The primary role of stratum corneum (SC) is protecting people'sur body from external potentially harmful substances. However, such a natural protective barrier restricts the systemic entry of most therapeutic agents except those with fair lipophilicity (log P > 1.5) and molecular weight < 500 Da. The stringency of the SC is originated from the tightly bound, rigid keratinocytes cell. These ‘dead’ cells consist of keratin filaments and various cross-linked proteins ^[1][2][3][20,21,22]. Due to their strong barrier nature, keratinocytes are popularly known as the “brick-mortar” layer, where ‘mortar’ is the surrounding intracellular multilamellar lipids. Around 10–20 of the corneocytes layer ultimately form the human upper strata or SC layer, which has a variable thickness of approximately 15 microns ^[4][23]. The skin routinely permits water to transport in and out of the body. Additionally, it shows some biasness to most of the small lipophilic molecules for transport in and out of the body. Challenges occur mainly for the permeation of large size molecules, proteins, peptides, or different biologics. That is why successful commercial transdermal delivery is still confined within a short range of drug molecules.

There are detailed studies and in-depth reviews on the transport mechanism of drugs by transdermal delivery. The studies revealed various drug transport pathways across the skin, which are transcellular (through the stratum corneum), intercellular (through the tight junctions of the cells), follicular or trans appendageal (sebum glands and sweat ducts) pathways ^[5][24]. In another type, by stripping or microneedling, small portions of the skin are removed to open up micro-sized pores for better drug penetration. Transdermal drug delivery can utilize the hair follicle and sebum glands as soft spots for drug penetration. Still, the appendages contribute to a minimum percentage (approximately 0.1%) of the total skin surface area ^[6][25]. Therefore, the stratum corneum is considered the targeted area of transdermal drug delivery. 

Drugs that are not well absorbed or undergoing first-pass metabolism via oral delivery are the primary target of the transdermal systems. Zero-order drug release often remains an objective of developing a transdermal system ^[7][26]. Controlled zero-order release kinetics provides a constant rate of drug release for a longer duration. In in vivo study, zero order release shows stable plasma concentration over a prolonged period. Some of the marketed transdermal products and their desirable properties are outlined in Table 1.

The dose is an essential concern for transdermal delivery. The majority of the transdermal products are meant for low-dose drugs (less than 20 mg) with one or two exceptions like methylphenidate patch (maximum dose 30 mg) ^[10][29]. Less potent and high-dose drugs could face problems in loading into the patch. The molecular weight of the drug is another primary concern. As shown in Table 1, marketed transdermal patches contain drugs with a molecular weight of less than 500 Da. Specific exceptions for dermatotherapy are fusidic acid (molecular weight 517 Da) and ketoconazole (531 Da) formulations. High molecular weight drugs face problems in skin permeation.

Optimizing a formulation for therapeutic effects generally implies that drug flux into the skin is maximized and obeys Fick’s first law. This requirement means that the product of drug concentration in the vehicle and drug partition coefficient between stratum corneum (SC) and vehicle be as large as possible ^[11][30]. For molecules to pass through the SC, they need to exhibit specific physicochemical properties that influence the rate of a drug’s permeation through the skin. Drugs with biphasic (water and lipid) solubility better permeate than those with high monophasic (water or lipid) solubility ^[12][31]. Highly hydrophilic drugs cannot penetrate the skin, while too lipophilic drugs have the propensity to remain in the layers of the SC. While the SC is lipophilic and favors the permeation of lipophilic drugs, the aqueous layers beneath the SC dictate that drugs should have some hydrophilic properties to pass through them. Minor structural changes of a drug, such as salt formation or esterification, can enhance aqueous or lipid solubility ^[13][14][3,32]. The distribution coefficient, log D value of a compound, is usually a good indication of whether a molecule would be a favorable candidate for transdermal permeation. Log D is the ratio of the sum of concentrations of a neutral and ionized compound in each of the two phases (octanol and an aqueous buffer) ^[15][33]. Log P value gives the same partition value for the neutral form of the substance.

The lipophilic nature of the SC had led to the belief that ionized drugs would be poor candidates for transdermal delivery. The transcellular route is regarded as having intermediate properties, whereas the intracellular route is mainly regarded for allowing the delivery of lipophilic molecules. Ionized drugs cross the skin through the shunt route, but the amount of molecules that pass through that route is significantly lesser than unionized molecules that take the intracellular pathway. Drugs with very low or high partition coefficients fail to reach the systemic circulation. Molecules with log P values in the range of 1–3 are considered for good permeation enhancement ^[5][24].

An increase in the number of hydrogen bonding groups of the drug may inhibit its permeation across the layers of the SC. An increase in the magnitude of hydrogen bonding causes a considerable decrease in transdermal flux ^[16][34]. On another note, an indirect relationship exists between the melting point and the solubility of a drug. Hadgraft et al. ^[17][35] developed a model that accurately estimates the solubility constraint in the SC by using the melting point. Lowering the melting point of a drug increases solubility in the SC and ultimately permeates the skin. Molecules with high melting points, due to their low solubility both in water and fat, are generally problematic in transdermal drug delivery (TDD) ^[18][19][36,37]. Apart from the criteria mentioned above, two other points need to consider; cutaneous metabolism of a drug that can significantly reduce its pharmacological effect and skin irritation that may reduce the patient compliance. Overall the drug properties that are favorable for transdermal delivery are summarized below;