Amorphous solid dispersions (ASDs) of class II and IV biopharmaceutics classification system drugs in water-miscible polymers are a well-recognized means of enhancing dissolution, while such dispersions in hydrophobic polymers form the basis of micro- and nanoparticulate technologies. However, drug recrystallization presents significant problems for product development, and the mechanisms and pathways involved are poorly understood. Here, we outline the use of combined differential scanning calorimetry (DSC)-synchrotron X-ray diffraction to monitor the sequential appearance of polymorphs of olanzapine (OLZ) when dispersed in a range of polymers. In a recent study (Cryst. Growth Des. 2019, 19, 2751-2757), we reported a new polymorph (form IV) of OLZ which crystallized from a spray-dried dispersion of OLZ in polyvinylpyrrolidone. Here, we extend our earlier study to explore OLZ dispersions in poly(lactide-co-glycolide) (PLGA), polylactide (PLA), and hydroxypropyl methyl cellulose acetate succinate (HPMCAS), with a view to identifying the sequence of form generation on heating each dispersion. While spray-dried OLZ results in the formation of crystalline form I, the spray-dried material with HPMCAS comprises an ASD, and forms I and IV are generated upon heating. PLGA and PLA result in a product which contains both amorphous OLZ and the dichloromethane solvate; upon heating, the amorphous material converts to forms I, II, and IV and the solvate to forms I and II. Our data show that it is possible to quantitatively assess not only the polymorph generation sequence but also the relative proportions as a function of temperature. Of particular note is that the sequence of form generation is significantly more complex than may be indicated by DSC data alone, with coincident generation of different polymorphs and complex interconversions as the material is heated. We argue that this may have implications not only for the mechanistic understanding of polymorph generation but also as an aid to identifying the range of polymorphic forms that may be produced by a single-drug molecule.
Bibliographical noteFunding Information:
The authors would like to thank the Centre for Doctoral Training in Advanced Therapeutics and Nanomedicine and the EPSRC for funding (EP/L01646X). We further thank the Diamond Light Source for the provision of beamtime (EE17450), and Dr Oxana Magdysyuk for assistance during DSC-XRD experiments.
The authors would like to thank the Centre for Doctoral Training in Advanced Therapeutics and Nanomedicine and the EPSRC for funding (EP/L01646X). We further thank the Diamond Light Source for the provision of beamtime (EE17450), and Dr Oxana Magdysyuk for assistance during DSC–XRD experiments.
Copyright 2020 Elsevier B.V., All rights reserved.
- amorphous solid dispersion
- differential scanning calorimetry
- pharmaceutical materials
- X-ray diffraction
ASJC Scopus subject areas
- Molecular Medicine
- Pharmaceutical Science
- Drug Discovery