Solution-Mediated Phase Transformation on Crystal Facets of Carbamazepine–Saccharin Cocrystals

Abstract

The purpose of the present study was to investigate the effect of crystal facets on solution-mediated phase transformation (SMPT) at cocrystal surfaces during dissolution in aqueous media. Previously, we reported that SMPT occurred rapidly at the particle surfaces of various carbamazepine cocrystals in aqueous media (Mol. Pharmaceutics 2020, 17, 10, 3825–3836). However, SMPT has not been studied focusing on the differences between each facet of a single crystal. In this study, a carbamazepine–saccharin cocrystal (CBZ-SAC) was used as a model cocrystal. We have succeeded in obtaining millimeter-sized CBZ-SAC crystals. The crystal facets were identified by X-ray diffraction (Miller indexing). The surface roughness of each crystal facet was evaluated with a 3D microscope. Each crystal facet was observed by scanning electron microscopy before and after soaking in a phosphate buffer (pH 6.5, 30 s). Real-time polarized light microscopy was used to directly observe rapid SMPT in the buffer. Precipitated crystals on the facets were identified by microscopic Raman spectroscopy. After contact with the buffer, carbamazepine dihydrate (CBZ DH) (needlelike crystal) rapidly (<10 s) crystallized on the whole surface of the (010), (101), and (111) facets but not on the (001), (100), and (110) facets. On the (001) facet, CBZ DH crystals precipitated only at the scratches and cracks but not on the smooth surface. On the (100) facet, CBZ DH crystals were observed near the edge side but not in the center of the facet. These results suggest that each facet can have different properties as a substrate for heterogeneous nucleation. Possible reasons for the difference among crystal facets were discussed, such as the degree of supersaturation, hydrophobicity, liquid phase epitaxy, and surface roughness. In conclusion, the rate and extent of SMPT from a cocrystal to its free form were found to differ significantly among each crystal facet of a single cocrystal for the first time in this study. Controlling the habit of crystals is important in the production of pharmaceutical cocrystals.

Surface-Induced Thermal Decomposition of Energetic Cocrystal CL-20/MTNP Based on In Situ Morphology and Crystal Structure Characterizations

“…We believe that all the results will be valuable for the comprehensive understanding of the thermal stability and engineering applications of ECCs. Since cocrystallization has been applied in many areas, this mechanism will be also valuable for the stability estimation of other organic cocrystals, e.g., the stability of pharmaceutical cocrystals in aqueous solution. − …”

An In Vitro Model for Cocrystal Dissolution with Simultaneous Surface and Bulk Precipitation

“…Surface precipitation is undesirable as it can severely restrict the cocrystal system from reaching the desired supersaturation target . Omori and co-workers studied this phenomenon extensively ,,− and showed that (1) the cocrystal may not generate any bulk supersaturation when the surface precipitation is excessive, (2) the surface precipitation rate is a strong function of the coformer type, (3) similar to bulk precipitation, the surface precipitation rate is also affected by the presence of dissolved polymers in the medium, and (4) different facets of a cocrystal may show different surface precipitation rates. These findings stress the importance of systematically selecting coformers, polymers, and surfactants to control the DSP behavior of cocrystal systems to maximize drug absorption through sustained levels of supersaturation.…”