Complex investigation of the effect mechanism of polyvinylpyrrolidone in the additive-assisted crystallization of famotidine.

Utilizing the positive impact of additives, including pharmaceutical excipients, to achieve favorable crystal morphology and polymorphism is a widely researched area. Despite the obvious benefits of additive-assisted crystallization, the quantification of process parameter influences on the effect mechanism of additives is usually discussed only from a nucleation inhibition point of view or focusing on technological feasibility. Accordingly, the relevant literature can be divided into technological and mechanism studies, but it lacks a complex combined approach. However, to develop robust crystallization procedures, the systematic analysis of process conditions is essential. Thus, understanding the molecular-scale effect mechanism is also crucial to designing these complex processes. Therefore, in this work, the effect of a pharmaceutical binder, poly(vinyl pyrrolidone) (PVP), and several process parameters were investigated on the nucleation of famotidine (FMT), an antihistamine, both experimentally and theoretically. To systematically investigate the effect of PVP concentration, temperature, and supersaturation, we applied the Design of Experiment (DoE) methodology combined with a camera-aided analytical set-up. Based on the experimental data, the nucleation rate of FMT was studied according to the Classical Nucleation Theory (CNT). Finally, molecular simulations were conducted, and a possible effect mechanism was suggested for the PVP-effected nucleation of FMT. This way, the complex DoE-based process parameter investigation and molecular scale interpretation of these effects is a novel approach of the subject. The experimental results revealed that the nucleation inhibiting effect of PVP is dependent on the set temperature, while increasing FMT concentration generally counterforces it. Based on the CNT calculations, PVP decreased the nucleation rate of FMT by orders of magnitude. Additionally, molecular modelling suggests the effect mechanism of PVP is manifested through H-bonding and steric hindrance.