Templated Reactive Crystallization of Active Pharmaceutical Ingredient in Hydrogel Microparticles Enabling Robust Drug Product Processing

Commercialization of most promising active pharmaceutical ingredients (APIs) is impeded either by poor bioavailability or challenging physical properties leading to costly manufacture. Bioavailability of ionizable hydrophobic APIs can be enhanced by its conversion to salt form. While salt form of the API presents higher solution concentration than the non-ionized form, poor physical properties resulting from particle anisotropy or non-ideal morphology (needles) and particle size distribution not meeting dissolution rate targets can still inhibit its commercial translation. In this regard, API physical properties can be improved through addition of non-active components (excipients or carriers) during API manufacture. In this work, a facile method to perform reactive crystallization of an API salt in presence of the microporous environment of a hydrogel microparticle is presented. Specifically, the reaction between acidic antiretroviral API, raltegravir and base potassium hydroxide is performed in the presence of polyethylene glycol diacrylamide hydrogel microparticles. In this bottom-up approach, the spherical template hydrogel microparticles for the reaction lead to monodisperse composites loaded with inherently micronized raltegravir-potassium crystals, thus improving API physical properties without hampering bioavailability. Overall, this technique provides a novel approach to reactive crystallization while maintaining the API polymorph and crystallinity. & COPY; 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.

Automated summary

The commercialization of promising active pharmaceutical ingredients (APIs) is hindered by poor bioavailability and challenging physical properties. This study presents a method to improve API physical properties by performing reactive crystallization of an API salt in the presence of a hydrogel microparticle. The use of spherical template hydrogel microparticles leads to composites loaded with micronized crystals, enhancing API physical properties without affecting bioavailability.