Trace polymer coated clarithromycin spherulites: Formation mechanism, improvement in pharmaceutical properties and development of high-drug-loading direct compression tablets

Abstract

Clarithromycin (CLA) is a high dose antibiotic drug exhibiting poor flowability and tabletability, making the tablet development challenging. This study aims to develop spherulitic CLA by introducing trace amount of polymer in crystallization solution. Its formation mechanism, physicochemical properties and potential for the direct compression (DC) tablets development were also investigated. Morphological analyses and the in situ observation on crystallization process revealed that the CLA spherulites are formed by fractal branching growth from both sides of the threadlike precursor fibers. 1H NMR analysis and nucleation time monitoring indicated that the existence of hydroxypropyl cellulose in solution slowed down the crystal nucleation and growth rate by forming hydrogen bonding interactions with CLA molecules, making the system maintain high supersaturation, providing high driving forces for CLA spherulitic growth. In comparison to commercial CLA, the CLA spherulites exhibit profoundly improved flowability, tabletability and dissolution behaviors. XPS, contact angle and Raman mapping analysis confirmed the presence of a thin HPC layer on the surfaces and interior of CLA spherulitic particles, resulting in increasing powder plasticity, interparticulate bonding strength and powder wettability, thus better tabletability and dissolution performances. The improved flowability and tabletability of CLA spherulites also enabled the successful development of DC tablet formulation with a high CLA loading (82.8 wt%) and similar dissolution profiles to reference listed drug. This study provides a novel solid form of CLA with superior manufacturability for further development.