The Influence of Gastrointestinal Biomolecules on Solid-State Transformations in Pharmaceutical Particulates

Adsorptionof gut relevant biomolecules onto particlesafter oraladministration of solid oral dosage forms is expected to form a "gastrointestinalcorona", which could influence solution-mediated solid-statetransformations on exposure of drug particles to gastrointestinalfluids. Low-frequency Raman (LFR) spectroscopy was used in this studyto investigate in situ solid-state phase transformationsunder biorelevant temperature and pH conditions along with the presenceof biomolecules. Melt-quenched amorphous indomethacin was used asa model solid particulate, and its solid-state behavior was evaluatedat 37 & DEG;C and pH 1.2-6.8 with or without the presence oftypical bile salt/phospholipid mixtures emulating fed-state conditions.Overall, a change in the solid-state transformation pathway from amorphousto crystalline drug was observed, where an intermediate & epsilon;-formthat initially formed at pH 6.8 was suppressed by the addition ofendogenous gastrointestinal biomolecules. These solid-state changeswere corroborated using time-resolved synchrotron small- and wide-angleX-ray scattering (SAXS/WAXS). Additionally, the bile salt and phospholipidmixture partly prevented the otherwise strong aggregation betweendrug particles at more acidic conditions (pH & LE; 4.5) and helpedto shift the balance against the intrinsic hydrophobicity of indomethacinas well as the plasticization effect brought about by the physiologicaltemperature (i.e., the stickiness arising from the supercooled liquidstate at 37 & DEG;C). The overall results highlight the importanceof evaluating the impact that endogenous biomolecules may have onthe solid-state characteristics of drug molecules in dissolution media,where analytical tools such as LFR spectroscopy can serve as an attractiveavenue for accessing time-resolved solid-state information on time-scalesthat are difficult to achieve with other techniques such as X-raydiffraction.