, so many properties of S-SEDDS (e.g. excipients
selection, specificity, and characterization) are the sum of the corresponding properties of both SEDDS
and solid dosage forms. For instance, the characterizations of SE pellets contain not only the
assessment of self-emulsification, but also friability, surface roughness, and so on. In the 1990s, S-
SEDDS were usually in the form of SE capsules, SE solid dispersions and dry emulsions, but other solid
SE dosage forms have emerged in recent years, such as SE pellets/tablets, SE
microspheres/nanoparticles and SE suppositories/implants.
SOLIDIFICATION TECHNIQUES FOR TRANSFORMING LIQUID/
SEMISOLID SEDDS TO S-SEDDS

Capsule filling with liquid and semisolid self-emulsifying formulations

Capsule filling is the simplest and the most common technology for the encapsulation of liquid or
semisolid SE formulations for the oral route. For semisolid formulations, it is a four-step process: (i)
heating of the semisolid excipient to at least 20 8C above its melting point; (ii) incorporation of the
active substances (with stirring); (iii) capsule filling with the molten mixture and (iv) cooling to room
temperature. For liquid formulations, it involves a two-step process: filling of the formulation into the
capsules followed by sealing of the body and cap of the capsule, either by banding or by microspray
sealing [15]. In parallel with the advances in capsule technology proceeding, liquid-Oros technology
(Alza Corporation) has been designed for controlled delivery of insoluble drug substances or peptides.
This system is based on osmotic principles and is a liquid SE formulation system. It consists of an
osmotic layer, which expands after coming into contact with water and pumps the drug formulation
through an orifice in the hard or soft capsule [16,17]. A primary consideration in capsule filling is the
compatibility of the excipients with the capsule shell. The liquid/semisolid lipophilic vehicles
compatible with hard capsules were listed by Cole et al. [18]. The advantages of capsule filling are
simplicity of manufacturing; suitability for low-dose highly potent drugs and high drug loading (up to
50% (w/w)) potential.
Spray drying

Essentially, this technique involves the preparation of a formulation by mixing lipids, surfactants, drug,
solid carriers, and solubilization of the mixture before spray drying. The solubilized Drug Discovery
Today Volume 13, Numbers 13/14 July 2008 REVIEWS www.drugdiscoverytoday.com 607 Reviews
POST SCREEN liquid formulation is then atomized into a spray of droplets. The droplets are introduced
into a drying chamber, where the volatile phase (e.g. the water contained in an emulsion) evaporates,
forming dry particles under controlled temperature and airflow conditions. Such particles can be
further prepared into tablets or capsules. The atomizer, the temperature, the most suitable airflow
pattern and the drying chamber design are selected according to the drying characteristics of the
product and powder specification.

Adsorption to solid carriers

Free flowing powders may be obtained from liquid SE formulations by adsorption to solid carriers. The
adsorption process is simple and just involves addition of the liquid formulation onto carriers by mixing
in a blender. The resulting powder may then be filled directly into capsules or, alternatively, mixed with
suitable excipients before compression into tablets. A significant benefit of the adsorption technique
is good content uniformity. SEDDS can be adsorbed at high levels (up to 70% (w/w)) onto suitable
carriers [19]. Solid carriers can be microporous inorganic substances, highsurface-area colloidal
inorganic adsorbent substances, cross-linked polymers or nanoparticle adsorbents, for example, silica,
silicates, magnesium trisilicate, magnesium hydroxide, talcum, crospovidone, cross-linked sodium
carboxymethyl cellulose and crosslinked polymethyl methacrylate [20]. Cross-linked polymers create
a favorable environment to sustain drug dissolution and also assist in slowing down drug
reprecipitation [21]. Nanoparticle adsorbents comprise porous silicon dioxide (Sylysia 550), carbon
nanotubes, carbon nanohorns, fullerene, charcoal and bamboo charcoal [22].
Melt granulation

Melt granulation is a process in which powder agglomeration is obtained through the addition of a
binder that melts or softens at relatively low temperatures. As a ‘one-step’ operation, melt granulation
offers several advantages compared with conventional wet granulation, since the liquid addition and
the subsequent drying phase are omitted. Moreover, it is also a good alternative to the use of solvent.
The main parameters that control the granulation process are impeller speed, mixing time, binder
particle size, and the viscosity of the binder. A wide range of solid and semisolid lipids can be applied
as meltable binders. Thereinto, Gelucire1, a family of vehicles derived from the mixtures of mono-/di-
/tri-glycerides and polyethylene glycols (PEG) esters of fatty acids, is able to further increase the
dissolution rate compared with PEG usually used before, probably owing to its SE property [23]. Other
lipid-based excipients evaluated for melt granulation to create solid SES include lecithin, partial
glycerides, or polysorbates. The melt granulation process was usually used for adsorbing SES (lipids,
surfactants, and drugs) onto solid neutral carriers (mainly silica and magnesium aluminometa silicate)
[24,25].
Melt extrusion/extrusion spheronization

Melt extrusion is a solvent-free process that allows high drug loading (60%) [15], as well as content
uniformity. Extrusion is a procedure of converting a raw material with plastic properties into a product
of uniform shape and density, by forcing it through a die under controlled temperature, product flow,
and pressure conditions [26]. The size of the extruder aperture will determine the approximate size of
the resulting spheroids. The extrusion–spheronization process is commonly used in the
pharmaceutical industry to make uniformly sized spheroids (pellets). The extrusion–spheronization
process requires the following steps: dry mixing of the active ingredients and excipients to achieve a
momogenious powder; wet massing with binder; extrusion into a spaghetti-like extrudate;
spheronization from the extrudate to spheroids of uniform size; drying; sifting to achieve the desired
size distribution and coating (optional). In the wet masses comprising SES (polysorbate 80 and mono-
/ di-glycerides), lactose, water and MCC, the relative quantities of SES and water had a significant effect
on the extrusion force, size spread, disintegration time, and surface roughness of pellets. Studies
suggested that the maximum quantity of this SES that can be solidified by extrusion spheronization
occupies 42% of the dry pellet weight [27]. Generally, the higher the water level, the longer the
disintegration time [28]. The rheological properties of wet masses may be measured by an extrusion
capillary. It has been shown that SES containing wet mass with a wide range of rheological
characteristics can be processed, but a single rheological parameter cannot be used to provide
complete characterization of how well it can be processed by extrusion–spheronization [29]. Applying
extrusion–spheronization, SE pellets of diazepam and progesterone and bi-layered cohesive SE pellets
have been prepared [7,30,31].

Dosage form development of S-SEDDS

Dry emulsions

Dry emulsions are powders from which emulsion spontaneously occurs in vivo or when exposed to an
aqueous solution. Dry emulsions can be useful for further preparation of tablets and capsules. Dry
emulsion formulations are typically prepared from oil/ water (O/W) emulsions containing a solid
carrier (lactose, maltodextrin, and so on) in the aqueous phase by rotary evaporation [32], freeze-
drying [33] or spray drying [34–36]. Myers and Shively obtained solid state glass emulsions in the form
of dry ‘foam’ by rotary evaporation, with heavy mineral oil and sucrose. Such emulsifiable glasses have
the advantage of not requiring surfactant [32]. In freeze-drying, a slow cooling rate and the addition
of amorphous cryoprotectants have the best stabilizing effects, while heat treatment before thawing
decreases the stabilizing effects [33]. The technique of spray drying is more frequently used in
preparation of dry emulsions. The O/W emulsion was formulated and then spray-dried to remove the
aqueous phase. The most exciting finding in this field ought to be the newly developed enteric-coated
dry emulsion formulation, which is potentially applicable for the oral delivery of peptide and protein
drugs. This formulation consisted of a surfactant, a vegetable oil, and a pH-responsive polymer, with
lyophilization used [37]. Recently, Cui et al. prepared dry emulsions by spreading liquid O/W emulsions
on a flat glass, then dried and triturated to powders [38].

Self-emulsifying capsules

After administration of capsules containing conventional liquid SE formulations, microemulsion

droplets form and subsequently disperse in the GI tract to reach sites of absorption. However, if
irreversible phase separation of the microemulsion occurs, an improvement of drug absorption cannot
be expected. For handling this problem, sodium dodecyl sulfate was added into the SE formulation
[39]. With the similar purpose, the supersaturatable SEDDS was designed, using a small quantity of
HPMC (or other polymers) in the formulation to prevent precipitation of the drug by generating and
maintaining a supersaturated state in vivo. This system contains a reduced amount of a surfactant,
thereby minimizing GI side effects [40,41]. Besides liquid filling, liquid SE ingredients also can be filled
into capsules in a solid or semisolid state obtained by adding solid carriers (adsorbents, polymers, and
so on). As an example, a solid PEG matrix can be chosen. The presence of solid PEG neither interfered
with the solubility of the drug, nor did it interfere with the process of self-microemulsification upon
mixing with water [42,43]. Oral administration of SE capsules has been found to enhance patient
compliance compared with the previously used parenteral route. For instance, low molecular weight
heparin (LMWH) used for the treatment of venous thrombo-embolism was clinically available only via
the parenteral route. So, oral LMWH therapy was investigated by formulating it in hard capsules.
LMWH was dispersed in SMEDDS and thereafter the mixture was solidified to powders using three
kinds of adsorbents: microporous calcium silicate (FloriteTM RE); magnesium aluminum silicate
(NeusilinTM US2) and silicon dioxide (SylysiaTM 320). Eventually these solids were filled into hard
capsules [44]. In another study, such adsorbents were also applied to prepare SE tablets of gentamicin
that, in clinical use, was limited to administration as injectable or topical dosage forms [19]

Self-emulsifying sustained/controlled-release tablets

Combinations of lipids and surfactants have presented great potential of preparing SE tablets that have
been widely researched. Nazzal and Khan evaluated the effect of some processing parameters
(colloidal silicates—X1, magnesium stearate mixing time— X2, and compression force—X3) on
hardness and coenzymum Q10 (CoQ10) dissolution from tablets of eutectic-based SMEDDS. The
optimized conditions (X1 = 1.06%, X2 = 2 min, X3 = 1670 kg) were achieved by a face-centered cubic
design [45]. In order to reduce significantly the amount of solidifying excipients required for
transformation of SEDDS into solid dosage forms, a gelled SEDDS has been developed by Patil et al. In
their study, colloidal silicon dioxide (Aerosil 200) was selected as a gelling agent for the oil-based
systems, which served the dual purpose of reducing the amount of required solidifying excipients and
aiding in slowing down of the drug release [46]. SE tablets are of great utility in obviating adverse
effect, as disclosed by Schwarz in a patent. Inclusion of indomethacin (or other hydrophobic NSAID),
for example, into SE tablets may increase its penetration efficacy through the GI mucosal membranes,
potentially reducing GI bleeding. In these studies, the SES was composed of glycerol monolaurate and
TyloxapolTM (a copolymer of alkylphenol and formaldehyde). Polyethylene oxide successfully
illustrated its suitability for controlled-release matrices. The resultant SE tablets consistently
maintained a higher active ingredient concentration in blood plasma over the same time frame
compared with a non-emulsifying tablet [47]. The newest advance in the research field of SE tablet is
the SE osmotic pump tablet, where the elementary osmotic pump system was chosen as the carrier of
SES. This system has outstanding features such as stable plasma concentrations and controllable drug
release rate, allowing a bioavailability of 156.78% relative to commercial carvedilol tablets [48].

Self-emulsifying solid dispersions

Although solid dispersions could increase the dissolution rate and bioavailability of poorly water-
soluble drugs, some manufacturing difficulties and stability problems existed. Serajuddin pointed out
that these difficulties could be surmounted by the use of SE excipients [52,53]. These excipients have
the potential to increase further the absorption of poorly water-soluble drugs relative to previously
used PEG solid dispersions and may also be filled directly into hard gelatin capsules in the molten state,
thus obviating the former requirement for milling and blending before filling [9,54]. SE excipients like
Gelucire1 44/14, Gelucire1 50/02, Labrasol1, Transcutol1 and TPGS (tocopheryl polyethylene glycol
1000 succinate) have been widely used in this field [52–55]. For example, Gupta et al. prepared SE
solid dispersion granules using the hot-melt granulation method. Seven drugs, including four carboxylic
acid containing drugs, a hydroxyl-containing drug, an amide-containing drug (phenacetin) and a drug
with no proton-donating groups (progesterone) were chosen. Gelucire1 50/13 was used as the
dispersion carrier, whereas Neusilin US2 was used as the surface adsorbent [25].
Self-emulsifying beads

In an attempt to transform SES into a solid form with minimum amounts of solidifying excipients, Patil
and Paradkar investigated loading SES into the microchannels of porous polystyrene beads (PPB) using
the solvent evaporation method. PPB with complex internal void structures are typically produced by
copolymerizing styrene and divinyl benzene. They are inert, stable over a wide pH range and to
extreme conditions of temperature and humidity. This research concluded that PPB were potential
carriers for solidification of SES, with sufficiently high SES to PPB ratios required to obtain solid form.
Geometrical features, such as bead size and pore architecture of PPB, were found to govern the loading
efficiency and in vitro drug release from SES-loaded PPB [56].

Self-emulsifying sustained-release microspheres

Zedoary turmeric oil (ZTO; a traditional Chinese medicine) exhibits potent pharmacological actions
including tumor suppressive, antibacterial, and antithrombotic activity. With ZTO as the oil phase, You
et al. prepared solid SE sustained-release microspheres using the quasi-emulsion–solvent-diffusion
method of the spherical crystallization technique. ZTO release behavior could be controlled by the ratio
of hydroxypropyl methylcellulose acetate succinate to Aerosil 200 in the formulation. The plasma
concentration–time profiles (Figure 2) were achieved after oral administration of such microspheres
to rabbits, with a bioavailability of 135.6% with respect to the conventional liquid SEDDS [57].

Self-emulsifying nanoparticles

Nanoparticle techniques have been useful in the production of SE nanoparticles. Solvent injection is
one of these techniques. In this method, the lipid, surfactant, and drugs were melted together, and
injected drop wise into a stirred non-solvent. The resulting SE nanoparticles were thereafter filtered
out and dried. This approach yielded nanoparticles (about 100 nm) with a high drug loading efficiency
of 74% [58]. A second technique is that of sonication emulsion–diffusion–evaporation, by which co-
loading 5-fluorouracil (5-FU) and antisense EGFR (epidermal growth factor receptor) plasmids in
biodegradable PLGA/O-CMC nanoparticles was realized. The mixture of PLGA (poly-lactide-co-
glycolide) and O-CMC (O-carboxmethyl-chitosan) had a SE effect, with no need to add another
surfactant stabilizer. Eventually the 5-FU and plasmid encapsulation efficiencies were as high as 94.5%
and 95.7%, respectively, and the 5-FU release activity from such nanoparticles could be sustained for
as long as three weeks [59]. More recently, Trickler et al. developed a novel nanoparticle drug delivery
system consisting of chitosan and glyceryl monooleate (GMO) for the delivery of paclitaxel (PTX). These
chitosan/ GMO nanoparticles, with bioadhesive properties and increased cellular association, were
prepared by multiple emulsion (o/w/o) solvent evaporation methods. The SE property of GMO
enhanced the solubility of PTX and provided a foundation for chitosan aggregation, meanwhile causing
near 100% loading and entrapment efficiencies of PTX. These advantages allow the use of lower doses
of PTX to achieve an efficacious therapeutic window, thus minimizing the adverse side effects
associated with chemotherapeutics like PTX [60].

Self-emulsifying suppositories

Some investigators proved that S-SEDDS could increase not only GI adsorption but also rectal/vaginal
adsorption [61]. Glycyrrhizin, which, by the oral route, barely achieves therapeutic plasma
concentrations, can obtain satisfactory therapeutic levels for chronic hepatic diseases by either vaginal
or rectal SE suppositories. The formulation included glycyrrhizin and a mixture of a C6–C18 fatty acid
glycerol ester and a C6–C18 fatty acid macrogol ester [62].

Self-emulsifying implants

Research into SE implants has greatly enhanced the utility and application of S-SEDDS. As an example,
1,3-bis(2-chloroethyl)-1- nitrosourea (carmustine, BCNU) is a chemotherapeutic agent used to treat
malignant brain tumors. However, its effectiveness was hindered by its short half-life. In order to
enhance its stability compared with that released from poly (d,l-lactide-co-glycolide) (PLGA) wafer
implants, SES was formulated with tributyrin, Cremophor RH 40 (polyoxyl 40 hydrogenated castor oil)
and Labrafil 1944 (polyglycolyzed glyceride). Then the self-emulsified BCNU was fabricated into wafers
with flat and smooth surface by compression molding. Ultimately, SES increased in vitro half-life of
BCNU up to 130 min contrasted with 45 min of intact BCNU. In vitro release of BCNU from SE PLGA
wafers were prolonged up to 7 days. Such wafers had higher in vitro antitumor activity and were less
susceptible to hydrolysis than those wafers devoid of SES [63]. Loomis invented copolymers having a
bioresorbable region, a hydrophilic region and at least two cross-linkable functional groups per
polymer chain. Such copolymers show SE property without the requirement of an emulsifying agent.
These copolymers can be used as good sealants for implantable prostheses [64].
CONCLUSION
As mentioned above, numerous studies have confirmed that SSEDDS substantially improved
solubility/dissolution, absorption and bioavailability of poorly water-soluble drugs. As improvements
or alternatives of conventional liquid SEDDS, S-SEDDS are superior in reducing production cost,
simplifying industrial manufacture, and improving stability as well as patient compliance. Most
importantly, S-SEDDS are very flexible to develop various solid dosage forms for oral and parenteral
administration. Moreover, GI irritation is avoidable and controlled/sustained release of drug is
achievable. There is still a long way to go, however, before more solid SE dosage forms (except for SE
capsules) appear on the market. Because there exist some fields of S-SEDDS to be further exploited,
such as studies about human bioavailability and correlation of in vitro/in vivo. Moreover, the
researches of S-SEDDS lose their balance, that is, SE implants/suppositories/microspheres have not
been as extensively studied as SE tablets/pellets/capsules. It is also worth pointing out some issues to
which much attention should be paid, for example physical aging phenomenon associated with
glyceride, oxidation of vegetable oil [65], and interaction between drugs and excipients [66]. Selection
of suitable excipients is the main hurdle of developing S-SEDDS [53]. Thus, these aspects should
represent the major future working directions for S-SEDDS.
REFERENCES
1 Lipinski, C. (2002) Poor aqueous solubility—an industry wide problem in drug discovery. Am. Pharm.
Rev. 5, 82–85

2 Palmer, A.M. (2003) New horizons in drug metabolism, pharmacokinetics and drug discovery. Drug
News Perspect. 16, 57–62

3 Gursoy, R.N. and Benita, S. (2004) Self-emulsifying drug delivery systems (SEDDS) for improved oral
delivery of lipophilic drugs. Biomed. Pharmacother. 58, 173–182

4 Prajapati, B.G. and Patel, M.M. (2007) Conventional and alternative pharmaceutical methods to
improve oral bioavailability of lipophilic drugs. Asian J. Pharm. 1, 1–8

5 Attama, A.A. et al. (2003) The use of solid self-emulsifying systems in the delivery of diclofenac. Int.
J. Pharm. 262, 23–28

6 Nazzal, S. et al. (2002) Optimization of a self-nanoemulsified tablet dosage form of ubiquinone using
response surface methodology: effect of formulation ingredients. Int. J. Pharm. 240, 103–114

7 Abdalla, A. and Mader, K. (2007) Preparation and characterization of a selfemulsifying pellet

formulation. Eur. J. Pharm. Biopharm. 66, 220–226

8 Franceschinis, E. et al. (2005) Self-emulsifying pellets prepared by wet granulation in high-shear

mixer: influence of formulation variables and preliminary study on the in vitro absorption. Int. J. Pharm.
291, 87–97

9 Hauss, D.J. (2007) Oral lipid-based formulations. Adv. Drug. Deliv. Rev. 59, 667– 676

10 Friedman, D. Non-aqueous compositions for oral delivery of insoluble bioactive agents. US Pat
20070190080

11 Constantinides, P.P. (1995) Lipid microemulsions for improving drug dissolution and oral absorption:
physical and biopharmaceutical aspects. Pharm. Res.

12, 1561– 1572 12 Hauss, D.J. et al. (1998) Lipid-based delivery systems for improving the
bioavailability and lymphatic transport of a poorly water-soluble LTB4 inhibitor. J. Pharm. Sci. 87, 164–
169
13 Caliph, S. et al. (2000) Effect of short-, medium- and long-chain fatty acid-based vehicles on the
absolute oral bioavailability and intestinal lymphatic transport of halofantrine and assessment of mass
balance in lymph-cannulated and noncannulated rats. J. Pharm. Sci. 89, 1073–1084

14 Attama, A.A. and Mpamaugo, V.E. (2006) Pharmacodynamics of piroxicam from self-emulsifying
lipospheres formulated with homolipids extracted from Capra hircus. Drug. Deliv. 13, 133–137

15 Jannin, V. et al. (2008) Approaches for the development of solid and semi-solid lipid-based
formulations. Adv. Drug. Deliv. Rev. 60, 734–746

16 Dong, L. et al. (2000) A novel osmotic delivery system: L-OROS SOFTCAP. Proceedings of the
International Symposium on Controlled Release of Bioactive Materials, July, Paris (CD ROM)

17 Dong, L. et al. (2001) L-OROS HARDCAP: a new osmotic delivery system for controlled release of
liquid formulation. Proceedings of the International Symposium on Controlled Release of Bioactive
Materials, June, San Diego (CD-ROM)

18 Cole, E.T. et al. (2008) Challenges and opportunities in the encapsulation of liquid and semi-solid
formulations into capsules for oral administration. Adv. Drug. Deliv. Rev. 60, 747–756

19 Ito, Y. et al. (2005) Oral solid gentamicin preparation using emulsifier and adsorbent. J. Control
Release 105, 23–31

20 Fabio, C. and Elisabetta, C. Pharmaceutical composition comprising a water/oil/ water double

microemulsion incorporated in a solid support. WO2003/013421

21 Boltri, L. et al. (1997) Enhancement and modification of etoposide release from crospovidone
particles loaded with oil-surfactant blends. Pharm. Dev. Technol. 2, 373–381

22 Venkatesan, N. et al. (2005) Liquid filled nanoparticles as a drug delivery tool for protein
therapeutics. Biomaterials 26, 7154–7163

23 Seo, A. et al. (2003) The preparation of agglomerates containing solid dispersions of diazepam by
melt agglomeration in a high shear mixer. Int. J. Pharm. 259, 161–171

24 Gupta, M.K. et al. (2001) Enhanced drug dissolution and bulk properties of solid dispersions
granulated with a surface adsorbent. Pharm. Dev. Technol. 6, 563–572

25 Gupta, M.K. et al. (2002) Hydrogen bonding with adsorbent during storage governs drug dissolution
from solid-dispersion granules. Pharm. Res. 19, 1663–1672
26 Verreck, G. and Brewster, M.E. (2004) Melt extrusion-based dosage forms: excipients and
processing conditions for pharmaceutical formulations. Bull. Tech. Gattefosse. 97, 85–95

27 Newton, M. et al. (2001) The influence of formulation variables on the properties of pellets
containing a self-emulsifying mixture. J. Pharm. Sci. 90, 987–995

28 Newton, J.M. et al. (2005) Formulation variables on pellets containing selfemulsifying systems.
Pharm. Tech. Eur. 17, 29–33

29 Newton, J.M. et al. (2005) The rheological properties of self-emulsifying systems, water and
microcrystalline cellulose. Eur. J. Pharm. Sci. 26, 176–183

30 Tuleu, C. et al. (2004) Comparative bioavailability study in dogs of a self-emulsifying formulation of

progesterone presented in a pellet and liquid form compared with an aqueous suspension of
progesterone. J. Pharm. Sci. 93, 1495–1502

31 Iosio, T. et al. (2008) Bi-layered self-emulsifying pellets prepared by co-extrusion and

spheronization: influence of formulation variables and preliminary study on the in vivo absorption. Eur.
J. Pharm. Biopharm. 10.1016/j.ejpb.2007.11.014

32 Myers, S.L. and Shively, M.L. (1992) Preparation and characterization of emulsifiable glasses: oil-in-
water and water-in-oil-in-water emulsion. J. Colloid Interface Sci. 149, 271–278

33 Bamba, J. et al. (1995) Cryoprotection of emulsions in freeze-drying: freezing process analysis. Drug.
Dev. Ind. Pharm. 21, 1749–1760

34 Christensen, K.L. et al. (2001) Technical optimization of redispersible dry emulsions. Int. J. Pharm.
212, 195–202

35 Hansen, T. et al. (2004) Process characteristics and compaction of spray-dried emulsions containing
a drug dissolved in lipid. Int. J. Pharm. 287, 55–66

36 Jang, D.J. et al. (2006) Improvement of bioavailability and photostability of amlodipine using
redispersible dry emulsion. Eur. J. Pharm. Sci. 28, 405–411

37 Toorisaka, E. et al. (2005) An enteric-coated dry emulsion formulation for oral insulin delivery. J.
Control Release 107, 91–96

38 Cui, F.D. et al. (2007) Preparation of redispersible dry emulsion using Eudragit E100 as both solid
carrier and unique emulsifier. Colloid. Surf. A: Physicochem. Eng. Asp. 307, 137–141
39 Itoh, K. et al. (2002) Improvement of physicochemical properties of N-4472 part I: formulation
design by using self-microemulsifying system. Int. J. Pharm. 238, 153–160

40 Gao, P. and Morozowich, W. (2006) Development of supersaturatable selfemulsifying drug delivery

system formulations for improving the oral absorption of poorly soluble drugs. Expert. Opin. Drug.
Discov. 3, 97–110

41 Gao, P. et al. (2003) Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel

with improved oral bioavailability. J. Pharm. Sci. 92, 2386–2398

42 Li, P. et al. (2007) Development and characterization of a solid microemulsion preconcentrate

system for oral delivery of poorly water soluble drugs. Controlled Release Society Annual Meeting,
Long Beach, CA, June

43 Li, P. et al. Novartis Pharmaceuticals Corp. Spontaneously dispersible pharmaceutical compositions.

WO2006/050123

44 Ito, Y. et al. (2006) Preparation and evaluation of oral solid heparin using emulsifier and adsorbent
for in vitro and in vivo studies. Int. J. Pharm. 317, 114–119

45 Nazzal, S. and Khan, M.A. (2006) Controlled release of a self-emulsifying formulation from a tablet
dosage form: stability assessment and optimization of some processing parameters. Int. J. Pharm. 315,
110–121

46 Patil, P. et al. (2004) Effect of formulation variables on preparation and evaluation of gelled self-
emulsifying drug delivery system (SEDDS) of ketoprofen. AAPS Pharm. Sci. Tech. 10.1208/pt050342
http://www.aapspharmscitech.org/articles/pt0503/ pt050342/pt050342.pdf

47 Joseph, S. Solid self-emulsifying dosage form for improved delivery of poorly soluble hydrophobic
compounds and the process for preparation thereof. US Pat 20030072798

48 Wei, L.L. et al. (2007) Investigations of a novel self-emulsifying osmotic pump tablet containing
carvedilol. Drug. Dev. Ind. Pharm. 33, 990–998

49 Gandhi, R. et al. (1999) Extrusion and spheronization in the development of oral controlled-release
dosage forms. PSTT 2, 160–170

50 Serratoni, M. et al. (2007) Controlled drug release from pellets containing waterinsoluble drugs
dissolved in a self-emulsifying system. Eur. J. Pharm. Biopharm. 65, 94–98
51 Hamdani, J. et al. (2003) Physical and thermal characterizations of Precirol1 and Compritol1 as
lipophilic glycerides used for the preparation of controlled-release matrix pellets. Int. J. Pharm. 260,
47–57

52 Serajuddin, A.T.M. (1999) Solid dispersion of poorly water-soluble drugs: early promises,
subsequent problems, and recent breakthroughs. J. Pharm. Sci. 88, 1058– 1066

53 Vasanthavada, M. and Serajuddin, A.T.M. (2007) Lipid-based self-emulsifying solid dispersions. In

Oral Lipid-Based Formulations: Enhancing Bioavailability of Poorly Water-Soluble Drugs (Hauss, D.J.,
ed.), pp. 149–184, Informa Healthcare

54 Serajuddin, A.T.M. et al. (1988) Effect of vehicle amphiphilicity on the dissolution and bioavailability
of a poorly water-soluble drug from solid dispersions. J. Pharm. Sci. 77, 414–417

55 Khoo, S.M. et al. (2000) The formulation of halofantrine as either non-solubilising PEG 6000 or
solubilising lipid based solid dispersions: physical stability and absolute bioavailability assessment. Int.
J. Pharm. 205, 65–78

56 Patil, P. and Paradkar, A. (2006) porous polystyrene beads as carriers for selfemulsifying system
containing loratadine. AAPS Pharm. Sci. Tech. 10.1208/ pt070128
http://www.aapspharmscitech.org/articles/pt0701/pt070128/ pt070128.pdf

57 You, J. et al. (2006) Study of the preparation of sustained-release microspheres containing zedoary
turmeric oil by the emulsion–solvent-diffusion method and evaluation of the self-emulsification and
bioavailability of the oil. Colloid. Surf. B. 48, 35–41

58 Attama, A.A. and Nkemnele, M.O. (2005) In vitro evaluation of drug release from self micro-
emulsifying drug delivery systems using a biodegradable homolipid from Capra hircus. Int. J. Pharm.
304, 4–10

59 Hu, Y.X. et al. (2005) Preparation and evaluation of 5-FU/PLGA/gene nanoparticles. Key Eng. Mat.
288–289 147-150

60 Trickler, W.J. et al. (2008) A novel nanoparticle formulation for sustained paclitaxel delivery. AAPS
Pharm. Sci. Tech. 10.1208/s12249-008-9063-7

61 Kim, J.Y. and Ku, Y.S. (2000) Enhanced absorption of indomethacin after oral or rectal administration
of a self-emulsifying system containing indomethacin to rats. Int. J. Pharm. 194, 81–89
62 Takada, K. and Murakami, M. Glycyrrhizin preparations for transmucosal absorption. US Pat
6890547

63 Chae, G.S. et al. (2005) Enhancement of the stability of BCNU using self-emulsifying drug delivery
systems (SEDDS) and in vitro antitumor activity of self-emulsified BCNU-loaded PLGA wafer. Int. J.
Pharm. 301, 6–14

64 Loomis, G.L. Bioresorbable compositions for implantable prostheses. US Pat 6403758

65 Halbaut, L. et al. (1997) Oxidative stability of semi-solid excipient mixtures with corn oil and its
implication in the degradation of vitamin A. Int. J. Pharm. 147, 31–40

66 Chambin, O. et al. (2004) Influence of cryogenic grinding on properties of a selfemulsifying

formulation. Int. J. Pharm. 278, 79–89