Triboluminescence from Pharmaceutical Formulations.

Triboluminescence (TL) is shown to enable selective detection of trace crystallinity within nominally amorphous solid dispersions (ASDs). ASDs are increasingly used for the preparation of pharmaceutical formulations, the physical stability of which can be negatively impacted by trace crystallinity introduced during manufacturing or storage. In the present study, TL measurements of a model ASD consisting of griseofulvin in polyethylene glycol produced limits of detection of 140 ppm. Separate studies of the particle size dependence of sucrose crystals and the dependence on polymorphism in clopidogrel bisulfate particles are both consistent with a mechanism for TL closely linked to the piezoelectric response of the crystalline fraction. Whereas disordered polymeric materials cannot support piezoelectric activity, molecular crystals produced from homochiral molecules adopt crystal structures that are overwhelmingly symmetry-allowed for piezoelectricity. Consequently, TL may provide a broadly applicable and simple experimental route for sensitive detection of trace crystallinity within nominally amorphous materials.

Second Harmonic Generation Guided Raman Spectroscopy for Sensitive Detection of Polymorph Transitions.

Second harmonic generation (SHG) was integrated with Raman spectroscopy for the analysis of pharmaceutical materials. Particulate formulations of clopidogrel bisulfate were prepared in two crystal forms (Form I and Form II). Image analysis approaches enable automated identification of particles by bright field imaging, followed by classification by SHG. Quantitative SHG microscopy enabled discrimination of crystal form on a per particle basis with 99.95% confidence in a total measurement time of ∼10 ms per particle. Complementary measurements by Raman and synchrotron XRD are in excellent agreement with the classifications made by SHG, with measurement times of ∼1 min and several seconds per particle, respectively. Coupling these capabilities with at-line monitoring may enable real-time feedback for reaction monitoring during pharmaceutical production to favor the more bioavailable but metastable Form I with limits of detection in the ppm regime.

Conformational polymorphism of tolbutamide: A structural, spectroscopic, and thermodynamic characterization of Burger's forms I-IV.

Crystal polymorphism of the anti-diabetic drug Tolbutamide (TB) has been studied using various analytical techniques. TB crystallizes in four polymorphic forms (Forms I-IV), which differ in their mode of packing and in molecular conformation but with similar hydrogen bonding synthon (urea tape motif). All the structures were solved from single crystal X-ray data, except for Form IV, which was solved using conventional powder X-ray diffraction (PXRD) data. The conformational differences in the TB molecule arise primarily from torsional variations in the alkyl tail which result in two types of conformers (U and chair). The packing differences are mainly due to the orientation of adjacent molecules in the hydrogen bonding networks. Based on the DSC data, thermodynamic stability relationships of polymorphic pairs were evaluated and graphically visualized in a schematic energy-temperature diagram. Form II is found to be the thermodynamically stable polymorph from absolute zero to approximately 353 K and beyond which Form I(H) is the stable polymorph. The anisotropic lattice contraction of TB polymorphs which resulted in severe variations in PXRD patterns at ambient and low temperature was highlighted. The present work also highlights and resolves several discrepancies in the published data on the structural and thermodynamic features of TB polymorphs.