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Bulletin of Pharmaceutical Research 2014;4(1):1-8 An Official Publication of Association of Pharmacy Professionals ISSN: 2249-6041 (Print); ISSN: 2249-9245 (Online)

Eby George* and Manju Maria Mathews
Dept. of Pharmaceutics, Nirmala College of Pharmacy, Muvattupuza-686 673, Ernakulam, Kerala, India
*E-mails: [email protected], [email protected] Tel.: +91 9249985184.
Received: December 18, 2013 / Revised: January 06, 2014 / Accepted: January 07, 2014

The objective of present work was to develop and evaluate a Minoxidil emulgel and compare its
properties with Minoxidil gels. When gel and emulsion are used in combination the dosage form is
referred as Emulgel. For preparing the emulgel, first, Minoxidil was dissolved in solvent system
comprising water and propylene glycol in ratio 35:15 with liquid paraffin as oil phase. The prepared

w/o emulsion was then mixed with carbopol gel solution in 1:1 ratio and finally neutralized with
triethanolamine to form emulgel. Total eight formulations were prepared of which four were gels
and other four were Emulgels. The gels were evaluated for physicochemical parameters, in vitro

drug release and ex vivo permeation study. Among developed formulations, F1 showed 56.30%
cumulative release after 8 h, whereas F6 showed 72.31% release after 8 h.
Key words:
Minoxidil, Emulgel, Spreadability, Carbopol 934, Alopecia.


balding. Topically applied Minoxidil was shown Androgenetic alopecia occurs in both men and to improve blood flow in human balding scalp. A women and is characterized by the progressive topical formulation of Minoxidil then was loss of hair from the scalp in a defined pattern. developed to exploit this side effect (Gupta et al Alopecia means hair loss which is the most 2012). This led to the development of a topical common problem of modern societies, which formulation of emulgels which are, emulsions, create much economical and psychological either of the oil-in-water or water in oil type; effect; affecting about 70% males and 30% gelled by mixing with a gelling agent. There is no females. Recently, a great effort has been made marketed formulation of minoxidil emulgel till to treat hair loss or alopecia. One of the most date. Therefore, present research has been common types of alopecia is androgenic alopecia undertaken with the aim to develop an emulgel and alopecia areata (Kaur et al 2010). formulation of minoxidil. Chemically, Minoxidil is 2, 4-diamino-6- piperidinopyrimidine-3-oxide, soluble in water
to the extent of approximately 2 mg/ml, is more Materials
readily soluble in propylene glycol or ethanol, Minoxidil (Yarrowchem Products, Mumbai), and is nearly insoluble in acetone, chloroform, or Carbopol 934 (Himedia laboratories Private Ltd, ethyl acetate (Lowenthal and Affrime, 1980). Mumbai), Propylene glycol, Triethanolamine, Minoxidil was introduced in the early 1970s as a Ethanol, Propyl paraben, Span 80, Light liquid treatment for hypertension. Hypertrichosis was paraffin and mentha oil were purchased from a common side-effect in those taking Minoxidil Nice Chemicals, Kochin. All other chemicals and tablets and included the regrowth of hair in male reagents used were of the analytical grade. George and Mathews Bull. Pharm. Res. 2013;3(3) De-ionized distilled water was used throughout formulations were prepared using varying amount of gelling agent and penetration The method only differed in the process of Determination of solubility of Minoxidil
making gel in different formulations. The The solubility studies were performed in preparation of emulsion was same in all the distilled water, by adding excess amount of drug formulations. The gel bases were prepared by in each case and keeping the flasks containing dispersing Carbopol 934 in distilled water excess amount of drug containing phosphate separately with constant stirring at a moderate buffer pH 7.4 on a rotary shaker for 24 h. After speed using mechanical shaker. Formulations F5, 24 h, solutions were analyzed spectro- F6, F7, and F8 were prepared by carbopol 934 as photometrically at 275.6 nm, which was the gelling agent. The pH values of all the absorption maxima determined earlier and drug formulations were adjusted to 6-6.5 using concentrations were calculated. triethanolamine (TEA). The oil phase of the emulsion was prepared by dissolving Span 80 in Determination of partition coefficient
light liquid paraffin while the aqueous phase was n-Octanol and water were pre-saturated with prepared by dissolving Minoxidil in purified each other for 24 h before experiment. To the water. Methyl paraben was dissolved in pre-equilibrated buffer (10 ml), known quantity propylene glycol and mixed with aqueous phase of drug was dissolved. Ten ml of octanol was added to equal volume of drug solution in a Mentha oil was also mixed in oil phase. Both the separating funnel. The system was kept for 24 h oily and aqueous phases were separately heated with intermittent shaking. Finally, water layer to 70°C to 80°C, then the aqueous phase was was separated, clarified by centrifugation and added to the oil phase with continuous stirring until it got cooled to room temperature (Mohamed, 2004). The obtained emulsion was Drug-Excipient interaction study
mixed with the gel in 1:1 ratio with gentle The infrared (IR) spectra were recorded using an stirring to obtain the Emulgel (Table 1).
FTIR spectrophotometer by the KBr pellet method in the wavelength region between 7800 Evaluation of gels/emulgels
and 350 cm-1. The spectra obtained for Minoxidil Following parameters were used for the and physical mixtures of Minoxidil with polymer evaluation of gels/emulgels: were compared to check compatibility of drug with carbopol 934. Homogeneity Preparation of Minoxidil gels
All developed gels were tested for homogeneity Required amount (1 g) of Minoxidil was by visual inspection after the gels have been set dissolved in solvent mixture (Ethanol:water:: in the container. They were tested for their 1:1). The required amount of carbopol 934 was appearance and presence of any aggregates. weighed and transferred to the solvent mixture. Allow the polymer to swell completely without Grittiness constant stirring. After complete swelling, the dispersion was constantly stirred at 500 rpm for microscopically for the presence of particles. If about 2 h. Later, the speed was reduced to avoid no appreciable particulate matter is seen under air entrapment. After 2 h, the hydrogel solution light microscope, the gel preparation fulfils the containing the drug was neutralized by the requirement of freedom from particular matter addition of the alkali triethanolamine to obtain and from grittiness as desired for any topical gel with maximum viscosity. preparation. Preparation of Minoxidil emulgel Measurement of pH The emulgel was formulated in three different The pH of Minoxidil gel formulations were steps. Step 1 was formulation of emulsion either determined by using digital pH meter. One gram o/w or w/o. Step 2 was formulation of gel base. of gel was dissolved in 100 ml of distilled water Now, step 3 involves incorporation of emulsion for pH measurement in triplicate and average into gel base with continuous stirring. Different values were calculated. George and Mathews Bull. Pharm. Res. 2013;3(3) Table 1. Formulation plan of Minoxidil gel and emulgels
Minoxidil gels
Minoxidil emulgels
(% w/w)
Propylene glycol Light liquid paraffin Drug content studies with >50 mm but <70 mm. The results were Minoxidil gel (500 mg) was taken and dissolved expressed in terms of the spreading area as a in 50 ml of phosphate buffer pH 7.4. The function of the applied mass (Garg et al 2002). volumetric flasks were kept for 2 h and shaken well in a shaker to mix it properly. In vitro drug release studies
The solution was passed through the Whatman Before experiment, the cellophane membrane filter paper and filtrates were analyzed for drug was washed in the running water and then content spectrophotometrically at 285 nm soaked in distilled water for 24 h to remove against corresponding gel concentration as glycerin present on it. The in vitro diffusion studies of prepared gels were carried out in hollow tube diffusion cell using prehydrated Viscosity studies cellophane membrane and phosphate buffer pH The measurement of viscosity of formulations 7.4 (100 ml) as receptor compartment. 500 mg was done with a Brookfield Viscometer. The gels of each of formulation was spread uniformly on were rotated at 10 and Emulgels at 20 rpm using the membrane (Yamaguchi et al 1996). spindle no. 64. At each speed, the corresponding The donor compartment was kept in contact dial reading was noted (Martinez et al 2007). with a receptor compartment and the temperature was maintained at 37±0.5°C. The Spreadability solution on the receptor side were stirred by The spreadability was determined by parallel externally driven teflon coated magnetic bars. At plate method which is widely used for predetermined time intervals, 5 ml of solution determining and quantifying the spreadability of from the receptor compartment was pipetted semisolid preparations. Various formulations out and immediately replaced with fresh 5 ml (1 g) were pressed between two 20 ´ 20 cm phosphate buffer. horizontal plates, the upper of which weighed The drug concentration on the receptor fluid was 125 g. The spread diameter Φ was measured determined spectrophotometrically at 285 nm after 1 min. Under these experimental against appropriate blank. Calculation of conditions, the term semi stiff was applied to percentage drug release was done using the samples with <50 mm and semi fluid to those (Conc. of drug (in mg) x Volume of receptor compartment) x 100 Label claim (amount of drug in donor compartment)
Ex vivo evaluation
house. The skin was then soaked in sodium Ex vivo release study was conducted using bromide solution for 5-6 h and washed with preserved or fresh chicken skin from slaughter water so as to remove adhering fat tissue. The George and Mathews Bull. Pharm. Res. 2013;3(3) epidermis was thoroughly washed with water, Higuchi Model dried at 25% relative humidity, wrapped in Ideally, controlled drug-delivery systems should aluminium foil and stored in freeze until further deliver the drug at a controlled rate over a use. For ex vivo permeation studies, skins were desired duration. It has been shown that in the allowed to hydrate for 1 h before being mounted case of hydrophilic matrices, swelling and on the Franz diffusion cell with the stratum erosion of the polymer occurs simultaneously, corneum (SC) facing the donor compartment. and both of them contribute to the overall drug- The sample was applied on the skin and then fixed in between donor and receptor Higuchi tried to relate the drug release rate to compartment of Franz diffusion cell. The the physical constants based on simple laws of receptor compartment contained phosphate diffusion. Release rate from both a planar buffer pH 7.4 an the temperature of the medium surface and a sphere was considered. Higuchi was thermostatically controlled at 37±1.0°C by was the first to derive an equation to describe surrounding water jacket and the medium was the release of a drug from an insoluble matrix as stirred with bar magnet using magnetic stirrer. the square root of a time-dependent process Aliquots, withdrawn at predetermined intervals based on Fickian diffusion. of time, were spectrophotometrically estimated at 285 nm against their respective blank formulation treated in the same manner. where, Qt is the amount of drug released in time Kinetic data analysis: Drug release models
t, and kH is the release rate constant for the (Singhvi and Singh, 2011; Dash et al 2010; Sharma et al 2011) Zero order release kinetics Determination of diffusion exponent
Zero order release kinetics refers to the process To find out the mechanism of drug release, first of constant drug release from a drug delivery 60% drug release data was fitted in Korsmeyer– device such as oral osmotic tablets, transdermal systems, matrix tablets with low-soluble drugs and other delivery systems. In its simplest form, zero order release can be represented as: where Mt/M∞ is fraction of drug released at time t, k is the rate constant and n is the release exponent. The n value is used to characterize where Q is the amount of drug released or different release mechanisms as given in table dissolved (assuming that release occurs rapidly for cylindrical shaped matrices. after the drug dissolves), Q0 is the initial amount of drug in solution (it is usually zero), and K0 is RESULTS AND DISCUSSION
the zero order release constant. The plot made Solubility and partition coefficient study
was cumulative % drug release vs time (zero From the solubility studies, the drug order kinetic model). concentration was found to be 2.5 mg/ml in water. The logarithmic value of partition First order release kinetics coefficient (log P) was found to be 1.25. The The rate laws predicted by the different results obtained also indicated that the drug mechanisms of dissolution both alone and in combination, have been discussed by Higuchi. lipophilicity, which fulfils the requirements of formulating it into a gel and emulgel formulation (data not produced). where, C0 is the initial concentration of drug and Physicochemical properties
K is first order constant. The equation in All formulations were found to be free of resemblance to the other rate law equations, predicts a first order dependence on the concentration gradient (i.e. Cs - Ct) between the preparation with a smooth homogeneous static liquid layer next to the solid surface and texture and glossy appearance (Table 2,
the bulk liquid. Figure 1).

George and Mathews Bull. Pharm. Res. 2013;3(3) Table 2. Physicochemical characteristics of formulations
Formulation Homogeneity Grittiness
Phase separation
White to cream in colour Slight separation of oil phase White to cream in colour White to cream in colour White to cream in colour Excellent +++, Good ++, absent -, present + irritation. This may be due to the addition of base triethanolamine to the resultant gel and emulgel solution during mixing so as to neutralize the acidic groups present in the polyacrylate chains of carbopol polymer. There was no significant change in pH values as a function of time for all formulations. The
viscosity of gels and Emulgels were found to
increase with increase in the concentration of the polymer used. The viscosity of emulgels was higher as compared to corresponding gels since the emulgels was formulated by finally mixing emulsion with the carbopol gel in 1:1 ratio. The Fig. 1. Prepared gels and emulgels of Minoxidil
emulgels showed comparatively high % drug content than that of the corresponding gel pH, viscosity and drug content
formulations. This indicated homogenous The pH of the formulations was in the range of distribution of drug throughout the emulgels 6.34 to 7.52, which lies in the normal pH range which could be due to high entrapment of drug of the skin and would not produce any skin in the internal phase of emulsion (Table 3).
Table 3. Results of pH, viscosity and drug content studies
Drug content*
Formulation code
*Each reading is an average of three determinations


presence of oil phase in emulgels reduces the As per results of spreadability studies, the shearing stress (Table 4).
spreading area was found to decrease with increase in viscosity, since spreadability and In vitro drug release
viscosity are inversely proportional. The The release of Minoxidil from the gels and emulgels were found to show excellent Emulgels was varied according to concentration spreadability since they are less viscous and the of polymer. The release of the drugs from gel George and Mathews Bull. Pharm. Res. 2013;3(3) Table 4. Results of spreadability studies
Spread diameter*
Formulation code
Spreading area (S)
*Each reading is an average of three determinations formulations ranked in the order F1 > F2 >F3 > F4, Where the amounts of the drug released after 8 h were 76.42%, 68.22%, 62.31%, 59.69% respectively. Drug release from the emulsified gel formulation can be ranked in the following descending order: F6 > F5 >F7> F8 where the amount of the drug released after 8 h were 64.35%, 53.96%, 52.32%, 51.32% respectively. The progressive increase in the amount of drug released from the formulations attributed to gradual decrease with increase in concentration of polymer. It has been concluded that, if we increase the concentration of polymer, the diffusion of drug through the membrane also Fig. 3. Comparative drug release profiles of
decreases (Figure 2, 3).
formulations F5-F8 for F1 and F6 was 0.845 and 0.840 suggesting that the Emulgel followed anomalous transport or non-fickian diffusion (Zero order release). Determination of mechanism of release from Diffusion exponent (n) The value of diffusion exponent, n = 0.845 and 0.840 for F1 and F6 indicated anomalous non- Fickian diffusion of drug from both gels and emulgels. Fick's laws of diffusion describe the spatial and temporal variation of the molecules in the aqueous solution. In Fickian diffusion, the drug flux or the rate of permeation through a Fig. 2. Comparative drug release profiles of
formulations F1-F4 concentration gradient. A fundamental criterion for Fickian diffusion is that the surface Kinetics of drug release
The release kinetics data indicated that the immediately and remains constant throughout release of drug from Emulgel F6 best fits to zero the sorption process i.e. polymer chain at surface order release model because the correlation must instantaneously reach saturation. Although coefficient values were higher in case of zero Fickian diffusion theories have been thoroughly order equation and the release from gel F1 fits to developed, most of the polymer-solvent systems Higuchi model. The release rate is independent do not obey such a simplified description. of the concentration of the drug. The release Diffusion process in which the mean square exponent value of Korsmeyer-Peppas Equation displacement (MSD) of drug grows non linearly George and Mathews Bull. Pharm. Res. 2013;3(3) with time are referred to as Anomalous or non- of release is affected by the viscosity of swollen Fickian i.e. the release pattern is irregular and is polymers. This process is evident from the in independent of drug concentration. In reality, vitro drug release data of both gels and emulgels the mean square displacement does not increase i.e. the release of minoxidil profoundly decreased linearly with time in anomalous diffusion and with increase in polymer concentration. The does no longer exist. diffusion exponent calculated by Korsmeyer- These complexities associated with the transport Peppas plot signifies that the mechanism of drug mechanisms are also associated with the release from both gel and emulgel follows physical properties of the polymers. The kinetics Anomalous diffusion (Table 5).
Table 5. Regression co-efficients (R2) values of kinetic models for formulation F1 and F6
R2 values
Formulation code
Drug release mechanism
Anomalous transport (non-Fickian) F2 (Emulgel)
Anomalous transport (non-Fickian)
Ex vivo permeation study

more promising than Minoxidil gels. Best formulations (F1 and F6) selected were subjected to ex vivo release study through chicken skin using Franz diffusion cell. The ex vivo release displayed better estimate of drug permeation characteristics through animal skin. Minoxidil emulsified in oil phase showed higher release through skin as compared to minoxidil solubilized in hydrophilic gel matrix of carbopol. The presence of oil phase enhanced the drug permeation through stratum corneum, which is considered to be the main barrier to the permeation of drugs through skin. The amount of drug permeated through skin after 8 hours from F1 and F6 was 56.3% and 72.31% (Das and Fig. 4. Comparison of ex vivo permeability study
Ahmed, 2007) (Figure 4).
The results of present studies confirmed the We would like to thank Prof. Dr. S. Kuppuswamy feasibility of using Minoxidil emulgels over (Head of the Department, Pharmaceutics, Minoxidil gels for developing an effective and Nirmala College of Pharmacy, Muvattupuzha, safe topical delivery system for the treatment of Kerala) and Prof. John Joseph (Principal, Nirmala androgenetic alopecia. Hence, an effective College of Pharmacy, Muvattupuzha) for kind Emulgel of Minoxidil is recommended as being support and help in conducting research work.
Das MK, Ahmed AB. Formulation and ex-vivo evaluation of gel for alopecia condition. Int. J. Pharm. Res. Allied Sci. rofecoxib gel for topical application. Acta Pol. Pharm. 2007;64(5):461-7. Kaur LP, Garg R, Gupta GD. Development and evaluation of Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modeling topical gel of Minoxidil from different polymer bases in on drug release from controlled drug delivery systems. application of alopecia. Int. J. Pharm. Pharm. Sci. 2010; Acta Pol. Pharm. 2010;67(3):217-23. Garg A, Aggarwal D, Garg S, Singla AK. Spreading of semisolid formulations: An update. Pharm. Tech. 2002; pharmacokinetics of Minoxidil. J. Cardiovasc. Pharmacol. 1980;2(2):S93-106. Gupta S, Shahi S, Tadwee I, Zadbuke N, Tribhuvan S, Martinez MAR, Gallardo JLV, de Benavides MM, Lopez- Sonawane U. Enhanced topical formulation of Minoxidil Duran JDG, Lara VG. Rheological behavior of gels and George and Mathews Bull. Pharm. Res. 2013;3(3) meloxicam release. Int. J. Pharm. 2007;333(1-2):17‐23. Res. 2011;45(1):25-31. Singhvi G, Singh M. Review: In vitro drug release Mohamed MI. Optimization of chlorphenesin emulgel characterization models. Int. J. Pharm. Stud. Res. 2011; formulation. AAPS J. 2004;6(3):81-7. [DOI: 10.1208/aaps Yamaguchi Y, Sato H, Sugibayashi K, Morimoto Y. Drug Sharma R, Walker RB, Pathak K. Evaluation of the kinetics release test to assess quality of topical formulations in and mechanism of drug release from Econazole nitrate japenese market. Drug Dev. Ind. Pharm. 1996; nanosponge loaded carbapol hydrogel. Ind. J. Pharm. Edu. 22(7):569‐77. [DOI: 10.3109/03639049609063210]


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Canadian Pari-Mutuel canadienne du pari mutuel Schedule of Drugs Agri-Food Canada Agroalimentaire Canada © Her Majesty the Queen in Right of Canada, (2011), as represent-ed by the Canadian Pari-Mutuel Agency. All rights reserved. No part of this publication may be reproduced, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, or stored in a retrieval system, without prior