Effect of critical material attributes and process parameters on polymorph selection in crystalline solid dispersions
Hernández Espinell, José R.
MetadataShow full item record
The inadvertent occurrence of polymorphic phase transformations during the formulation of crystalline solid dispersions (CSDs) hinders the implementation of continuous polymer-based formulation processes. Although polymorphic stability of the active pharmaceutical ingredient (API) is thought to be a prerequisite to implement continuous polymer-based formulation processes, it is a widely understudied topic. Hence, the control of polymorphism would need to be addressed if there is any prospect of continuous polymer-based strategies such as hot melt extrusion (HME) to be successfully implemented as an alternative solid dosage formulation strategy in integrated, continuous end-to-end pharmaceutical manufacturing. In this thesis, three polymorphic APIs (acetaminophen, flufenamic acid, and artemisinin) with different thermodynamic relationships between their most stable polymorphs are employed to evaluate the feasibility of APIs prone to polymorphic transformations in the formulation of CSDs. The influence of three solid dispersion preparation methods (solvent evaporation, solvent-fusion, and fusion) on the polymorphic form obtained in CSDs was investigated in Chapter 2 and it is shown that preparative methods have a significant influence on the polymorphic outcome and the phase diagrams elucidation, which are often used to justify thermodynamic design spaces. Moreover, in Chapter 3, the polymorphic APIs were subjected to individually and combined critical process parameters characteristic of HME processes to determine the effect on the polymorphic stability of the metastable form during the processing conditions. It is demonstrated that thorough understanding of the thermodynamic and kinetic design space for the API-polymer systems leads to polymorphic control in the produced CSDs. Ultimately, the occurrence of solvent-mediated polymorphic transformations (SMPTs) employing non-conventional solvents (polymer melts) was explored in Chapter 4 as it limits the application of polymer-based formulation processes. The results demonstrate that the SMPT induction time of APIs in polymer melts is driven by diffusivity. This behavior proves that the induction time for the SMPT can be tuned by understanding the dispersant’s physicochemical properties which allow to kinetically stabilize metastable forms under given process conditions. The work presented here helps to gain fundamental understanding of the CSDs processing needs, which will lead to the broader application of continuous polymer-based strategies for drug products containing APIs prone to polymorphism.