(M0930-02-14) Development of Powdered SERS Tags for Direct Compression: Toward On-Dose Authentication for Anti-Counterfeiting and Medication Management

Purpose: On-dose authentication, which enables direct tagging of pharmaceutical tablets for anticounterfeiting, has attracted increasing attention. We are developing a Stealth Nanobeacon (NB), which are a cost-effective, ink-type surface-enhanced Raman scattering (SERS) tag composed of gold nanoparticle (AuNP) aggregates with adsorbed reporter molecules, enabling authentication using a portable Raman spectrometer¹⁾. In this study, we aimed to prepare powdered NB by spray drying. Unlike conventional SERS tags that depend on substrates or inks, our original approach enables direct incorporation of powdered SERS-active NB into tablets by physical mixing with excipients and compression. This study evaluates the SERS performance of the resulting tablets and their practical applicability for on-dose authentication.

Methods: Adenine hydrochloride was added as a reporter molecule to an aqueous dispersion of gold nanoparticles (AuNPs), followed by the addition of sodium chloride to induce aggregation. The aggregation was halted when localized surface plasmon resonance appeared in the near-infrared region of the absorption spectrum, yielding a liquid-phase Stealth Nanobeacon (NB) composed of chain-like AuNP aggregates. The NB was mixed with 5% HPMC TC-5R aqueous solution at predetermined concentrations (3.14, 6.28, and 12.5 v/v%) and spray-dried using an inlet temperature of 120 °C and a spray liquid rate of 4.5 mL/min. The resulting powders were designated as SD-NB3.14-D0, SD-NB6.28-D0, and SD-NB12.5-D0, respectively. Because the presence of NaCl in NB was considered a potential factor affecting tablet properties, the solution was centrifuged at 3000 rpm for 30 seconds, and the supernatant was replaced with purified water to remove NaCl from NB.This desalting process was repeated one to three times prior to spray drying, resulting in the preparation of SD-NB3.14-D2, and D3, respectively. The NB powders were then physically mixed with granulated lactose to achieve final NB powders contents of 1, 5, and 10 w/w%, along with 0.5 w/w% magnesium stearate. The mixtures were directly compressed into tablets under a compression force of 9.5–10.5 kN. Tablet hardness was evaluated, and the surface SERS intensity distribution of the tablets was analyzed using a Raman microscope.

Results: At all NB concentrations tested, a characteristic SERS peak around 735 cm⁻¹, attributed to adenine in the NB, was clearly detected from the powders. These results indicate that NB can be successfully powdered by spray-drying at an inlet temperature of 120 °C retain its SERS activity. This SERS activity preservation effect could be attributed to the stabilizing effect of HPMC, which prevented disintegration or excessive aggregation of the AuNP chains during the drying process, thereby maintaining plasmon resonance. Furthermore, the average SERS peak intensity of tablets containing powdered NB increased proportionally with increasing NB concentration (R² = 0.999999). However, tablet hardness decreased from 109.5 ± 13.7 N in NB-free tablets to 66.5 ± 11.9 N in tablets containing 3.14% NB. This is probably due to the crystallization of salts contained in the NB suspension used for spray drying, which reduced the plastic deformability of the powder and weakened tablet integrity. In contrast, tablets prepared using SD-NB3.14-D3—obtained via three rounds of centrifugation for desalting—showed no significant reduction in hardness (103 ± 13.8 N), and the SERS signal remained comparable. These findings demonstrate that the desalting process can effectively minimize the impact of NB incorporation on tablet properties while maintaining analytical performance. In addition, the distribution of the 735 cm⁻¹ SERS peak intensity across tablet surfaces suggested the potential for individual tablet identification, highlighting a promising application for medication management.

Conclusion: This study demonstrated the successful powdering of SERS tags (NB) and their incorporation into tablets via direct compression while retaining sufficient SERS activity and tablet hardness for authentication purposes. These results indicate the feasibility of on-dose authentication using powdered SERS tags. Future work will explore the powdering of NB with various excipients and evaluate their SERS performance, potentially enabling applications in other powder-based processes such as printing or dry coating, beyond direct compression.

References: 1) Takao Fukuoka, Toshiya Yasunaga, Kyoko Namura, Motofumi Suzuki, Akinobu Yamaguchi, Plasmonic Nanotags for On-Dose Authentication of Medical tablet, Advanced Materials interfaces, 2300157 (2023)

Acknowledgements: This study was partly supported by the Innovative Science and Technology Initiative for Security Grant Number JPJ004596, ATLA, Japan.