Impact\nof Polymers on the Kinetics of the Solid-State\nPhase Transition of Piracetam Polymorphs

Metastable polymorphs of active pharmaceutical ingredients\ncan\noccasionally be used to enhance bioavailability or make processing\nmore convenient. However, the thermodynamic instability of metastable\npolymorphs poses a severe threat to the quality and performance of\nthe drug products. In this study, we used hot-stage microscopy and\npowder X-ray diffraction to quantitatively analyze the kinetics of\nthe solid–solid phase transition of piracetam (PCM) polymorphs\nin the absence and presence of several polymeric excipients. The Forms\nI and II of PCM are enantiotropically related polymorphs, and the\ntransition point is 75 °C. We found that 1 wt % polymer can strongly\naffect the transformation rate of Form II to Form I of PCM above 75\n°C. PVP K30 has the highest <i>T</i><sub>g</sub> and\nthe strongest inhibitory effect on the transition, whereas PEG has\nthe lowest <i>T</i><sub>g</sub> and the weakest effect on\nthe transition. Below 75 °C, the addition of 1 wt % PEG can decrease\nthe transformation rate from Form I to Form II of PCM by a few orders\nof magnitude, whereas no phase transition occurs in the presence of\nthe other investigated polymers. The inhibitory effects of the same\nconcentration of polymers on the kinetics of the solid–solid\nphase transition of piracetam polymorphs are considerably greater\nthan those on the crystallization of PCM from the amorphous phase,\nespecially at low temperatures. We propose that the low segmental\nmobility of polymers enriched between the crystalline phases can considerably\ninhibit the nucleation and growth of the stable form at the interface\nduring the phase transition. Our findings deepen the current understanding\nof the mechanisms underlying the solid-state phase transition of polymorphic\ndrugs in the presence of polymeric excipients, providing a promising\nformulation approach for stabilizing the metastable pharmaceutical\npolymorphs.