Adhesion is one of the most critical parameters for product quality, efficacy, and safety of transdermal delivery systems (TDS) [1]. Although several in vitro techniques (e.g., peel adhesion, tack, and shear strength) have been routinely used to test adhesive performance, the in vivo human skin testing is still the most reliable method for the evaluation of TDS [[2], [3], [4]]. These tests mainly focus on surface adhesion for industrial applications, rather than on human skin. While adhesiveness affects drug absorption, clinical studies focus mainly on effectiveness and less on adhesiveness [2]. The FDA provides a scoring system based on the percentage adherent area of the patch, which is generally estimated visually [5,6]. Currently guidance on adhesion data analysis and evaluation is lacking. Adhesive performance may change with the wearing period. Sometimes, poor cohesive strength of the adhesive may lead to the formation of a ‘dark-ring’ on the skin, which is a mix of adhesive, textile fibers, and dust. The formation of the dark ring reduces the contact between the skin and the adhesive film, leading to poor absorption from that area, especially for the patches worn for longer periods. Reports suggest that two nitroglycerin patches with good adherence of 94.8 % saved ∼ 14.5 % in costs compared to a patch with only 78.9 % adherence [7].

Pressure-sensitive adhesives (PSA) adhere to substrates through interatomic and intermolecular forces at the adhesive-skin interface. A PSA spreads on the adherend only if its surface energy is lower than that of the adherend. To ensure adhesion to skin, the PSA's surface energy must be below the skin's lowest critical surface tension of 28 dynes/cm [8,9]. Adhesion involves complex interactions between the viscoelastic properties of the PSA and skin physiology, combining bonding and debonding processes through viscous flow and elastic distortion. Factors such as the concentration of the PSA, drugs, excipients, flexible backing, and release liner impact adhesive performance [[10], [11], [12]].

Adhesion testing using tack and peel methods do not provide adequate models for adhesion on human skin because there are major differences between artificial testing surfaces and human stratum corneum surface [13]. It should be noted, however, that slight changes in interaction between the polymers and other ingredients (API, plasticizer, tackifying resins etc.) result in marked changes of adhesion to steel that are not likely to be seen on living human skin. Results of the liner release test may vary with storage because of migration of small molecules, crystallization and polymer chain rearrangement. These 3D changes due to storage/aging of TDS may affect the adhesive performance, crystalline/amorphous status of the drug and its solubility in the skin moisture [[13], [14], [15], [16]]. Currently there is a lack of evidence for a relationship between in vitro adhesion tests and in vivo adhesion performance. There is no official test recommended for measuring adhesive strength in TDS monographs of any of the pharmacopeias. Hence, there is a need to develop new in vitro methods for testing adhesive performance of TDS, and to improve the correlation between in vitro data and in vivo performance.

Interferometry (IFM) is a technique widely used in the field of mechanical engineering to study heat-transfer, fluid flow, combustion etc. For the first time, this microscopic technique is adapted to study the surface properties of a transdermal patch. IFM uses the principle of light wave superposition to measure surface roughness. The process involves splitting light into two beams that travel different paths and then combining them to create interference. When the light waves interact, they produce an interference pattern that depends on the phase difference between them [17]. By comparing the interference pattern of a standard wave and a test wave, the shape and features of the surface that is being tested can be determined.

Thermal IR-Imaging works on a simple principle that all objects emit infrared energy as a function of their temperature. This form of energy is invisible to the human eye, can be detected and translated into a visual image by a thermal imaging system. The hotter an object is, the more thermal energy it emits, which is called a “heat signature”. The sensors in the IR camera convert the energy readings into an electrical signal, which is then processed to produce an image. The uniformity in the heat distribution pattern across the area of the skin where the patch is adhered, is studied to investigate the performance of a transdermal patch.

The overall objective of this study is to develop new in vitro test methods that can be predictive of in vivo TDS adhesion performance and potentially distinguish clinically meaningful differences in the TDS products. A battery of mechanical analyses, imaging, and spectroscopy techniques for testing adhesive performance, along with the gold standard in vitro release (IVRT) and In Vitro Permeation (IVPT) were conducted and analyzed. In this proof-of-concept study, we used 14 mg nicotine patches from two different brands: GSK (reference) and CVS (test) as model transdermal drug delivery systems. It is expected that the new in vitro adhesion testing methods will aid the industry in evaluating potential failure modes related to TDS adhesion and aid in the development of generic TDS. The above comprehensive series of tests offers valuable insights to industry and academia in developing generic transdermal patches by differentiating products based on their adhesiveness and predicting adhesion problems in the early development stages of a transdermal patch.