(T0930-11-63) Solid-State NMR and FTIR Reveal Moisture-Triggered Adhesion Loss in Rotigotine Patches

Purpose: Transdermal patches frequently suffer from adhesion issues, potentially compromising treatment efficacy for diverse patient populations. Environmental factors, particularly moisture and heat, significantly impact patch adhesion properties. This study aimed to systematically investigate the effects of temperature and humidity on rotigotine matrix patches using solid-state nuclear magnetic resonance (NMR) and Fourier Transform Inferred- Attenuated Total Reflectance (FTIR-ATR) spectroscopy.

Methods: Rotigotine matrix patches were developed using components similar to those found in commercially available Neupro® patch. Briefly, key components (rotigotine and polyvinyl pyrrolidone K-30 (PVP-K30)) were dissolved in ethanol. Sodium metabisulfite, ascorbyl palmitate, and DL-alpha-tocopherol were then added and mixed into the mixture. Silicone pressure-sensitive adhesive (PSA) 4302 was then added and kept on stirring overnight. Following drying and lamination with a backing membrane, the final patches were obtained for further studies (Figure 1 a&b). The effect of temperature and humidity study was then conducted in the stability chamber (Environ CAB, Lab-Line). Briefly, human dermatomed skin was thawed for 45 min in distilled water to wash the glycerin. Pieces of skin (from the same skin donor) were then cut and mounted on the donor compartment of the Franz diffusion cell apparatus. Phosphate buffer (pH 6.2) with 5% w/v Brij 20 was filled in the receiver compartment. The Franz diffusion cell setup was then kept in the stability chamber and equilibrated for 45 min at 32 ± 2 °C and 75 ± 5% relative humidity (RH). After equilibration, the skin was dried using kimpwipes to get rid of any water droplets/moisture on the skin surface. Rotigotine patches were then placed on the dried skin surface. Cello tape (as a patch protector) was adhered to the top of the patches to avoid any direct contact of the patch with moisture. Patch samples were collected at 0,2,4,6,8,12 and 24 hr for solid-state NMR and FTIR-attenuated total reflectance (ATR) analysis (Figure 1 c). For solid-state NMR analysis, 1H direct polarization and 1H-13C cross-polarization magic-angle spinning (CPMAS) spectra were acquired with 14.1 T NMR spectrometer (Bruker Avance III console) to measure 1H and 13C spectra, respectively, by using an MFL’s 1H-X-Y triple resonance MAS probe. Each spectrum was measured by packing the formulation sample into a 3.2 mm rotor that was spun at 12 kHz for NMR measurement under 90 kHz SPINAL-64 1H decoupling. The 1H (70-100 % ramp) and 13C pulse powers applied simultaneously during a 1 ms CP mixing block were 67 kHz and 50 kHz, respectively. For FTIR analysis, Bruker (Model: Invenio S FTIR spectrophotometer) with platinum ATR device was used. Briefly, samples were directly kept on the crystals to get the spectra after the calibration of the instrument.

Results: Solid-state NMR analysis revealed a time-dependent increase in moisture uptake within the rotigotine patch upon exposure to the 75 ± 5% relative humidity (RH) and 32 ± 2°C conditions. The patch sample at the 24-hour time point exhibited the highest moisture content compared to all other time points. This was evidenced by the progressive increase in signal intensity observed at the ~4.7 ppm region of the spectra, which corresponds to the presence of water molecules (H2O) (Figure 2 a). Additionally, after 24 hour of experiment, rotigotine patches developed air pocket within the patch formulation (Figure 2 b). This observation is corroborated by the findings from FTIR spectroscopy, where a progressive intensification of the broad peak exceeding 3000 cm⁻¹ was observed. This spectral signature is characteristic of water (H₂O) absorption, confirming the time- dependent uptake of moisture within the patch (Figure 3).

Conclusion: Solid-state NMR and FTIR analyses revealed a time-dependent increase in moisture content within rotigotine patches exposed to 75 ± 5% RH and 32 °C. This suggests moisture uptake is a potential cause of patch adhesion failure. Therefore, incorporating non-hygroscopic agents like mannitol and lactose becomes necessary to enhance moisture protection in future patch formulations. To our knowledge, this is the first investigation to employ solid-state NMR and FTIR spectroscopy to assess adhesion failure in transdermal patches, specifically focusing on the molecular-level changes occurring within the patch matrix.

References: 1. Cilurzo, F., C.G. Gennari, and P. Minghetti, Adhesive properties: a critical issue in transdermal patch development.Expert opinion on drug delivery, 2012. 9(1): p. 33-45.
2. Liu, C., et al., A systemic evaluation of drug in acrylic pressure sensitive adhesive patch in vitro and in vivo: the roles of intermolecular interaction and adhesive mobility variation in drug controlled release. Journal of Controlled Release, 2017. 252: p. 83-94.
3. Song, W., et al., Probing the role of chemical enhancers in facilitating drug release from patches: mechanistic insights based on FT-IR spectroscopy, molecular modeling and thermal analysis. Journal of controlled release, 2016. 227: p. 13-22.
4. Luo, Z., et al., Effect of Chemical Penetration Enhancer-Adhesive Interaction on Drug Release from Transdermal Patch: Mechanism Study Based on FT-IR Spectroscopy, 13C NMR Spectroscopy, and Molecular Simulation. AAPS PharmSciTech, 2021. 22(5): p. 1-14.
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Acknowledgements: This work was supported by NSFCREST Center for Complex Materials Design for Multidimensional Additive Processing (CoManD), Grant/Award Number:1735968.


Figure 1: a) Composition of rotigotine adhesive matrix patch formulation; b) Image of rotigotine
matrix adhesive patch after laminating it with a backing membrane; and c) Stability chamber setup
utilized to conduct the effect of temperature and humidity study with Franz diffusion cells maintained
at 75 ± 5% RH and 32 ± 2 °C.


Figure 2: a) Solid-state NMR spectra of rotigotine patch samples collected at 0, 2, 4, 6, 8, 16 and
24-hour time points showing an increase in moisture absorption at the region of ~4.7 ppm with an increase in
time of exposure; b) Rotigotine patch images at 0 and 24 hours of exposure to 32 ± 2 °C and 75 ±
5% RH conditions (n=3).


Figure 3: FTIR spectra of rotigotine patch samples collected at 0, 4, 6, 8, 16 and 24 hour time
points showing increase in moisture absorption at region of >3000 cm⁻¹ with increase in time of
exposure (n=3).