The assessment of polymorphism is a problematical issue for regulatory agencies, because variations among crystalline forms of active pharmaceutical ingredient (API) can lead to changes in the efficacy and safety of formulated product. Such conversions are very hard to be detected, thus, the development of techniques for the identification, characterization and quantification of polymorphs results essential in all stages of the manufacturing process. The presence of excipients in formulated products may change the crystal stability of an API, by catalyzing a polymorphic transformation or stabilizing the less stable form. As paradox, all suitable analytical techniques (spectroscopies, thermal analysis, NMR and DRX, and others) for polymorphic analysis are affected by excipients. A deep understanding of the polymorphism-excipient relationship is in full accordance with Quality by Design (QbD) paradigm, the systematic approach focused in quality building into a product based in the full understanding of the products and process. In this work, a novel approach based on thermal stress, MIR monitoring, multivariate curve resolution with alternating least squares (MCR-ALS) and kinetic analysis was developed and applied to monitor polymorphism behavior of model API in formulated products. Commercial tablets, physical mixtures and commercial API, were processed and analyzed under the proposed approach. Commercial tablets of MFA revealed a fast conversion to Form II, contrasting to the behavior of the pure API. Physical mixtures showed similar behavior to commercial tablets, thus reduction in transformation times was related to MFA-excipients physical interaction, even at surface level. Calorimetric studies support the conclusion obtained. The developed approach could be extended to others APIs and other stress sources (humidity, solvents, mechanical forces and its combinations), being a valuable tool for QbD environment.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.