Search

Adsorption of gut relevant biomolecules onto particles after oral administration of solid oral dosage forms is expected to form a “gastrointestinal corona”, which could influence solution-mediated solid-state transformations on exposure of drug particles to gastrointestinal fluids. Low-frequency Raman (LFR) spectroscopy was used in this study to investigate in situsolid-state phase transformations under biorelevant temperature and pH conditions along with the presence of biomolecules. Melt-quenched amorphous indomethacin was used as a model solid particulate, and its solid-state behavior was evaluated at 37 °C and pH 1.2–6.8 with or without the presence of typical bile salt/phospholipid mixtures emulating fed-state conditions. Overall, a change in the solid-state transformation pathway from amorphous to crystalline drug was observed, where an intermediate ε-form that initially formed at pH 6.8 was suppressed by the addition of endogenous gastrointestinal biomolecules. These solid-state changes were corroborated using time-resolved synchrotron small- and wide-angle X-ray scattering (SAXS/WAXS). Additionally, the bile salt and phospholipid mixture partly prevented the otherwise strong aggregation between drug particles at more acidic conditions (pH ≤ 4.5) and helped to shift the balance against the intrinsic hydrophobicity of indomethacin as well as the plasticization effect brought about by the physiological temperature (i.e., the stickiness arising from the supercooled liquid state at 37 °C). The overall results highlight the importance of evaluating the impact that endogenous biomolecules may have on the solid-state characteristics of drug molecules in dissolution media, where analytical tools such as LFR spectroscopy can serve as an attractive avenue for accessing time-resolved solid-state information on time-scales that are difficult to achieve with other techniques such as X-ray diffraction.

The noninvasive in situmonitoring of the status of drug retention and implant integrity of subcutaneous implants would allow optimization of therapy and avoid periods of subtherapeutic delivery kinetics. A proof-of principle study was conducted to determine the use of microspatially offset low-frequency Raman spectroscopy (micro-SOLFRS) for nonintrusive in situanalysis of subcutaneous drug delivery systems. Caffeine was used as the model drug, and it was embedded in a circular-shape Soluplus matrix via vacuum compression molding. For the exploratory analysis, prototype implants were positioned underneath skin tissue samples, and various caffeine concentrations (1–50% w/w) and micro-SOLFRS displacement settings (Δz= 0–8 mm) were tested from the pseudo three-dimensional (3D)-imaging perspective. This format allowed the optimization of real-time micro-SOLFRS analysis of implants through skin tissue that was embedded in an agarose hydrogel. Notably, this analytical approach allowed the temporal and spatial erosion of the implant and solid-state transformations of caffeine to be distinguished. The spectrometric results correlated with complementary high-performance liquid chromatography (HPLC) determination of changes in drug concentration, illustrating drug dissipation/diffusion characteristics. The discovered capability of micro-SOLFRS for in situmeasurements of drugs and implants makes it attractive for biomedical diagnostics that, ultimately, could result in development of a new point-of-care technology.