Formulation Development and Evaluation of Terbinafine Hydrochloride Transdermal Patch Using Clove Oil as a Natural Permeation Enhancer

 Pradnya R. Shenavi and Prof. Dipali Hamde  

Dr. Vedprakash Patil Pharmacy College, Chh. Sambhajinagar, Maharashtra, India

*Correspondence: shenavipradnya@gmail.com

DOI: https://doi.org/10.71431/IJRPAS.2026.5623

INTRODUCTION

Transdermal drug delivery systems (TDDS) are advanced dosage forms that deliver drugs through the skin into systemic circulation in a controlled and predetermined manner. Compared with oral and injectable dosage forms, transdermal systems are non-invasive, avoid hepatic first-pass metabolism, reduce dosing frequency and can maintain relatively steady plasma drug levels. These advantages make TDDS especially useful for long-term therapy and for drugs that undergo gastrointestinal degradation or extensive first-pass metabolism [1–3].

Figure 1. Schematic representation of transdermal drug delivery system and drug diffusion pathway.

Despite these advantages, the stratum corneum remains the principal barrier to transdermal permeation. Its lipid-rich “brick and mortar” structure permits only limited passage of drug molecules. Drugs intended for transdermal delivery generally require suitable physicochemical characteristics, including adequate lipophilicity, low molecular size and sufficient potency. In many cases, permeation enhancers are required to temporarily modify the skin barrier and improve drug diffusion [3–5].

Figure 2. Skin barrier and principal permeation pathways relevant to transdermal delivery.

Terbinafine hydrochloride is an antifungal agent of the allylamine class. It inhibits squalene epoxidase, interferes with ergosterol biosynthesis and produces fungicidal activity against dermatophytes. Oral terbinafine therapy may be associated with gastrointestinal disturbance, hepatic side effects and first-pass metabolism, whereas conventional topical formulations may require repeated application and may not provide sufficient drug penetration into deeper skin layers. Therefore, a controlled transdermal patch can be considered a promising alternative delivery system for improved antifungal therapy [6–8].

Figure 3. Chemical structure of terbinafine hydrochloride.

Natural permeation enhancers such as essential oils and terpenes have attracted attention because they can improve drug permeation with comparatively lower irritation potential than several synthetic enhancers. Clove oil contains eugenol and related volatile constituents that may enhance partitioning and diffusion through the stratum corneum by interacting with skin lipids. The present research was therefore designed to formulate and evaluate terbinafine hydrochloride transdermal patches using HPMC E5 and PVA as film-forming polymers and clove oil as a natural permeation enhancer.

MATERIALS AND METHODS

Materials

Terbinafine hydrochloride was used as the active pharmaceutical ingredient. HPMC E5 and PVA were selected as film-forming polymers. Propylene glycol was used as plasticizer and clove oil was used as a natural permeation enhancer. Distilled water, ethanol and other reagents were used as analytical-grade solvents and excipients. Major materials and instruments used in the study are summarized below.

Preformulation studies

The drug sample was examined for organoleptic properties such as color, odor, texture and appearance. Melting point was determined using the capillary method. Solubility was studied in water, methanol, ethanol, phosphate buffer pH 7.4 and chloroform. The λmax of terbinafine hydrochloride was determined using UV-visible spectrophotometry and calibration standards of 2–10 µg/mL were prepared for analytical estimation.

Drug-excipient compatibility was assessed by Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). FTIR spectra of the pure drug and physical mixtures were compared for characteristic functional group peaks. DSC thermograms of pure drug and drug-excipient mixtures were compared for changes in onset temperature, peak temperature and enthalpy.

Experimental design

A Design of Experiments (DoE) approach was used to optimize formulation variables. Two independent variables were selected: HPMC E5 concentration (350, 575 and 800 mg) and clove oil concentration (20, 50 and 80 mL). Drug release (%) and skin permeation (%) were selected as dependent responses. A total of nine formulations (F1–F9) were prepared.

Table 1. Composition of terbinafine hydrochloride transdermal patches

Preparation of transdermal patches

Transdermal patches were prepared by the solvent casting method. Accurately weighed PVA was dissolved in hot distilled water under continuous stirring until a clear solution was formed. HPMC E5 was dispersed and allowed to swell to obtain a uniform polymeric solution. Terbinafine hydrochloride was dissolved separately in methanol and added gradually to the polymeric solution. Propylene glycol was incorporated as a plasticizer, followed by addition of clove oil with continuous stirring. The homogeneous solution was degassed, cast into a flat petri dish, dried at room temperature for 24 h and carefully peeled from the surface. Dried films were cut into patches and stored in aluminium foil in a desiccator until evaluation.

Figure 4. Prepared terbinafine hydrochloride transdermal patch and folding endurance evaluation.

Evaluation of transdermal patches

Prepared patches were evaluated for visual appearance, color, transparency, surface texture, flexibility and tackiness. Thickness was measured at different points using a micrometer and average values were recorded. Folding endurance was determined by repeatedly folding the patch at the same position until cracks appeared or the film broke. Drug content uniformity was determined spectrophotometrically after suitable extraction and dilution. Moisture content was determined to assess film stability and suitability during storage.

In vitro drug release studies were performed using diffusion methodology at predetermined time intervals. The release medium samples were withdrawn, suitably diluted and analyzed by UV-visible spectrophotometry. Skin permeation studies were performed to evaluate the effect of clove oil on transdermal transport of terbinafine hydrochloride. The optimized formulation was subjected to one-month stability testing and evaluated for physical appearance, thickness, folding endurance, drug content and drug release.

RESULTS

Preformulation and compatibility studies

Terbinafine hydrochloride was observed as a white to off-white crystalline, odorless, slightly bitter powder. The melting point was found to be 194–196°C. The drug was slightly soluble in water and phosphate buffer pH 7.4, soluble in ethanol and chloroform, and freely soluble in methanol. The calibration data showed a concentration-dependent increase in absorbance from 0.110 at 2 µg/mL to 0.415 at 10 µg/mL, confirming suitability of the UV method for drug estimation.

Figure 5. UV absorption maximum (lambda max) of terbinafine hydrochloride.

FTIR analysis showed characteristic peaks of terbinafine hydrochloride including N–H stretching, aromatic and aliphatic C–H stretching, C≡C stretching, aromatic C=C stretching, C–N stretching and C–O stretching. No major disappearance or significant shift of characteristic peaks was observed in the drug-excipient mixture. DSC analysis showed a pure drug peak temperature of 204.9°C and drug-excipient mixture peak temperature of 203.9°C, indicating acceptable compatibility between the drug and excipients.

Figure 6. FTIR spectra of pure terbinafine hydrochloride and terbinafine hydrochloride with excipients.

Figure 7. DSC thermograms of pure terbinafine hydrochloride and terbinafine hydrochloride with excipients.

Table 3. DSC compatibility data of terbinafine hydrochloride

The DSC thermogram of pure terbinafine hydrochloride showed an onset temperature at 198.6°C, a sharp peak temperature at 204.9°C, and an endset temperature at 215.5°C, indicating the characteristic melting behavior of the crystalline drug. The sharp endothermic peak confirms the purity and crystalline nature of terbinafine hydrochloride. The enthalpy value of the pure drug was found to be 132 mJ, which reflects the energy required for melting of the crystalline structure.

In the drug–excipient mixture, the onset temperature slightly shifted to 188.7°C, while the peak temperature was observed at 203.9°C and the endset temperature at 211.2°C. The slight reduction in onset and endset temperatures may be due to dilution of the drug with excipients or minor physical interaction within the formulation matrix. However, the main melting peak of terbinafine hydrochloride remained nearly unchanged, with only a small shift from 204.9°C to 203.9°C. This indicates that there was no significant chemical interaction or incompatibility between the drug and selected excipients.

The enthalpy decreased slightly from 132 mJ to 126 mJ, which may be attributed to reduced crystallinity or uniform dispersion of drug in the excipient blend. Overall, DSC results confirm good drug–excipient compatibility.

Design of experiment results

The DoE trial batches showed that increasing HPMC E5 concentration generally increased cumulative drug release, while clove oil had a pronounced influence on skin permeation. Drug release ranged from 60% to 91%, and skin permeation ranged from 60% to 78%. The highest response values were observed in F9, which contained the highest levels of both HPMC E5 and clove oil.

Table 4. DoE trial batch results

ANOVA for drug release indicated that the model was significant (F-value 43.25; p = 0.0003). HPMC E5 showed a highly significant effect on drug release (p < 0.0001), whereas clove oil showed a less significant direct effect on drug release (p = 0.4558). For skin permeation, the model was also significant (F-value 39.31; p = 0.0062). Clove oil showed a significant effect on permeation (p = 0.0040), supporting its role as a natural permeation enhancer.

Figure 8. DoE contour and 3D surface plots showing the effect of HPMC E5 and clove oil on drug release.

Figure 9. DoE contour and 3D surface plots showing the effect of HPMC E5 and clove oil on skin permeation.

Physical evaluation of patches

The prepared transdermal patch formulations were evaluated for their physical appearance, surface characteristics, flexibility, thickness, folding endurance, drug content, and moisture content to determine their suitability for transdermal application. All formulations produced transparent to slightly translucent films, indicating proper solubilization and uniform dispersion of drug and excipients within the polymeric matrix. The transparent nature of the films is generally considered desirable in transdermal patch development because it improves patient acceptability and provides an aesthetically pleasing appearance after application on the skin. Slight translucency observed in some formulations may be attributed to variation in polymer concentration, drug loading, or the presence of permeation enhancer within the matrix. However, no formulation showed visible cracks, air bubbles, roughness, or phase separation, suggesting that the solvent casting method was suitable for preparing uniform terbinafine hydrochloride transdermal films.

The surface texture of all formulations was found to be smooth and uniform. Smoothness of the patch surface is an important quality attribute because rough or uneven films may cause discomfort, poor adhesion, and non-uniform drug release during application. A smooth surface also indicates proper interaction between the polymer, plasticizer, and drug molecules. The absence of visible drug crystals on the surface further suggests that terbinafine hydrochloride was uniformly incorporated within the polymeric network. This uniformity is important for maintaining consistent drug release and avoiding dose variation during therapy. Flexibility of the prepared patches improved with optimized polymer and plasticizer composition. Flexibility is an essential characteristic of transdermal patches because the formulation must withstand bending, stretching, and movement after application to the skin. Films with insufficient flexibility may crack or break during handling or application, while overly soft films may become sticky and difficult to remove from the casting surface. The improvement in flexibility observed in optimized formulations can be attributed to the role of plasticizer, which reduces brittleness by increasing the mobility of polymer chains. Plasticizers such as propylene glycol also contribute to film softness and may enhance drug diffusion through the polymer matrix. The optimized balance between film-forming polymer and plasticizer resulted in films with good mechanical strength and handling properties.

Table 5. Physicochemical evaluation of terbinafine hydrochloride transdermal patches

The thickness of the formulated patches ranged from 0.21 mm to 0.35 mm. Thickness uniformity is an important parameter because it directly affects drug content, mechanical strength, folding endurance, and drug release behavior. Very thin films may lack sufficient mechanical integrity, whereas excessively thick films may retard drug release and reduce patient comfort. The observed thickness range indicated that the casting solution was spread uniformly and dried properly. Minor differences in thickness among batches may be due to variation in polymer concentration, viscosity of the casting solution, and total solid content. Formulations containing higher polymer concentration generally tend to produce thicker films due to increased matrix density. The optimized batch F9 showed suitable thickness, indicating proper film formation and uniform distribution of formulation components.

Folding endurance values ranged from 185 to 298, demonstrating good flexibility and mechanical resistance of the prepared films. Folding endurance reflects the ability of a patch to withstand repeated folding at the same point without breaking. This test is particularly important for transdermal patches because they are frequently subjected to mechanical stress during packaging, storage, handling, and application. Higher folding endurance values indicate better elasticity and durability. The formulations with higher folding endurance were considered more suitable because they are less likely to crack or tear during use. The optimized formulation F9 exhibited excellent folding endurance, suggesting that the polymer and plasticizer ratio was appropriate for producing a mechanically stable patch. This result confirms that the film can maintain its integrity during normal handling and skin application.

Drug content of the prepared formulations ranged from 92.14% to 99.12%. Drug content uniformity is a critical quality parameter in transdermal drug delivery systems because each patch must deliver a consistent and accurate dose of drug. The results indicated that terbinafine hydrochloride was uniformly distributed within the polymer matrix. Formulations showing higher drug content suggest better drug entrapment and minimal loss during preparation and drying. Slight variation in drug content may be due to differences in polymer viscosity, distribution of drug in the casting solution, or minor losses during film removal. The optimized batch F9 showed the highest drug content of 99.12%, indicating excellent uniformity and efficient incorporation of terbinafine hydrochloride into the patch. This high drug content supports the suitability of F9 for further evaluation and potential therapeutic use.

Moisture content of the patches ranged from 2.10% to 2.84%, which indicates acceptable moisture retention within the films. Moisture content plays an important role in maintaining patch flexibility, stability, and microbial safety. Very low moisture content may make the patch brittle, while excessive moisture may lead to stickiness, microbial growth, or instability of the drug and polymer matrix. The observed values suggest that the prepared films contained sufficient moisture to maintain flexibility without compromising stability. The low moisture content also indicates that the films were properly dried after casting. Controlled moisture levels are beneficial for maintaining the physical integrity of the patch during storage.

Among all formulations, the optimized batch F9 showed excellent physical appearance, smooth and uniform surface, excellent flexibility, and slight tackiness. Slight tackiness is advantageous for transdermal application because it may improve contact between the patch and skin surface. Good contact is necessary for efficient drug transfer from the patch to the skin. However, excessive tackiness is undesirable because it may cause handling difficulties or discomfort during removal. The slight tackiness observed in F9 indicates an appropriate balance between adhesion and handling properties. Overall, the evaluation results confirmed that formulation F9 possessed desirable physicochemical and mechanical properties. Its uniform appearance, suitable thickness, high folding endurance, excellent drug content, and acceptable moisture content indicate that it is a promising optimized transdermal patch formulation for terbinafine hydrochloride delivery.

In vitro drug release and skin permeation

The in vitro release profile demonstrated controlled release of terbinafine hydrochloride from all patches. Cumulative release increased gradually with time, confirming the matrix-type release behavior of the polymeric films. F9 showed the highest release among the formulations, reaching 91.05% at 8 h. The improved release may be due to the optimized HPMC E5 matrix, which provided an appropriate balance of film integrity and diffusion pathways.

Table 6. In vitro cumulative drug release profile (%)

Figure 10. In vitro cumulative drug release profile of terbinafine hydrochloride transdermal patches.

Skin permeation studies indicated that F9 produced the maximum permeation of 78%, followed by F7 and F8. The higher permeation of F9 may be attributed to the presence of clove oil at the highest level, which likely improved drug partitioning into the skin and disrupted the stratum corneum lipid arrangement. Overall, F9 exhibited the best balance of controlled release and enhanced transdermal permeation.

Table 7. Skin permeation of terbinafine hydrochloride transdermal patches

Stability study

The optimized formulation F9 was evaluated for one month. The formulation remained smooth and transparent without visible physical changes. Thickness showed only a minor change from 0.30 mm to 0.31 mm, folding endurance decreased slightly from 298 to 294, drug content reduced from 99.12% to 98.42%, and drug release at 8 h decreased 91.05% to 90.8%. These results indicate that F9 retained satisfactory physical, mechanical and release characteristics during short-term storage.

Table 8. Stability study of optimized formulation F9

DISCUSSION

The results indicate that HPMC E5 and PVA can form flexible, uniform and mechanically stable transdermal patches of terbinafine hydrochloride. The use of propylene glycol improved flexibility and reduced brittleness, while the inclusion of clove oil improved skin permeation. The drug content values above 92% for all formulations indicate adequate uniformity of drug distribution within the polymeric matrix. The optimized batch F9 showed the highest drug content and good moisture characteristics, suggesting uniform film formation and acceptable stability.

DoE analysis demonstrated that HPMC E5 concentration was a key factor influencing drug release. Higher HPMC E5 levels may promote matrix hydration and diffusion-controlled release by forming a consistent polymer network. Clove oil showed a significant influence on skin permeation, supporting the expected mechanism of natural penetration enhancers. Essential-oil-based enhancers can improve permeation by disturbing lipid packing of the stratum corneum and increasing drug partitioning into skin layers [3,5,9].

The optimized formulation F9, containing 800 mg HPMC E5 and 80 mL clove oil, provided the highest release and permeation values. Although higher polymer concentration can sometimes retard drug diffusion, the present formulation achieved improved release, possibly because of better film hydration, uniform drug distribution and synergistic influence of clove oil. The stability study further showed that the optimized formulation maintained its quality attributes over one month. This suggests that terbinafine hydrochloride transdermal patches with natural permeation enhancers may be useful for sustained antifungal delivery.

CONCLUSION

The study successfully developed terbinafine hydrochloride transdermal patches using the solvent casting method. The selected polymers and excipients produced films with acceptable appearance, thickness, folding endurance, drug content and moisture content. Compatibility studies using FTIR and DSC confirmed that there was no major drug-excipient incompatibility. Among the nine formulations, F9 was selected as the optimized formulation due to its excellent physical characteristics, highest drug content (99.12%), cumulative drug release of 91.05% at 8 h, maximum skin permeation of 78% and satisfactory one-month stability. The findings support the potential of clove oil as a natural permeation enhancer for terbinafine hydrochloride transdermal drug delivery. Further in vivo permeation, skin irritation, antifungal efficacy and long-term stability studies are recommended before clinical application.

ACKNOWLEDGEMENT

The author acknowledges Dr. Vedprakash Patil Pharmacy College, Chh. Sambhajinagar, for providing the academic and laboratory support for the thesis work from which this research article was prepared.

CONFLICT OF INTEREST

The author declares no conflict of interest.

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