Formulation Development of Ketoconazole

Ophthalmic Formulation
Varsha R. Sandhan*, S.B. Gondkar, R. B. Saudagar
Department of Quality Assurance Techniques, R.G. Sapkal College of Pharmacy, Anjaneri, Nashik-422213,
Maharashtra, India

ABSTRACT:
The poor bioavailability and therapeutic response exhibited by conventional ophthalmic solutions due to rapid precorneal
elimination of drug may be overcome by the use of ophthalmic gel systems. The purpose of the present study was to
develop ophthalmic gel formulations of ketoconazole. Intraocular delivery of topically applied drugs such as ketoconazole
is hampered by elimination of the solution due to tear turnover, so an mucoadhesive gel was formulated. Ketoconazole gels
were prepared using sodium carboxymethylcellulose (NaCMC) as a mucoadhesive polymer and xanthan gum as a viscosity
increasing agent. Gels were evaluated for various parameters like appearance, pH, drug content, gel strength, bioadhesion,
viscosity, In-vitro drug release, isotonisity, sterility, antifungal activity, ocular irritancy and stability studies. The gel
strength, bioadhesion and isotonisity shown quality parameter for ophthalmic formulation. The optimized formulation
containing 1% w/v Na CMC and 0.2% w/v xanthan gum have shown 97.66% drug release up to 8 hrs. This is sufficient for
antifungal activity. Diffusion studies have shown that a Korsmeyers-peppas is the best-fit model. This study found that an
optimized formulation having improved viscosity and better mucoadhesive property may improve the bioavaibility of
ocular administration of ketoconazole in gel form and can be alternative to the conventionally administered oral
formulation and effectively used to prolong residence time.

KEYWORDS: Ophthalmic drug delivery, Bioavaibility, mucoadhesive polymer, fungal keratitis.

INTRODUCTION:
Ophthalmic drug delivery is one of the most interesting and challenging endeavors facing the pharmaceutical scientist. Eye
drops are conventional ophthalmic delivery systems often result in poor bioavailability and therapeutic response, because
high tear fluid turnover and dynamics cause rapid precorneal elimination of the drug. A high frequency of eye drop
instillation is associated with patient non-compliance. Inclusion of excess drug in the formulation is an attempt to overcome
bioavailability problem is potentially dangerous if the drug solution drained from the eye is systemically absorbed from the
Nasolachrymal duct. The specific aim of designing a therapeutic system is to achieve an optimal concentration of a drug at
the active site for the appropriate duration.[1] Ophthalmic mycosis is emerging as a major cause of vision loss and
morbidity, and can be life-threatening. Fungal keratitis is one of the major causes of ophthalmic mycosis. Fungal keratitis is
usually characterized by a corneal epithelial defect and inflammation of the corneal stroma.

Table 1. Composition of formulation batches as per 32 factorial design

Ingredient (%) Formulation code
F1 F2 F3 F4 F5 F6 F7 F8 F9
Ketoconazole(w/v) 1 1 1 1 1 1 1 1 1
Sodium Carboxymethylcellulose(w/v) 0.2 0.4 1 0.2 0.4 1 0.2 0.4 1
Xanthan Gum(w/v) 0.2 0.2 0.2 0.4 0.4 0.4 1 1 1
Sodium metabisulphite(w/v) 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02
Bezalkonium chloride(v/v) 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01
PEG 400(v/v) 60 60 60 60 60 60 60 60 60
Purified water(v/v) 40 40 40 40 40 40 40 40 40

If untreated, fungal keratitis can lead to corneal scarring and vision loss. It is usually caused by Aspergillus, Candida, and

https://rjpdft.com/HTML_Papers/Research%20Journal%20of age%20Forms%20and%20Technology__PID__2013-5-6-1.html 03/06/24, 11.21

Halaman 1 dari 8
%
 Fusarium species.[2] Ketoconazole is antifungal drug and has a broad spectrum of activity, including against Aspergillus,
Candida, and Fusarium species. When it given orally for long term treatment of fungal keratitis it has some disadvantages.
Hence topical 1% formulation is suitable for treatment of fungal keratitis. These have been reported to inhibit the
progression of corneal fungal infections and were not associated with significant corneal toxicity.[2] To increase the patient
compliance and to have convenience of administration, ophthalmic gel of Ketoconazole was prepared by using
mucoadhesive polymers which can be increases its residence time and subsequent bioavailability.

MATERIALS AND METHOD:

Materials
Ketoconazole was gifted by Glenmark Pharmaceuticals Ltd. (Nashik, India), Na CMC was obtained from Reliance
Cellulose and Xanthan gum obtained from Signet Chemicals. All other chemicals used were of analytical grade.

Method
32 factorial design was used for composition of different formulations (Table 1.) all different formulations were prepared as
per Table 2.

Table 2. Experimental Design as per 32 Factorial Design

Formulation Coded values
code X1 % (W/V) X2 % (W/V)
F1 -1 0.2 -1 0.2
F2 0 0.4 -1 0.2
F3 +1 1 -1 0.2
F4 -1 0.2 0 0.4
F5 0 0.4 0 0.4
F6 +1 1 0 0.4
F7 -1 0.2 +1 1
F8 0 0.4 +1 1
F9 +1 1 +1 1

Accurately weighed quantity of the Ketoconazole was dissolved in PEG 400. The Sodium metabisulphite was added to
above mixture with continuous stirring. The Na CMC and Xanthan gum was sprinkled over of deionised water and was
allowed to hydrate for 12 hours to produce a clear solution. The Bezalkonium chloride was added to the above polymer
dispersion. Both drug solution and polymer dispersion were autoclaved at 121°C for 20 min. and polymer dispersion was
slowly added to the drug solution under aseptic condition.

Evaluation of ophthalmic gel

Determination of clarity, pH and drug content
The clarity was determined visually. The pH of each formulation was determined by using Digital pH meter (Digital pH
meter 335). [3]

The drug content determined by 0.5gm of gel was taken in 100 ml beaker; in that beaker 50 ml methanol was added.
Aliquot 1 ml from this solution was diluted up to 10ml with methanol to get the final concentration of 10 µg/ml. The
absorbance of prepared solution was measured at 242.8 nm by using UV visible spectrophotometer. [4]

Compatibility Study [5, 6]

Compatibility study was carried out by using Fourier transform infrared spectrophotometer (8400 s Shimadzu). FTIR study
was carried on pure drug and physical mixture of drug and polymers. Physical mixtures samples kept for 1 month at 400C.
The infrared absorption spectrum of Ketoconazole and physical mixture of drug and polymers was recorded with a KBr
disc over the wave number 4000 to 400 cm-1.

Rheological study [7]

The rheological properties of gels were determined by the Brookfield viscometer; type DV-II + PRO using spindle no.62
and 63.Viscosity of the formulations were taken at two different temperatures that is at room temperature and the 370C with

https://rjpdft.com/HTML_Papers/Research%20Journal%20of age%20Forms%20and%20Technology__PID__2013-5-6-1.html 03/06/24, 11.21

Halaman 2 dari 8
%
 varying shear rate.

Measurement of the gel strength [8, 9]

A sample of 50 g of the gel was put in a 50 ml graduated cylinder. A weight of 14.33 g was placed on the gel surface. The
gel strength, which is an indication for the ophthalmic gel at physiological temperature, was determined by the time in
seconds required by the weight to penetrate 5 cm into the gel. All measurements were performed in triplicate (n=3). The
apparatus used for measuring gel strength is shown in Fig.1

Fig.1: Gel strength measuring device (A) weights (B) device

(C) Graduated cylinder (D) gel

Bioadhesive Strength [8, 9]

“Detachment Stress is the force required to detach the two surfaces of mucosa when a formulation/gel is placed in between
them”. The detachment stress was measured by using a modified analytical balance. A fresh goat corneal membrane was
obtained from local slaughter house. A section of fresh cornea was cut from the goat eye and washed with Saline solution.
A corneal membrane was fixed on a flat surface of object (such as bottom of vial) which was moistened with saline
Solution. Another object which is having flat surface at bottom (such as vial) was used to which other corneal membrane
was attached. This object was attached to the one side of pan (with cornea attached to flat surface in downward position).
Formulations were placed onto a corneal membrane surface of object which was fixed in position. Then height of second
object was adjusted so that corneal surface of both objects came in intimate contact. Two minute contact time was given to
ensure intimate contact between tissues and formulation. Then weight was kept rising in the pan until the adjustable object
get detached. The weight required to detach the ocular mucosa surfaces gave the mucoadhesive strength assessed in terms
of weight (gm). The mucoadhesive strength was measured in forms of force of adhesion in Newton’s by using equation 1.
All measurements were performed in triplicate (n=3).

Detachment Stress (dyne /Cm2) = m×g/A…………. (1)

Where, m= weight required for detachment of two vials in gms,
g= Acceleration due to gravity (980 cm/s2)
A= Surface area exposed.
The Apparatus for Bioadhesive study shown in Fig.2

Fig. 2: Modified Balance for Bioadhesive Study

A: Modified balance, B: Weighing pan, C: Glass vials, D: Gel, E: Corneal mucosa W: Weight

Isotonisity Evaluation [10]

The formulations were mixed with few drops of diluted blood on a slide. The diluted blood was prepared by using
Grower’s solution and Slide was observed under microscope at 45x magnification. The shape of blood cells were compared
with standard marketed ophthalmic formulation.

In-vitro Drug Release Study [11, 12]

In-vitro release study of the formulated ophthalmic gel was carried out by using diffusion cell through egg membrane as a
biological membrane. Diffusion cell with inner diameter 24mm was used for the study. the formulation 0.5 gm were placed
in donor compartment and Freshly prepared 100 ml artificial tear fluid (sodium chloride 0.670g, sodium bicarbonate
0.200g, calcium chloride dehydrated 0.008g,purified water q.s 100ml.) in receptor compartment. Egg membranes were
mounted in between donor and receptor compartment. The position of the donor compartment was adjusted so that egg
membrane just touches the diffusion medium. The whole assembly was placed on the thermostatically controlled magnetic
stirrer. The temperature of the medium was maintained at 37°C ± 0.5°C. 2ml of sample is withdrawn from receiver
compartment after 30 min, 1, 2, 3, 4, 5, 6, 7and 8 hrs and same volume of fresh medium is replaced. The withdrawn
samples was diluted to 10ml in a volumetric flask with methanol and analyzed by UV spectrophotometer at 242.8nm.

Antifungal Activity [13, 14]

An agar diffusion method was used for the determination of antifungal activity of formulations. Inocula were prepared by

https://rjpdft.com/HTML_Papers/Research%20Journal%20of age%20Forms%20and%20Technology__PID__2013-5-6-1.html 03/06/24, 11.21

Halaman 3 dari 8
%
 suspending 1-2 colonies of Candida albicans (NCIM no. 3102) from 24 hr cultures in Sabouraud's medium into tubes
containing 10 ml of sterile saline. The inoculum (0.5 ml) was spread over the surface of agar and the plates were dried at
35°C for 15 min prior to placing the formulation. The bores of 0.5 cm diameter were prepared and 20 µl samples of
formulation (1% w/v) were added in the bores. After incubation at 35°C for 24 h, the zone of inhibition around the bores
was measured.

Test for Sterility [15, 16]

The sterility test was carried out as per IP (1996) method. The optimized formulation was incubated for not less than 14
days at 30 -350c in the fluid thioglycolate medium and at 20-250c in soyabean casein digest medium to find out growth of
fungi in formulation.

Ocular Irritancy Test [17, 18]

The optimized formulation was used for eye irritancy study. The protocol was approved by Institutional Animal Ethics
Committee with approval no-IAEC/01.
The Modified Draize Eye Irritation: The 03 Albino rabbits weighing 1.5 to 2 kg. According to the draize test, the amount of
formulation was applied to the eye is 100µl was placed into the lower cul-de-sac. Test solution was instilled in left eye and
saline solution was instilled in right eye. The evaluation of ocular lesions was made at 1, 4, 24, 48,72hrs, and 1 week after
administration. 3 day washing period with saline was carried out. The rabbit was observed periodically for redness,
swelling, watering of the eye.
Accelerated stability studies [19]
The formulations were stored at room temperature and 40± 2°C with RH 60± 5% and 75± 5% respectively. The
formulations were evaluated mainly for their physical characteristics at the predetermined intervals of 3 months and after 6
months like appearance/clarity, pH, viscosity and drug content.

RESULTS AND DISCUSSION:

Clarity, pH and Drug content
On careful visual inspection against dark and white background, all the prepared ophthalmic gel formulations were found
to be free from any suspended particulate matter. All the formulations were found to be clear. This also indicates that the
PEG 400 can be a good solubilizing agent at 60% v/v concentration for solubilizing 1% ketoconazole in prepared
formulation.

The pH of all the formulations from F1 to F9 was found to be in the range of 6.5 to 6.8 pH values of formulations shown in
Table 3. Ideally, the ophthalmic solutions should possess pH in the range of 6.5-8.5, so as to minimize discomfort or
excessive tear flux causing faster drainage of the instilled dose due to corneal irritation.

The percentage drug content of all prepared ophthalmic formulations was found to be in the range of 98-102%. Table
3.Therefore uniformity of content was maintained in all formulation.

Fig.3: Fourier Transform Infra-red overlay of drug with individual polymer

Table 3. Evaluation Parameters
Sr. Formulation Observed Gel strength (sec) Detachment stress Drug content Cumulative Drug
No code pH (±S.D.) (±S.D.) (dyne/cm2) (±S.D.) (%) (±S.D.) Release (%) (±S.D.) after
8hrs
1 F1 6.75±0.01 0.916±0.1357 1105.15±100 98.15±0.85 32.53±0.030
2 F2 6.52±0.01 1.176±0.0493 1333.29±66.71 100.04±1.000 59.31±0.69
3 F3 6.74±0.02 5.09±0.1682 1842.96±142 101.25±0.6726 97.66±0.03
4 F4 6.5±0.208 2.92±2.0344 1611.38±111.38 98.976±0.9900 30.78±0.04
5 F5 6.54±0.02 8.913±1.8170 2205.93±105 98.97±1 53.60±0.024
6 F6 6.66±0.02 4.57±0.4453 1694.08±194.08 98.17±1.0424 83.79±0.01
7 F7 6.51±0.015 30.299±0.9209 3280.81±20 100.42±1 28.57±0.025
8 F8 6.52±0.02 12.493±3.4525 2615.41±84.59 98.11±0.89 51.35±0.025
9 F9 6.83±0.04 2.66±0.3523 1335.48±104.52 98.91±2 62.97±0.015

Table 4. Viscosity of Formulations at 370C

rpm Viscosity (cps) at 370C
Formulation code

https://rjpdft.com/HTML_Papers/Research%20Journal%20of age%20Forms%20and%20Technology__PID__2013-5-6-1.html 03/06/24, 11.21

Halaman 4 dari 8
%
 F1 F2 F3 F4 F5 F6 F7 F8 F9
0.5 550.8 3496 39832 33353 43431 39592 74864 55428 27354
1.0 529.9 3209 27234 23635 25195 25555 49070 37672 21595
1.5 516.8 2959 20956 18876 18396 18716 36072 28234 18516
2.0 505.6 2696 17936 16137 14397 15297 29934 22735 15357

Fig. 4: Viscosity profile of formulations at 37°C

Compatibility Study
Infra-red spectra of drug and polymers showed matching peaks with the drug spectra. Fig.3 The characteristic peaks of
drug were also present in the spectra of all drug- polymer combinations. Which indicate that there is compatibility between
drug and polymers.

Rheological study
Viscosity v/s rpm plots for all formulations shows decrease in viscosity as shear rate (rpm) was increased. As temperature
was increased the decrease in viscosity was observed. Which indicate that gel has the pseudoplastic flow. Concentration of
xanthan gum was a major factor affecting viscosity of formulations. In combination with Na CMC xanthan gum has shown
considerable increases in viscosity when concentration of Na CMC is 0.2% w/v to 0.4% w/v. But as the concentration of
Na CMC is increased from 0.2% w/v to 4% w/v and subsequently to 1% w/v the viscosity has decreased (Table 4.) which
may be because of greater swelling ability of xanthan gum than Na CMC.

Gel Strength
The gel strength was found to be affected by concentrations of gelling and mucoadhesive polymers. Optimal mucoadhesive
gel must have suitable gel strength so as to be administered easily and can be retained at ocular region without leakage after
administration. Gel strength of all formulations showed comparable results as that of viscosity results. (Table 3.)

Bioadhesive Strength
Bioadhesive force means the force with which gels bind to ocular mucosa. Greater bioadhesion is indicative of prolonged
residence time of a gel and thus prevents its drainage from cul-de-sac.

b. Blood cells with ketoconazole Formulation c. Blood cells with Gentamycin as marketed
(F3) formulation
Fig. 5: Shape of Blood cells

Fig. 6: In-vitro drug release profile of formulations

The Bioadhesion force increased significantly as the concentration of bioadhesion polymers increased. Results of this test
indicate that the variable xanthan gum and Na CMC both are having effect on bioadhesive strength. (Table 3.) It shows that
bioadhesive force was increased with the increasing concentration of the xanthan gum.

Isotonisity Evaluation
Isotonisity testing of formulations (F1, F5, F9 and F3) exhibited no change in the shape of blood cells (Fig.5) which reveals
the isotonic nature of the formulations as compared with standard marketed ophthalmic formulation. This indicates the
maintenance of tonicity in prepared formulations. Isotonisity was maintained to prevent tissue damage of eye.

In-vitro Drug Release Study

Out of nine formulations maximum release after 8 hrs was found for F3 formulation (Table 3). This indicates release of
97.66% drug available for antifungal activity of the drug.F3 formulation showed steady state release up to 8hrs which also
indicates that this formulation would show better contact with biological membrane.
In-vitro drug release profile of formulations shown in Fig.6

Optimization
A 32 full factorial design was selected and the 2 factors were evaluated at 3 levels, respectively. The percentage of Na CMC

https://rjpdft.com/HTML_Papers/Research%20Journal%20of age%20Forms%20and%20Technology__PID__2013-5-6-1.html 03/06/24, 11.21

Halaman 5 dari 8
%
 (X1) and xanthan gum (X2) were selected as independent variables and the dependent variable was % drug release.

Fig.7: Surface Response plot showing effect of sodium carboxymethylcellulose and xanthan gum on drug release.

The data obtained were treated using Design expert version 8.0.4.1 software and analyzed statistically using analysis of
variance (ANOVA). The data were also subjected to 3-D response surface methodology to study the interaction of Na CMC
(X1) and xanthan gum(X2) on dependent variable. The values of X1 and X2 were found to be significant at p <0.05, hence
confirmed the significant effect of both the variables on the selected responses. From this data optimum concentration of
Na CMC 1% w/v and xanthan gum 0.2%w/v was found (Fig.7).

Y1 (% CDR) = Y1 (% CDR) = 38.7576+61.1679*(A)-18.18013*(B)

From design expert version 8.0.4.1 five solutions were found in which optimum batch Na CMC 1%w/v and xanthan gum
0.2% w/v with desirability 1 was found to be optimum. From this data F3 batch was selected as optimum formulation.

Release Kinetics [20, 21]

In the present study, the drug release was analyzed by PCP Disso version v3 software to study the kinetics of drug release
mechanism. The factorial design batches followed korsmeyer peppas model kinetics. The R2 value of korsmeyer peppas
model was found close to one. The drug release was occurred by fickian diffusion mechanism as reflected by its n value
0.1758 (n<0.5).

Antifungal Activity
The study of indicate that ketoconazole retained its antifungal efficacy when formulated as an ophthalmic gel and drug was
active against selected strains of micro-organism.

Table 5. Zone of inhibition and % efficacy of formulations

Sr.no Formulation Candida albicans
Code Zone of Inhibition (mm) % Efficacy
±SD
1 Standard value 18 100
2 F1 09±1 50.00
3 F2 12.5±2.5 69.44
4 F3 18±5.65 100
5 F4 8.5±3.53 47.22
6 F5 12.5±7.77 69.44
7 F6 16.5±3.53 91.66
8 F7 04±1 22.22
9 F8 10±7.07 55.55
10 F9 14.5±7.77 80.55

F3 formulation showed 18mm zone of inhibition and 100% efficacy. (Table 5) Results obtained from antifungal activity of
F3 formulation resembles to release profile of drug which indicate the dependency of antifungal activity with drug release
from formulation.

Test for Sterility

There was no appearance of turbidity and hence no evidence of fungal growth when optimized formulation was incubated
for not less than 14 days at 300C to 350C in case of fluid thioglycolate medium and at 200C to 250C in case of soyabean-
casein digest medium. The preparations examined, therefore, passed the sterility test.

Ocular Irritancy Test

The results of the ocular studies indicate that the formulation F3 was non-irritant and no ocular damage or abnormal
clinical signs were visible.

https://rjpdft.com/HTML_Papers/Research%20Journal%20of age%20Forms%20and%20Technology__PID__2013-5-6-1.html 03/06/24, 11.21

Halaman 6 dari 8
%
 Table 6. Observations of Ocular Irritancy Study
Time Redness Swelling Watering
Rabbits
1,2,3 1,2,3 1,2,3 1,2,3 1.2,3 1,2,3
Right Eye Left Eye Right Eye Left Eye Right Eye Left Eye
At the time of installation(0hr) 0 1 0 0 1 1
10min 0 0 0 0 0 0
1hr 0 0 0 0 0 0
4hr 0 0 0 0 0 0
24hr 0 0 0 0 0 0
48hr 0 0 0 0 0 0
72hr 0 0 0 0 0 0
1 week 0 0 0 0 0 0

CONCLUSION:
This solubility enhanced ketoconazole 1% ophthalmic gel formulation fulfills all necessary parameters required for
ophthalmic use. This optimized formulation having improved viscosity and better mucoadhesive property may improve the
bioavaibility of ocular administration of ketoconazole in gel form and can be alternative to the conventionally administered
oral formulation.

REFERENCES:

1) Dhanpal R. et al, Ocular Drug Delivery System – A Review. International Journal of Innovative Drug Discovery.2012; 2(1):4-15.

2) Al-Badriyeh et al, Clinical Utility of Voriconazole Eye Drops in Ophthalmic Fungal Keratitis. Clinical Ophthalmology. 2010; 4:391–405.

3) Nagargojeet S., et al, Formulation and Evaluation of Ophthalmic Delivery of Fluconazole from Ion Activated in Situ Gelling System.
Scholars Research Library Der Pharmacia Letter. 2012; 4(4):1228-1235.

4) Pawar S. D. et al, Controlled Release In- Situ Forming Gatifloxacin Hcl for Ophthalmic Drug Delivery. International Research Journal of
Pharmacy. 2012; 3(6): 86-88.

5) Pavia D.L., Lampman G.M., Kriz G.S., Vyvyan J.R., Spectroscopy Infra red spectroscopy. Cengage learning, 2007. 26-107.

6) Suryawanshi S. S., Novel Polymeric in Situ Gels for Ophthalmic Drug Delivery System. International Journal of Research in Pharmacy and
Science. 2012; 2(1):67-83.

7) Shastri et al., Development and Evaluation of PH Triggered In-Situ Ophthalmic Gel Formulation of Ofloxacin. American Journal of Pharm
Tech Research. 2011; 1(4): 430-445

8) Gonjari1 I.D., et al, Use of Factorial Design in Formulation and Evaluation of Ophthalmic Gels of Gatifloxacin: Comparison of Different
Mucoadhesive Polymers. Drug Discoveries and Therapeutics. 2010; 4(6):423-434.

9) Shaha R.A., et al, Design and Evaluation of PH Dependant Mucoadhesive In situ Gel of Sodium Chromoglycate for Nasal Delivery.
International Journal of Advances in Pharmaceutical Research. 2011; 2(1): 64-77.

10) Dasankoppa F.S., et al, Formulation and Evaluation of a Novel In Situ Gum Based Ophthalmic Drug Delivery System of Linezolid. Science
Pharm. 2008; 76:515-532.

11) Reddy K. R., et al, Preparation and Evaluation of Aceclofenac Ophthalmic In-Situ Gels. Journal of Chemical, Biological and Physical
Sciences. 2011;1(2B): 289-298

12) Rathore K.S., In-Situ Gelling Ophthalmic Drug Delivery System: An Overview. International Journal of Pharmacy and Pharmaceutical
Sciences. 2010; 2(4)30-34

https://rjpdft.com/HTML_Papers/Research%20Journal%20of age%20Forms%20and%20Technology__PID__2013-5-6-1.html 03/06/24, 11.21

Halaman 7 dari 8
%
 13) Hosmani A., H., Synthesis and Evaluation of Nanostructure Particles of Salt of Ketoconazole for Solubility Enhancement. Digest Journal of
Nanomaterials and Biostructures. 2011; 6(3):1411-1418.

14) Method for Antifungal Disk Diffusion Susceptibility Testing of Yeasts; Approved Guidelines, 2nd edition, CLSI document, Aug.2009. 29(17)
M44-A2.

15) The Indian pharmacopeia, Government of India, Ministry of Health and Family Welfare, published by the Indian Pharmacopeia Commission,
Ghaziabad, 1996. 2: A117-A124

16) Akers M.J., Larrimore D.S., Guazzo M.D., Parenteral Quality control. 3rd edition revised and expanded, Informa Health Care,.2003. 57.

17) Kugalur G. P.et al, Formulation and Evaluation of Ketorolac Ocular PH-Triggered In-Situ Gel. International Journal of Drug Development
and Research. 2010; 2(3): 459-467

18) Huhtala A. et al, Corneal Models for the Toxicity Testing of Drugs and Drug Releasing Materials. Topics in Multifunctional Biomaterials and
Devices. 2008;1-24.

19) Stability Testing of New Drug Substances and Products [Q1A (R2)].2003. The International conference on Harmonization of Technical
Requirements for registration of pharmaceutical for human use (ICH).

20) Costa. P. et al. “Modeling and comparison of dissolution profiles”, European Journal of Pharmaceutical Sciences, 2001. 13: 123-133.

21) Lanao. J. M. et al. “Critical factors in the release of drugs from sustained release hydrophilic matrices”, Journal of Controlled Release, 2011.
154: 2-19.

Received on 15.07.2013
Modified on 17.08.2013
Accepted on 23.08.2013
© A&V Publication all right reserved
Research Journal of Pharmaceutical Dosage Forms and Technology. 5(6): November-December, 2013, 303-310

https://rjpdft.com/HTML_Papers/Research%20Journal%20of age%20Forms%20and%20Technology__PID__2013-5-6-1.html 03/06/24, 11.21

Halaman 8 dari 8
%