(189aa) Understanding Polymorphic Phase Transformations of Acetaminophen in Polymer-Based Formulation Processes

In recent years, advanced polymer-based formulation processes (e.g. hot melt extrusion, HME) have emerge as enabling technologies for continuous solid dosage formulations of active pharmaceutical ingredients (APIs). However, aside from thermal stability of the individual components (polymer + API), polymorphic stability of the API is thought to be a requirement when HME is employed to produce crystalline solid dispersions (CSDs). Polymorphism enables molecules to exhibit multiple crystalline phases with inherently different physical properties and it is known to occur in up to 80% of APIs. Acetaminophen (ACM) is a widely used analgesic that, to date, exhibit five polymorphic forms from which only two are stable at ambient conditions. Form I (ACM I) is the most stable and commercially available form, however, presents low compressibility, which renders the tableting process cumbersome. The metastable form, ACM II, possess higher compressibility and solubility, but it is not readily accessible without using additives in the crystallization process prior to the formulation. The present study shows how ACM I can be transformed into ACM II during the formulation process without additives to obtain CSDs. For the proof of principle study, the CSDs were obtained by temperature-simulated hot melt extrusion (TS-HME) experiments using a differential scanning calorimeter (DSC). The physical mixtures of ACM and polyethylene glycol 10,000 and the solid dispersions thereof were characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, DSC, thermogravimetric analysis, and hot stage microscopy. The results demonstrate that employing this method can provide access to CSDs of ACM II with high polymorphic purity. The polymorphic phase transformation process from ACM form I into form II can be controlled by precisely defined heating and cooling profiles. Ultimately, this investigation helps to gain fundamental understanding of the processing needs of CSDs with the desired polymorphic form while contributing to process intensification efforts.