Research Article

ISSN: 0974-6943

Hitesh C. Bari et al. / Journal of Pharmacy Research 2011,4(2),369-372

Available online through

www.jpronline.info

Design and optimization of chlordiazepoxide solid self-microemulsifying drug delivery system

Hitesh C. Bari* 1, Rajendra. C. Doijad1, Harinath N. More 1, John I. Disouza2
1
Department of Pharmaceutics, Bharati Vidyapeeth College of Pharmacy, Kolhapur, India.
2
Tatyasaheb Kore College of Pharmacy, Kolhapur, India.

Received on: 10-09-2010; Revised on: 18-12-2010; Accepted on:08-01-2011

ABSTRACT
The objective of the present study was to design and optimized chlordiazepoxide solid self microemulsifying drug delivery system prepared via spray drying for oral
administration. Four formulations were selected from pseudoternary phase diagram (ethyl oleate-labrasol+cremophor RH40-water) of highest microemulsion
region and exposed to spray drying. Reconstitution properties (dilution studies, globule size and zeta potential) and solid state characterization (PXRD, DSC and
SEM) of formulations were investigated. The dissolution characteristics of solid SMEDDS and commercial formulation (Librium) were indicated statistically
significant drug release in discriminating dissolution medium. Thus, this solid SMEDDS may provide useful solid dosage form to improve solubility and dissolution
rate of chlordiazepoxide and concomitantly bioavailability.

Key words: Chlordiazepoxide, self microemulsifying, solid SMEDDS, spray drying.

INTRODUCTION
Oral route is the easiest and most convenient way of non-invasive administration. Oral
drug delivery systems being the most cost effective have always contributing major role
in the worldwide drug delivery market. Approximately 40% of new drug candidates are
frequently associated with low oral bioavailability, high intra- and inter-subject variability, and a lack of dose proportionality. Often poor aqueous solubility and dissolution rate
in water rather than permeability though gastrointestinal epithelial barrier associated with
low oral drug bioavailability. To overcome this barrier, various formulation strategies are
exploited including the use of surfactants, lipids, permeation enhancers, micronisation,
salt formation, cyclodextrins, nanoparticles, liposomes and solid dispersions[1]. Recently,
much attention has been paid to lipid-based formulations with particular emphasis on selfmicroemulsifying drug delivery systems (SMEDDS)[2-7] after the commercial success of
Sandimmune Neoral TM (Cyclosporine A), Fortovase (Saquinavir) and Norvir (Ritonavir)
to improve oral bioavailability of lipophilic drug[8]. SMEDDS are defined as isotropic
mixtures of natural or synthetic oils, solid or liquid surfactants, or alternatively, one or
more hydrophilic solvents and co-solvents/surfactants that have a unique ability of forming fine oil-in-water (o/w) microemulsion upon mild agitation followed by dilution in
aqueous media, such as GI fluids[9]. The digestive motility of stomach and intestine
provides the agitation required for self-emulsification in vivo. SMEDDS offer advantages
over emulsion are thermodynamic stability, globule size (surface area), flexibility of
dosage form and autoclaving. Self emulsifying drug delivery system (SEDDS) produce
emulsion of globule size between 100-300 nm while SMEDDS gives clear emulsion of
<100 nm. Currently accepted view is that lipids may enhance bioavailability via a
number of potential mechanisms[9], including 1) reduction in gastric transit 2) increase in
effective luminal drug solubility 3) stimulation of intestinal lymphatic transport 4)
attenuate activity of intestinal p-glycoprotein drug efflux pump 5) changes in the physical
barrier function of the GI tract by enhancing permeability. Liquid SEDDS and SMEDDS
are inconvenient to use and incompatibility problems with the shells of the soft gelatin are
frequent[10]. Solid SMEDDS have recently been described and they overcome the disadvantages of liquid SMEDDS as well as exhibited more commercial potential and patient
acceptability[7,11-12].
Chlordiazepoxide (CDP), a member of 1,4-benzodiazepine group have poor aqueous
solubility and dissolution rate in water. It was selected as a model drug, which used as
antianxiety and sedative. It is a classical example of solubility which shows significant
reduction in solubility when going from pH 3 to 7 (the solubility of chlordiazepoxide
hydrochloride is 150 mg/ml and is ~0.1 mg/ml at neutral pH)[13]. Patient suffered from
achlorhydria or hypochloridia show increase pH of stomach content, which results in
reduction of solubility of drugs have pH dependent solubility like chlordiazepoxide and
hence decline bioavailability.
The objectives of the present study were:
1) To design and optimized a solid SMEDDS of chlordiazepoxide by spray drying, using

*Corresponding author.
Hitesh C. Bari
Department of Pharmaceutics,
Bharati Vidyapeeth College of Pharmacy,
Kolhapur, India.
Tel.: + 91-22/28461080
E-mail:barihitesh99@gmail.com

maltodextrin as water-soluble solid carrier. 2) reconstitution properties of the spray dried

powders were investigated and correlated to solid state characterization of the powders
performed by Scanning Electron Microscope (SEM), Differential Scanning Calorimetry
(DSC) and X-ray powder diffraction. 3) comparative determination of in vitro release
profile of solid SMEDDS and conventional tablet of chlordiazepoxide (Librium).
2. MATERIAL AND METHODS
2.1 Materials
Chlordiazepoxide was gift sampled from Centaur chemicals Pvt. Ltd., Goa. Captex 355
and 800 were procured from Abitech corporation, USA. Labrasol, maisine 1-35, capryol
90 were obtained from Gattefosse Pvt. Ltd., Mumbai. Cremophor RH40 was obtained
from Libraw pharma, New Delhi. Ethyl oleate, Tween80, PEG400, Maltodextrin and
Methanol (HPLC grade) were purchased from Lobachemie Pvt. Ltd., Mumbai. All other
chemicals and reagents were used of analytical grade.
2.2 Methods
2.2.1 Saturation solubility studies for screening of excipients
In order to find out appropriate solvents with good solubilizing capacity of CDP, the
saturation solubility of CDP was investigated in some oils and surfactants by shake flask
method. An excess amount of CDP was added to vial containing 5 ml of each solvent.
After sealing, the mixture was vortexed using a cyclomixer for 10 min in order to facilitate
proper mixing of CDP with the vehicles. Mixtures were kept for 72 hr at ambient
temperature to attain equilibrium, and afterwards, mixtures were centrifuged at 2000 rpm
for 15 min. Aliquots of supernatant was filtered through membrane filter (0.45 m) and
diluted with mobile phase (methanol:water). Drug content was quantified directly by
using high performance liquid chromatography (HPLC) technique.
2.2.2 Construction of pseudoternary phase diagram
From these, the extent of microemulsion region can be identified and its relation to other
phases can be established. The pseudo-ternary phase diagrams were constructed by drop
wise addition of double distilled water to homogenous liquid mixture of oil, surfactant,
and co-surfactant, at ambient temperature ( water titration method). From the result of
solubility studies ethyl oleate, labrasol and cremophor RH40 were selected as oily phase,
surfactant and co-surfactant respectively. At desired Km (ratio of surfactant to co-surfactant)
value (1:1, 2:1, 3:1, 4:1 and 5:1), S mix and oil were mixed at ratio of 1:1, 1.5:1, 2:1, 2.5:1,
3:1, 3.5:1, 4:1, 4.5:1 and 5:1 in pre-weighed test tube. To the resultant mixtures, double
distilled water was added dropwise till the first sign of turbidity in order to identify the end
point and after equilibrium; if the system became clear then the water addition was
continued. After complete equilibrium was reached, the mixtures were checked visually for
phase clarity and flow ability. The resultant emulsion with a clear or slightly bluish
appearance, exhibiting good stability (being stable after centrifugation for 10 min at 2000
rpm) and flow ability was defined as a microemulsion. A slightly less clear system, which
had a bluish white or bright white appearance, was defined as an emulsion. No attempt
was made to find out other region except boundary of microemulsion region in the ternary
phase diagram. After identifying highest microemulsion region at desired Km value,
randomly four formulations were selected to prepare liquid SMEDDS. Phase diagram was
constructed by using Chemix School (evaluation copy) software.

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2.2.3 Preparation of solid SMEDDS
Maltodextrin (10.0 gm) was dissolved in 100 ml bidistilled water by magnetic stirring
and sonicated for 5 min to completely dissolve. This solution was filtered through
whatman filter paper to remove any undissolved particles. The liquid SMEDDS (10.0
gm) was then added with constant stirring, and the solution was kept at 40 C to obtain
fine o/w emulsion. The emulsion was spray dried with lab scale spray dryer (Labultima
LU-222, Mumbai) under the following optimized condition given as follows: inlet
temperature-120 C, outlet temperature-80 C, aspirator speed-70%, feed rate-75 ml/hr
and compressed air flow rate-3 bar.
2.2.4 Reconstitution properties of solid SMEDDS
2.2.4.1 Dilution study by visual observation
Dilution study was done to study the effect of dilution on solid SMEDDS, because
dilution may better mimic the condition of stomach after oral administration. In this
method, solid SMEDDS and liquid SMEDDS (100.0 mg) were introduced into 100 ml
of double distilled water in a glass beaker that was maintained at 37 C, and the contents
mixed gently using a magnetic stirrer. The tendency to emulsify spontaneously and
progress of emulsion droplets were observed with respect to time. The emulsification
ability of SMEDDS was judged qualitatively good when clear microemulsion formed
and bad when there was turbid or milky white emulsion formed after stopping of
stirring[14].

3. RESULT AND DISCUSSION

3.1 Saturation solubility studies for screening of excipients
The pre-concentrate mixture should be clear, monophasic liquid at room temperature and
should have good solvent properties to allow presentation of drug in solution. The
objective of solubility study is to identify oil and surfactants with good solubilizing
capacity for CDP. Oil was selected on the basis of good solubilizing capacity for CDP as
well as ease of emulsification. From solubility data (Table1), ethyl oleate shows good
solubilizing potential for CDP amongst other oils investigated and also easily emulsified
with variety of surfactants. Amongst the various surfactants, cremophor RH40 have more
solubilizing potential for CDP followed by labrasol and also possess required HLB value
necessary for formation ethyl oleate o/w emulsion. However cremophor RH40 was selected as a co-surfactant instead of surfactant, due to allergic reaction associated with
chronic use[16] and labrasol chosen as a surfactant. Labrasol and cremophor RH40 were
successfully reported to improve bioavailability of hydrophobic drug such as artemether[7] ,
nimodipine[17] etc.

Table1: Solubility of CDP in various oils and surfactants

Sr. no.
1
2
3
4
5
6
7
8
9

2.2.4.2 Globule size and zeta potential determination

Solid SMEDDS formulations (10 mg) were diluted with 10 ml bidistilled water in a
beaker with constant stirring on a magnetic stirrer. The average droplet size, polydispersity index and zeta potential of microemulsion droplets from solid SMEDDS were
assessed by lesser light scattering technique using Malvern zetasizer at 25 C (Nano-ZS,
Malvern Instruments, UK).
2.2.5 Solid state characterization of solid SMEDDS
2.2.5.1 Powder X-ray diffraction (PXRD)
To obtain the changes in the crystallinity of the components of formulation prepared, the
PXRD study was carried out by using X ray diffractometer (Philips PW-3710, Holland).
The samples of pure drug, solid SMEDDS and physical mixture were taken and irradiated
with monochromatised CuKa radiation and analyzed between from 10 to 60 (2).

Oils and Surfactants

Solubility (mg/ml) at 25 C

Ethyl oleate
Captex 355
Captex 800
Maisine 35-1
Capryol 90
Labrasol
Tween 80
Cremophor RH40
PEG 400

1.600.09
1.370.05
0.3920.13
1.490.06
1.350.04
28.7430.16
22.430.06
92.520.11
19.890.18

3.2 Construction of pseudoternary phase diagram

Based on results of solubility studies ethyl oleate, labrasol and cremophor RH40 were
selected for microemulsion formulation. The boundary layer of microemulsion for each
desired Km value was observed at ambient temperature, due to there was no distinct
conversion of w/o to o/w emulsion observed. The region of microemulsion existence for
ethyl oleate-labrasol+cremophor Rh40-water (Km= 4) was determined by pseudoternary
plot shown in Figure1 (since microemulsion region at Km of 4 was bigger than 1, 2 and

2.2.5.2 Differential scanning calorimetry (DSC)

Thermograms of CDP, solid SMEDDS batches and physical mixtures were obtained
using DSC instrument (TA Instruments SDT-2960, USA) equipped with an intracooler.
Indium standard was used to calibrate the DSC temperature and enthalpy scale. The
powder samples was hermetically kept in the aluminum pan and heated at constant rate
10C/min, over a temperature range of 35C to 350C. Inert atmosphere was maintained by
purging nitrogen at the flow rate of 100 ml/min.
2.2.6 Morphological analysis of solid SMEDDS
The outer macroscopic structure (morphology) of the solid SMEDDS was investigated by
SEM (JEOL, Japan), operating at 20 kV. The sample was fixed on SEM stub and then
coated with thin layer of gold or platinum.
2.2.7 In vitro dissolution studies
To understand the characteristics of drug release from solid SMEDDS, an in vitro release
test was carried out. Dissolution studies were performed for the solid SMEDDS form and
conventional tablet form (Librium). The dissolution test was performed in USP type II
dissolution apparatus (Electrolab, Mumbai) according to United State Pharmacopoeia
dissolution procedure. The solid SMEDDS equivalent to 10 mg of CDP was filled into
hard gelatin capsules (capsule no. 00). Solid SMEDDS hard gelatin capsule put into
sinker and sinker was loaded with 900 ml of simulated gastric fluid without pepsin at 37
0.5 C with paddle speed of 100 rpm. Each sample (5 ml) was withdrawn at 5, 10, 15,
20, 25 and 30 min with replacement by an equal volume of temperature-equilibrated
media and filtered through 0.45 m pore size nylon filter. The amount of drug dissolved
determined by UV spectroscopy at max of 309 nm for simulated gastric fluid. Dissolution
studies were also performed in other media (phosphate buffer pH5.8 and 7.0 at max of 245
nm) to examine the effect of pH on drug release.

Figure1: Pseudoternary phase diagram of ethyl oleate-labrasol+cremophor RH40-water at

Km = 4 (Km = surfactant to cosurfactant ratio). Shaded area indicate microemulsion region.

3, region of 4 and 5 were quite similar). Four formulations of different combinations were
selected from phase diagram denoted by dots for further studies. The selected microemulsion
formulations were exposed to freeze thaw cycling and centrifugation at 2000 rpm, which
conformed the thermodynamic stability of microemulsion. Compositions of selected four
formulations were shown in Table2.

2.2.8 HPLC analysis of CDP

HPLC was carried out using HPLC system consisted of Jasco PU 2080 Plus intelligent
HPLC Pump (Jasco, Japan), equipped with HIQ SIL, C18 HS (250 x 4.6 mm) (KYA
technology, Japan), 5 m particle size column and Jasco UV 2075 Intelligent UV-VIS
detector (Jasco, Japan), with 20 l sample injector. It was operated by Jasco Borwin
Chromatography software version 1.5. The mobile phase15 (methanol:water in the ratio of
97:03) was run at a flow rate of 1 ml/min and detection was carried out at 245 nm.

Table2: Composition of CDP SMEDDS formulation

2.2.9 Statistical analysis

All data was expressed as a mean SD (n=3) and in vitro drug release were performed by
unpaired t-test by Graphpad Instat demo version. Difference were considered significant
when p < 0.05.

3.3 Reconstitution properties of solid SMEDDS

Sr. no.

Formulation

Drug (mg)/10 gm

%Composition (w/w)
Oil
Labrasol

Cremophor RH40

1
2
3
4

ME1
ME2
ME3
ME4

350
350
350
350

12.1
15.0
16.0
19.9

17.8
17.3
17.1
16.3

70.1
67.7
66.9
63.8

3.3.1 Dilution study by visual observation

A visual test was carried out to assess self emulsification of solid SMEDDS and liquid
SMEDDS in 100 ml bidistilled water at 37 C under gentle agitation. All solid SMEDDS

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formulations showed spontaneous microemulsification (< 1 min) as same as liquid
SMEDDS and there was no sign of phase separation or phase inversion of microemulsion.
3.3.2 Globule size and zeta potential determination
The droplet size of the emulsion is the crucial factor in the self-emulsificaion performance
because it determines the rate and extent of drug release as well as drug absorption. The
mean droplet size of all reconstituted solid SMEDDS were very low and all were found to
be in the nanometric range (<100 nm). Globule size in nano or micron range gives good
transparency and increase surface area for partitioning of drug between oil and water. Result
of globule size and zeta potential were summarized in Table3. There was no major
significant deviation in zeta potential of the tested SMEDDS formulations. The zeta
potential values of all solid SMEDDS were found to be in between -19 to -23. As the
proportion of surfactants decreases and oil increases, the zeta potential decline while
globule size increases. The zeta potential showed charge on the internal phase, which
will decide the stability of the system. An increase in the electrostatic repulsive forces
between microemulsion droplets prevents coalescence of microemulsion droplet, and a
decrease of electrostatic repulsive forces will result in phase separation.

3.5 Morphological analysis of solid SMEDDS

The SEM images of solid SMEDDS of batch ME2 were shown in Figure4. According to
SEM images, the solid SMEDDS consisted of well separated particles with no agglomeration. It has satisfactory regular spherical shape with small wrinkled wave like surface.
It may be the ability of maltodextrin to inhibit the agglomeration of particles.

Table3: Globule size and zeta potential of solid SMEDDS formulation

Batch code

Globule size (nm)

Zeta potential (mv)

1
2
3
4

ME1
ME2
ME3
ME4

56.97
58.64
65.94
72.43

-23.1
-22.1
-21.1
-19.1

3.4 Solid state characterization of solid SMEDDS

3.4.1 Powder X-ray diffraction (PXRD)
In the powder X-ray diffraction studies, the diffractograms of the representative batches
were taken to find out the effect on the crystallinity of the drug and excipients. In the
diffractograms of physical mixture and solid SMEDDS batches, complete amorphousization
of drug along with excipients occurred. There is no intense peak was observed which
revealed solubilization of drug in the formulation batches as shown in Figure2.

Figure2: Powder X-ray diffractograms of pure drug (A), physical mixture (B), ME2 (C) and ME3 (D

3.6 In vitro dissolution studies

The in vitro dissolution comparison of solid SMEDDS formulation in different dissolution media (SGF pH 1.2, phosphate buffer pH 5.8 and 7.0) were shown in Figure5-7. Drug
releases from solid SMEDDS formulations were found to be significantly higher as
compared with that of conventional chlordiazepoxide tablet (Librium). It could be
suggested that the solid SMEDDS formulation resulted in spontaneous formation of a
microemulsion with a small droplet size, which permitted a faster rate of drug release into
the aqueous phase, much faster than that of conventional chlordiazepoxide tablet
(Librium). Thus, this greater availability of dissolved chlordiazepoxide from the solid
SMEDDS formulations could lead to higher absorption and higher oral bioavailability.
From Figure5-7, it was also seen that changes in the dissolution medium had tremendous
effect on the drug release of marketed preparation (Librium), but no effect on solid
SMEDDS formulations. Solid SMEDDS formulations shows more than 90% drug release in 30 min in all dissolution media (except ME4 formulation) where as marketed
preparation shows < 50% and < 40% drug release in phosphate buffer pH 5.8 and 7.0
respectively. Solid SMEDDS shows statistically significant difference (p < 0.05) in
percent release of drug when compared with marketed preparation (phosphate buffer pH 5.8

Time (min)
Figure5: In-vitro release profile of solid SMEDDS formulation and
Librium in SGF
% Cumulative drug release

3.4.2 Differential scanning calorimetry (DSC)

DSC curves of pure drug, physical mixture and spray dried solid SMEDDS were shown
in Figure3. Pure CDP show sharp endothermic peak at near about 244 C, which may be
melting point of drug. The physical mixture didnt show any obvious peak for CDP, may
be due to more dilution by solid carrier or absence in the sample exposed to DSC. Very
small broad endothermic peaks (less heat of absorption) for CDP were found in solid
SMEDDS batches. It might be explained that CDP was present in the amorphous phase
of a molecular dispersion state in the matrix.

a
b
Figure4: SEM images of solid SMEDDS (a: x2000, bar-10 m; b: x5000,
bar-5 m)

% Cumulative drug release

Sr. no.

Figure3: DSC curves of CDP (A), physical mixture (B), ME2 (C), ME3
(D)

Time (min)
Figure6: In-vitro release profile of solid SMEDDS formulation and
Librium in phosphate buffer pH5.8

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% Cumulative drug release

the conventional tablet in discriminating dissolution medium (phosphate buffer pH 5.8

and 7.0). Thus, this solid self-microemulsifying system may provide a useful solid
dosage form for oral poorly water-soluble drug such as chlordiazepoxide to enhance
solubility and dissolution rate which may improve therapeutic performance.
5. AKNOWLEDGEMENT
The authors are thankful to Gattefosse (Mumbai), Centaur chemicals Pvt. Ltd. (Goa),
Abitech corporation (USA) and Libraw Pharma (New Delhi) for providing gift samples.
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Time (min)
Figure7: In-vitro release profile of solid SMEDDS formulation and
Librium in phosphate buffer pH7.0

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and 7.0). ME4 formulation failed to show > 90% drug release because of increased globule
size but it passes the dissolution test criteria as per USP. This observation can be
explained by the fact that CDP has ionizable group and thus its solubility and dissolution
is pH dependent. But in same case one can also conclude that in case of solid SMEDDS
formulation, dissolution of chlordiazepoxide is pH independent.
4. CONCLUSION
In the present investigation, the solid SMEDDS of chlordiazepoxide was prepared by
spray drying, using water-soluble maltodextrin as solid carrier for direct filling into hard
gelatin capsule for oral administration. The solid SMEDDS consisted of well-separated
spherical particles and maintained the rapid self-emulsifying ability as that of liquid
SMEDDS. Both DSC measurements and X-ray diffraction analysis suggested that chlordiazepoxide in the solid SMEDDS was in the amorphous molecular dispersion state. In
vitro dissolution test showed that the solid SMEDDS had a faster in vitro release rate than

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Source of support: Nil, Conflict of interest: None Declared

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