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Vol 1 | Issue 1 | Apr - Jun 2022                                                                                      Indian J Pharm Drug Studies | 30   

Original Article   

Formulation and Characterization of Clotrimazole Micro Emulsion for Topical 

Drug Delivery  

Vamakshi Thaker1, A.K. Singhai2, Dilip Kumar Tiwari3  

From, 1M. Pharmacy, 2Professor and Principal, 3Asstt. Professor, Department of Pharmaceutical, Lakshmi Narain College of Bhopal 

(M.P.) India. 

Correspondence to: Vamakshi Thaker, M. Pharmacy, Department of Pharmaceutical, Lakshmi Narain College of Bhopal (M.P.), India.  

Email:  vidhivamakshi@gmail.com   

ABSTRACT 

An antimycotic drug like clotrimazole is used for treating Candida albicans and other fungal infections. Clotrimazole seems to be a 

topical therapy treating vulvovaginal candidiasis, tineapedis, and oropharyngeal candidiasis. That is a synthetic azole antimycotic. By 

decreasing the production of ergosterol, this drug inhibits fungal growth. Clotrimazole has become a medication of interest for a variety 

of illnesses, including sickle cell anemia, malaria, and some cancers, in addition to its antimycotic properties. It is mixed with other 

molecules to create clotrimazole compounds with enhanced pharmacological effectiveness. Numerous novel pharmaceutical 

formulations enabling variable releases developed. Clotrimazole is a welltolerated, little-adverse drug. However, certain 

immunocompromised individuals are developing treatment resistance. In this study, we discussed the pharmaceutical chemistry, use, 

and pharmacology of clotrimazole.   

Key words: Clotrimazole antifungal drug, Topical drug delivery system, Clotrimazole micro emulsion gel. 

lotrimazole is a synthetic imidazole derivative most 

often used to treat yeast, dermatophyte infections of the 

vagina, and skin. This drug works well against 

Microsporum spp., Candida spp, Trichophyton spp., and 

Malazzesia furfur in vitro (1). It also shows modest activity in 

vitro action against Gram-positive bacteria and, at extremely 

high doses, activity against Gram-positive bacteria 

Trichomonas spp. Clotrimazole shows successful results in 

individuals who already failed to get treated by certain other 

antifungal medications such as nystatin, and amphotericin B. In 

the case of trichomonal vaginitis, the results aren't promising. 

Topical application of clotrimazole help treat skin infections 

caused by Candida or dermatophytes (2).   

Clotrimazole cream is equally efficient as Whitfield's 

ointment or tolnaftate in the treatment of dermatophytoses, and 

even as efficient as nystatin inside the treatment of cutaneous 

candidiasis in clinical studies. Clotrimazole topical 

formulations are typically well-tolerated, although in a few 

cases, local discomfort has prompted therapy discontinuation. 

(13). Clotrimazole has a molecular formulation of C22H17ClN2 

as well as a molecular weight of 344•8 g mol−1. Clotrimazole 

is in widespread use for the treatment of Candida albicans and 

other fungal infections. Its antimycotic properties were 

discovered in the late 1960s. As an active ingredient, it is 

marketed as a generic drug under various trade names and by 

various companies worldwide. In addition to its antimycotic 

activity, clotrimazole is used in the treatment of 

metronidazoleresistant Trichomoniasis to relieve symptoms 

(15) and displays activity against certain Gram-positive bacteria 

(16). It is a synthetic compound.  

 

 

 

 

 

Figure 1: The Chemical Structure of Clotrimazole (1-

[(2Chlorophenyl) Diphenylmethyl]-1H-Imidazole) (1).  

MATERIALS AND METHODS  

Polyethylene sorbitan mono-oleate (PSMO) and sorbitan mono-

oleate (SMO) acquired by P. C. Drug Center Co. Ltd. RCI 

Labscan Limited has acquired isopropyl-alcohol (IPA) (7). 

These were bought from the Orbit pharmaceutical, Gujarat 

Isopropyl palmitate (IPP). Sigma Aldrich bought fumed silica. 

C 

  



Thaker et al.                                                                              Clotrimazole Micro Emulsion for Topical Drug Delivery  

Vol 1 | Issue 1 | Apr - Jun 2022                                                                                      Indian J Pharm Drug Studies | 31   

During the tests, distilled water was utilized. All chemical 

products were medicinal and utilized without further 

purification.  

Pre-formulation Study  

Solubility - Solubility of clotrimazole determined in different 

oils, surfactants, and co-surfactant. Clotrimazole was added in 

excess to oils, surfactants, and co-surfactant and stirred for 24 h 

on a magnetic stirrer. Samples were centrifuged at 1500 RPM 

for 10 min after stirring, and the drug present in the supernatant 

get extracted at λ max 261 nm (8).  

pH- A standard solution of clotrimazole, 1mg/ml prepared. 

Further, diluted with USP buffers of pH 1.2, 4.5, and 6.8, each 

up to 10ml (5). Incubated the solutions for 2 hour at 37° C. To 

achieve an adequate solubility level aqueous samples were 

prepared with acetonitrile as a co-solvent at an effective final 

concentration of 10% (v/v). The samples were assayed for drug 

content by the validated HPLC method.  

FTIR Analysis- Test solution dissolved in 50mg of the 

substance to be examined in ethanol (96%) R and dilute to 5ml 

with the same solvent. Reference solution dissolves in 50mg of 

clotrimazole CRS in ethanol (96%) R and is diluted to 5ml with 

the same solvent. Plate thin layer chromatography F254 PLATE 

R. Mobile phase concentrated ammonia R1, propanol R, 

Toluene R (0.5:10:90 v/v/v)  

Solubility of the Drug in Different Solvents- Solubility is 

calculated using the following protocol. Partially insoluble in 

water, soluble in ethanol (96%), and methylene chloride. In 

different oils such as oleic acid, lemon oil, olive oil, and 

methane oil, the solubility of clotrimazole was studied. The 

maximum solubility of clotrimazole in mentha oil was 

discovered among the oils tested. The analgesic and cooling 

effects of mentha oil itself are sensory. Mentha oil is used for 

the oil phase for the clotrimazole microemulsion (6). Stability - 

Based on visual identification microemulsion with clotrimazole 

remained as clear liquid for two months without the occurrence 

of phase separation or flocculation at room temperature and 

refrigerator temperature. The results of various studies 

performed on ME gel were found to be satisfactory so, both 

were found to be stable for two months (4, 5).  

Drug Excipient Study- Accurately weighed amounts of 

clotrimazole (100 mg), and each selected excipient (500mg) 

were placed in a 5ml glass vial and mixed thoroughly. Closed 

vials containing blends were stored in ovens at 60°C and 40°C 

for 14 days. A standard clotrimazole sample without mixing 

with an excipient clotrimazole sample was kept under similar 

conditions. The amount of drug substance in blends was 

determined based on the expected drug to excipient ratio in the 

final formulation. Duplicate samples of drug–excipient blends 

were analyzed after 14 days by validated HPLC methods.         

Preparation of CTM Micro Emulsion and CTM Micro 

Emulsion-Based-Gels- The desired micro emulsion and micro 

emulsion-based gels with 1 percent w/w of clotrimazole have 

been selected. To obtain clotrimazole micro emulsions, the 

medicine has been dissolved. For clotrimazole-based gel, fumed 

silica dispersed in clotrimazole micro emulsions and produced.  

Preparation of Blank CTM Micro Emulsion and CTM Micro 

Emulsion Gel- Micro emulsion components in the preceding 

report, the region of micro emulsion chosen. The simple 

blending of IPP, 2:1 water and IPA, and 1:1 PSMO and SMO 

mixtures at 20% of concentrations produced two micro 

emulsions. 30% and 50%w/w for ME1 and in 20%, 40% w/w 

for ME2 1. Afterwards, 2.0 % 5 % of fumed silica were added 

into ME1 and ME2 to obtain micro emulsionbased gel 

designated as MBG1-1 to MBG1-2 and MBG2-1 to MBG2-2 

respectively.   

Table 1- Composition of Studied Micro Emulsion – Based - 

Gel Systems  

Micro 

emulsion   

Fumed 2.5% 

w/w  

silica  Fumed 5.0% 

w/w  

silica  

ME 1  MBG1 1   MBG1 2   

ME2  MBG2 1   MBG2 2   

Characterization of Blank CTM Micro Emulsion and CTM 

Micro Emulsion Based Gel- Important characters of CTM 

Micro emulsion and CTM Micro emulsion-based gel are-  

• The look has been seen visually.   

• Spreadability was achieved by the spreading of a low to 

high skin stretchable and retainable quantity of each 

formulation over the skin with sensational consideration in 

the + to +++ range.  

• Dilution tests and conductivity measurements have 

established the kind of micro emulsions.   

• The dilution inspection should be carried out by dropping 

into the water of each micro emulsion, classified for 

miscibility or immiscibility.  

• The conductivity meter CM-115 was tested (Orbit 

pharmaceutical, Gujarat).  

Determination of Transmittance of Clotrimazole Micro 

Emulsions- The %transmittance was checked against distilled 

water using a UV-visible spectrophotometer at λ max 630 nm 

(1, 2).   

T % = Antilog (2 - Absorbance)  

Drug Release Kinetics- The drug release kinetic study was 

performed to find drug release mechanisms from dissolution 

parameters by using various kinetic model equations. The zero-

order, first-order, Hixon Crowell, Korsmeyer Peppas, and 

Higuchi Plot models were tested.  



Thaker et al.                                                                              Clotrimazole Micro Emulsion for Topical Drug Delivery  

Vol 1 | Issue 1 | Apr - Jun 2022                                                                                      Indian J Pharm Drug Studies | 32   

Methods for Antifungal Activity- Following protocol was 

followed for measuring anti-fungal activity:  

• The cup-plate method was used for anti-fungal formulation.   

• Candida albicans suspension was poured into sterilized 

dextrose agar media (cooled at 40ºC) and was mixed 

thoroughly.   

• 20ml of the above-mentioned suspension was poured 

aseptically in a pre-sterilized Petri dish and was allowed to 

solidify. The surface of the agar plate was pierced via a 

sterile cork borer.  

• These wells were filled with an equal volume of the 

optimized batch of micro emulsion-based gel and marketed 

1 % clotrimazole gel followed by incubation at 18-24ºC, for 

72 h.   

• Fungal growth was detected and the zone of inhibitions was 

measured using an antibiotic zone reader.   

RESULTS  

Pre-formulation Studies  

Chemical Properties- It is a white powder or colorless 

crystalline powder. It has a melting point of 147-149° C. It is 

soluble in ethanol, acetone, and chloroform, but almost 

insoluble in water. It is odorless, tasteless, and subject to rapid 

decomposition in an acid solution. Clotrimazole hydrochloride 

has a melting point of 159° C.  

pH- The pH of clotrimazole in different solutions at initial and 

2hrs. It was observed that, at pH 1.2, pH 4.5, and pH 6.8. At 

initial time 98.94 ± 1.55, 98.85 ± 1.02, and 99.58 ± 1.72, 

respectively. The value observed at 2 hrs of 98.25, 98.25, and 

99.35, respectively.   

Table 2- pH Observed  

TIME  pH 1.2  pH 4.5  pH 6.8  

Initial  98.94 ± 1.55  98.85 ± 1.02  99.58 ± 1.72  

2 hrs  98.25  98.25  99.35  

FTIR Analysis- The FTIR Spectra of the clotrimazole and 

optimized clotrimazole microemulsion gel were recorded with 

KBr on an infrared spectrophotometer as shown in the figure.  

Solubility in Different Solvents- CLT experimental solubility 

values in buffers рН 2.0 and 7.4, 1-octanol and hexane 

expressed in molarity (S) in the temperature range (293.15-

313.15) К. The temperature dependences of the drug solubility 

in the studied solvents are shown in the figure 3, 4. Stated that 

studied solvents the compound solubility increased at higher 

temperatures. Clotrimazole is stable in the buffer solution pH 

range of 1.2 - 7.5, but it degrades in strongly acidic and basic 

media and at high temperatures (9, 10).  

 
Stability- Optimized micro emulsion & micro emulsion gel were 

subjected to a stability study for two months at room 

temperature and refrigeration conditions (2-8°C). During the 

period of storage, the ME was subjected for % transmittance, % 

assay & pH, while I gel was subjected for % transmittance, % 

assay, pH, consistency & viscosity (physical). Results are 

shown in Table 3 

Table 3- Result of stability study of micro emulsion at room temperature 

TEST  Initial time  1month  2month  

Transmittance %  99.6 ± 0.06  99.6 ± 0.21  99.4 ± 0.18  

Assay %  99.1 ± 0.26  98.8 ± 0.15  98.82 ± 0.13  

pH  5.50 ± 0.19  5.50 ± 0.14  5.50 ± 0.14  

Result of stability of Micro emulsion gel at room te mperature  

Assay %  99.26 ± 0.68  99.2 ± 0.28  99.2 ± 0.26  

pH  6.10 ± 0.25  5.92 ± 0.38  98.82 ± 0.13  

Transparency  Transparency & clear  Transparency & clear  Transparency & clear  



Thaker et al.                                                                              Clotrimazole Micro Emulsion for Topical Drug Delivery  

Vol 1 | Issue 1 | Apr - Jun 2022                                                                                      Indian J Pharm Drug Studies | 33   

Viscosity  Very good  Very good  Very good  

Result of stability stud y of micro emulsion at refrig eration temperature  

Transmittance %  99.9 ± 0.10  99.5 ± 0.10  99.4 ± 0.09  

Assay %  99.6 ± 0.22  99.1 ± 0.30  99.0 ± 0.30  

pH  5.46 ± 0.22  5.4 ± 0.20  5.42 ± 0.20  

result of stability of M icro emulsion gel at refriger ation temperature  

Assay %  99.6  ±  2.42  98.9  ±  1.23  98.6  ±  1.13  

pH  5.99  ±  0.20  5.99  ±  0.14  5.97  ±  0.12  

Transparency  Transparency & clear  Transparency & clear  Transparency & clear  

Viscosity  Very good  Very good  Very good  

Figure 4 - FTIR Spectroscopy of clotrimazole drug.   

Drug Excipient Chemical Compatibility- The total number of 

drug excipient blends in the study may be very high; therefore, 

excipient rank-ordered with their solubility for CLZ were 

selected primary screening. For example, oils such as capryl 90, 

lauroglycol 90, and capmul MCM C8 exhibiting higher 

solubility for clotrimazole were selected. As summarized in the 

table, every excipient clotrimazole had degraded approximately 

5-15% in 14 days at both storage conditions. The rate of 

degradation increased with an increase in temperature. A similar 

degradation peak of clotrimazole was evident in chromatograms 

of all samples. The representative chromatograms of the sample 

stored at 60o C for 14 days are shown in the figure. Which 

shows a well-resolved degradation product of clotrimazole. In 

the solution state, the stability of clotrimazole is pH-dependent.   

Preparation of CTM Micro Emulsion & CTM ME Gel- 

Following steps were followed in preparing CTM micro 

emulsion and CTM ME-based gel: The micro emulsions and 

micro emulsion based-gels which had desirable appearance 

were selected and were added with 1% w/w of clotrimazole. The 

drug was dissolved in micro emulsions to obtain clotrimazole 

micro emulsions. Fumed silica was dispersed in clotrimazole 

micro emulsions for the preparation of clotrimazole micro 

emulsion-based gel.   

Preparation of Blank Micro Emulsions and Micro Emulsion 

Based-Gels- Following steps were followed in preparing blank 

micro emulsion and ME-based gel: Micro emulsion components 

in the preceding report, the region of micro emulsion was 

chosen. The simple blending of IPP, 2:1 water and IPA, and 1:1 

PSMO and SMO mixtures at 20% of concentrations produced 

two micro emulsions. 30% and 50% w/w, respectively for ME1 

and in those of 20 %, 40 %, and 40 % w/w, respectively for ME 

2 1. Afterwards, 2.0 % and 5 % of fumed silica was added into 

ME1 and ME2 to obtain micro emulsion-based gel designated 

as MBG1-1 to MBG1-2 and MBG2-1 to MBG2-2, respectively. 

Table 7- Physical properties of clotrimazole micro emulsions 

and micro emulsion based-gels 

 

Characteristics of Clotrimazole Micro Emulsions and Micro 

Emulsion-Based Gels- Following characteristics were 

observed: 1%w/w clotrimazole was incorporated in ME1, ME2, 

andMBG2-2, and ME1-C, ME2- C, and MBG2-2-C, were 



Thaker et al.                                                                              Clotrimazole Micro Emulsion for Topical Drug Delivery  

Vol 1 | Issue 1 | Apr - Jun 2022                                                                                      Indian J Pharm Drug Studies | 34   

obtained respectively. No significant visual changes were 

observed. However, conductivity values of clotrimazole-loaded 

samples were low in comparison to their blank counterparts, 

while pH and spreadability showed remarkable change. The 

samples were water-in-oil type; therefore, clotrimazole located 

in the external oil phase, that resulted in lower conductivity. The 

rheological behaviour ofME1-C andME2-C still showed as 

Newtonian flow, also the MBG2-2-C still were shear-thinning 

like their blank counterparts. The viscosity of MBG2-2-C was 

raised slightly in comparison to its blank counterpart. 

Characteristics of Blank Micro Emulsions and Micro 

Emulsion-Based Gels- The obtained micro emulsions (ME1 

and ME2) were clear, pale yellowish liquids with little smell of 

alcohol and were immiscible with water. The results of dilution 

and conductivity exhibited that both ME1 and ME2 were water-

in-oil types since their HLB value was 9.65. 

 
Figure 5 - Characteristics clotrimazole micro emulsions and 

micro emulsion based-gel 

Table 8- Characteristics of blank micro emulsions and 

micro emulsion-based gels 

 

 

 
Figure 6- Characteristics of blank micro emulsions and 

micro emulsion based-gels 

 
Figure 7A: Clotrimazole formulation assay-based results 

7B: Clotrimazole formulation software based results 



Thaker et al.                                                                              Clotrimazole Micro Emulsion for Topical Drug Delivery  

Vol 1 | Issue 1 | Apr - Jun 2022                                                                                      Indian J Pharm Drug Studies | 35   

The pH of the formulations FA and FB was found to be 6.6 

± 0.07 and 6.1 ± 0.4respectively. The pH has been adapted to 

the appropriate physiological pH of 6.1-6.6. In USP, 

clotrimazole results were determined to be not less than 90.0 

percent and not more than 110.0 percent 20. ”Test findings 

using the established analytical technique. The F2 formulation 

of F2 drugs discovered 98.9 ± 0.46% whereas, the F3 

formulation produced 100.3 ± 0.71 %. Fig. shows FB as an 

optimal formulation based on the desired 

assessment.Researchers also determined that clotrimazole is 

often a suitable phenomenon for hydrogel integration. It also 

shows that the solubility problem of hydrophobic drugs also 

isn't addressed by alcoholic content. A hydrogel without any 

hard solvents that may irritate can be produced by co-solvents. 

It was discovered to be compatible with solvents as Carbomer 

was used as a gelling agent. The approach devised does not 

require the removal of polymer over the day and so saves time. 

Has an increased propensity and is much more patient adaptive, 

therefore more clinical studies are necessary. 

Drug release kinetics study- The kinetic research on drug 

release. The formulation of hydrogel based on micro emulsion 

is an effective promoter of the localization of clotrimazole to the 

skin. It was shown that the drug permeability of the optimized 

formula based on micro emulsion (in vitro) was below (92.04 

percent) its optimal hydrogel formulation based on micro 

emulsion (ex vivo) (96.12 percent ). This might be because of 

the drug partitioning into the oil phase of the hydrogel-based on 

micro emulsion that lowers drug release. 

Antifungal activity- The values of the mean zone of inhibition 

(in vitro antifungal activity) of optimum micro emulsion-based 

hydrogel batch and marketed formulation (15). For topical 

antifungal medicines, such as clotrimazole, effective formula is 

required. Their thermodynamically and isotopically stable 

characteristics are caused by surfactants and co-surfactants that 

lower interfacial tension from the oil to the water phase. 

Table 8- Drug Kinetics Release Study 

 

 

DISCUSSION 

Clotrimazole o/w micro emulsion by the titration technique 

throughout their experiment. Surfactants and co-surfactants 

have been combined and applied wisely to the water drop. The 

medicine was dissolved in the oil phase and stirred continually 

into the aforementioned solution. The solution allowed for clear 

and transparent liquid micro emulsion to be formed. The phase 

titration technique was used to manufacture clotrimazole loaded 

o/w micro emulsion. Surfactants and co-surfactants have been 

combined and applied wisely to the water drop. The drug was 

dissolved in the oil phase and stirred continually into the 

mentioned solution (14). All located clear and transparent liquid 

solutions.  

The greater clotrimazole solubility in the oil phase is 

essential since clotrimazole is a low water-soluble medicine. In 

different oils including oleic acid, lemon oil, olive oil, and 

mentha oil, the solubility of clotrimazole was studied (4). The 

maximum solubility of clotrimazole in mentha oil has been 

discovered among the oils that have been tested. The analgesic 

and cooling effects of mentha oil itself are sensory. Mentha oil 

has thus been used for the oil phase for the clotrimazole micro 

emulsion (11, 12). The maximal solubility of clotrimazol in 

tween 80 was shown. Tween 80 was therefore used as the 

surfactant for the formulation of clotrimazole. Micro emulsion 

for other co-surfactants including IPA and ethanol, clotrimazole 

demonstrated the highest solubility of propylene glycol. The 

skin is well permeated by propylene glycol. The co-surfactant 

is, therefore propylene glycol.   

Nevertheless, the further development of clotrimazole as a 

pharmaceutical is an area of intense research at present. There 

are prospects both for its exploitation in new indications and for 



Thaker et al.                                                                              Clotrimazole Micro Emulsion for Topical Drug Delivery  

Vol 1 | Issue 1 | Apr - Jun 2022                                                                                      Indian J Pharm Drug Studies | 36   

the development of new formulations. A scaffold based on 

clotrimazole is being used as a pharmacophore in the design and 

synthesis of novel antimalarial drugs that are cheap and easy to 

synthesize [22]. Palladium–clotrimazole complexes that exhibit 

enhanced cytotoxicity against tumour cell lines, in comparison 

with clotrimazole alone, are under investigation as novel 

antineoplastic agents [23]. Indeed, several other metal –

clotrimazole complexes, such as ruthenium– clotrimazole and 

platinum –clotrimazole, also display promising antineoplastic 

characteristics [24]. There is also intense interest in using 

clotrimazole and its metabolite as lead compounds in the 

strategic design of novel treatments for sickle cell disease, on 

the basis that they can reduce erythrocyte dehydration in vivo by 

inhibiting the so-called Gardos, calcium-dependent potassium 

channel that malfunctions in this disease.  

CONCLUSION  

In conclusion, clotrimazole is an effective, safe, and 

welltolerated drug with unusual chemistry that is widely used in 

the treatment of skin, vulvovaginal and oropharyngeal fungal 

infections. It is sold in most developed countries worldwide 

under a variety of trade names, and a large number of 

clotrimazole formulations are available.  

Although emerging resistance to clotrimazole may limit the 

future use of this drug in certain patient subpopulations, in the 

general population, its widespread use is likely to continue for 

the foreseeable future. The ongoing development of 

clotrimazole as a pharmaceutical is currently focused on finding 

new clinical indications for the drug, its use as a lead compound 

in structure-based drug design studies, and the optimization of 

formulated products to enhance drug delivery. New approaches 

to the formulation of clotrimazole include a buccal bio-adhesive 

film containing clotrimazole, which was found to inhibit oral 

candidiasis for up to 6 h (18), and a thermos-sensitive vaginal 

gel formulation formed by complexation of clotrimazole with 

beta-cyclodextrin, which has been shown to reduce the release 

rate of clotrimazole in comparison with standard preparations (17).  

This type of slow-release formulation may exhibit increased 

efficacy over other vaginal delivery systems, as traditional 

vaginal creams, pessaries and tablets tend to have short 

residency times in the vagina due to the natural cleansing 

process that takes place there. The use of liposomes containing 

clotrimazole may also provide increased residency in the 

vagina, thereby improving gel formulations for treatment (19). 

RS 100 nano-capsules have recently been studied in the 

treatment of C. Albicans and C. glabrata, and these have been 

reported as more active than free clotrimazole alone (20). Given 

the scale of the current market for vulvovaginal clotrimazole 

preparations, novel formulations that can demonstrate an 

advantage over pre-existing preparations could potentially 

attract a large revenue stream. Nano-fiber mats for oral 

applications are also superior in efficacy and have reduced 

toxicity over lozenges and powders in current use, although 

further pharmaceutics investigations are needed (21).  

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How to cite this article: Thaker V, Singhai A.K, Tiwari 

D.K. Formulation and Characterization of Clotrimazole 

Micro Emulsion for Topical Drug Delivery. Indian J Pharm 

Drug Studies. 2022;1(1):30-37. 

Funding: None                     Conflict of Interest: None Stated 

 


