**4. Discussion**

Preformulation studies play a very crucial role in successfully creating a formulation. In order to determine drug excipient compatibility, ATR–FTIR analysis was carried out. ATR–FTIR is a nondestructive and quick technique used for obtaining the IR spectrum of a pure drug (methotrexate), as well as various patch formulations (F1 to F9). It is used for the identification and characterization of interactions between drugs and synthetic, semisynthetic, and native macromolecules. The ATR–FTIR spectra revealed several peaks in the final formulation, which confirmed the chemical structure retained within the drug with efficient loading into the formulation. The current study showed no chemical interaction between methotrexate and the physical mixtures with polymers (EC, HPMC) used [33]. The solvent evaporation technique was employed for the formulation of methotrexateloaded transdermal-type patches having HPMC and EC at different concentrations [34]. The surface pH of the formulated patches was determined to investigate the possibilities of irritation during in vivo studies. This test is of utmost importance during transdermal drug delivery because alkaline or acidic pH causes irritation to the skin [35]. Uniform weight measurements and thicknesses were observed, which were evident due to low standard deviation values [26]. The folding endurance value is important during the formulation of transdermal patches. This test indicates that formulated patches can integrate with skin folding and do not break during use [24]. The drug release pattern of transdermal matrix-type patches can be affected by moisture uptake and moisture loss. In this study, the values of moisture content and moisture uptake were low. This indicates that the patches remain stable during long-term storage, and brittleness is reduced. Formulated patches are protected from microbial contaminations, having low moisture uptake and reduced bulkiness [8]. Tensile strength and elongation are related to the effectiveness of the plasticizer used in formulations [36]. It is necessary for the drug distribution to be homogenous and uniform because it helps in the evaluation of sustained drug deliveries from formulated patches. Uniform drug content data were observed from the formulated patches, which were revealed by low standard deviation values. Plasticizer use in the formulation of transdermal patches is necessary to improve the patch-forming properties

and physical appearance of the patches. This prevents the patches from cracking and breaking and increases patch flexibility for obtaining the desired mechanical properties [37]. The successfully formulated patch formulations were screened for their irritation potential, as withdrawal of the patch from the site of application resulted in irritation in the form of erythema and edema, so it is necessary for patch formulations to completely lack irritation potential in order to obtain patient acceptability and a therapeutic outcome [3]. The in vitro drug release profile of the methotrexate-loaded patches showed an initial burst release, followed by a gradually approaching plateau, giving an indication of the controlled-release behavior of the matrix formulations. This burst release might be due to the release of superficially adhered drug contents. Drug release could be prolonged by adjusting adequate ratios of EC and HPMC [38]. There was a decrease in the release rate with an increasing concentration of HPMC in the formulations. This is because increased proportions of HPMC in the matrix resulted in a proportionate decrease in the amount of water uptake, leading to lesser drug release. EC, owing to its hydrophobic nature, produced a retarded drug release from the matrix [16]. The optimized F5 formulation showed a controlled-release pattern. This is advantageous in the case of chronic conditions such as psoriasis because rapid or burst release is not useful owing to its toxicity potential due to greater drug release and faster absorption of the drug in inflamed psoriatic lesions. The Korsmeyer–Peppas model was used for kinetic drug profiling. Data were fitted into this model in order to investigate the Fickian or non-Fickian diffusion pattern, followed by formulated patches. The value of "n" determines whether the drug release mechanism that weathers the release pattern is Fickian or non-Fickian diffusion. If the value of "n" is equal to 0.5, the diffusion is said to be Fickian. If the value of "n" ranges between 0.5 and 1, the diffusion is said to be anomalous diffusion. When the value of "n" is equal to 1, the diffusion is said to be Case II transport behavior [39]. The in vitro skin permeation profile is considered a significant tool to exclude the risks of unfortunate drug effects. In vitro skin permeation experiments describe the rate and mechanism of the percutaneous absorption of drugs. Studies have shown that diffusion rate is affected due to the physicochemical characteristics of the formulations. These include hydrogen bonding, drug loading capacity, surface charge and mode of application [16]. The skin permeation experiment concluded that patch formulations play a significant role in controlling methotrexate release, as well as drug targeting to the skin. Studies have shown that diffusion rate is affected due to the physicochemical characteristics of the formulation. During skin retention studies, greater retention was observed. This might be due to the strong interaction of the drug with keratinocytes. It is also expected that more drug is retained in the dermis compared to the epidermis, as revealed by skin anatomy studies, which show the dermis layer is thicker than that of the epidermis. Regardless, the accumulation of more amounts of drug in the deeper layer of skin is advantageous, as these layers are mainly affected by psoriasis [40]. Stability studies performed for the formulated patches were carried out for 180 days. After specific intervals of 30 days, the formulated patches showed optimum stability with no obvious physicochemical changes [41].
