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Inhibiting or Accelerating Crystallization of Pharmaceuticals by Manipulating Polymer Solubility.
Mol Pharm
August 2019
School of Chemistry and Chemical Engineering , Shanghai Jiao Tong University, 800 Dongchuan Road , Shanghai 200240 , China.
Polymers play a central role in controlling the crystallization of pharmaceuticals with effects as divergent as amorphous form stabilization and the acceleration of crystallization. Here, using pyrazinamide and hydrochlorothiazide as model pharmaceuticals, it is demonstrated that the same functional group interactions are responsible for these opposing behaviors and that whether a polymer speeds or slows a crystallization can be controlled by polymer solubility. This concept is applied for the discovery of polymers to maintain drug supersaturation in solution: the strength of functional group interactions between drug and polymer is assessed through polymer-induced heteronucleation, and soluble polymers containing the strongest-interacting functional groups with drug are shown to succeed as precipitation inhibitors.
View Article and Find Full Text PDFProbing the Interplay between Amorphous Solid Dispersion Stability and Polymer Functionality.
Mol Pharm
July 2018
Department of Chemistry and the Macromolecular Science & Engineering Program , The University of Michigan, Ann Arbor , Michigan 48109 , United States.
Amorphous solid dispersions containing a polymeric component often impart improved stability against crystallization for a small molecule relative to the pure amorphous form. However, the relationship between side chain functionalities on a polymer and the ability of a polymer to stabilize against crystallization is not well understood. To shed light on this relationship, a series of polymers were functionalized from a parent batch of poly(chloromethylstyrene- co-styrene) to investigate the effect of functionality on the stability in amorphous solid dispersions without altering the physical parameters of polymers, such as the average molecular weight or backbone chain chemistry.
View Article and Find Full Text PDFInfluence of Chemical Functionality on the Rate of Polymer-Induced Heteronucleation.
Cryst Growth Des
June 2017
Department of Chemistry and the Macromolecular Science and Engineering Program, The University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109-1055, United States.
Polymer-induced heteronucleation can dramatically increase the nucleation rate of pharmaceuticals. However, directly comparing the heteronucleation rates of different polymer functionalities is often convoluted with changing physical or structural aspects of heteronuclei. Here, we report a methodology for comparing nucleation efficiencies of different functionalities on polymer heteronuclei of uniform topology with the goal of identifying those functionalities that best accelerate nucleation of a model pharmaceutical.
View Article and Find Full Text PDFPolymorphism in phenobarbital: discovery of a new polymorph and crystal structure of elusive form V.
Chem Commun (Camb)
March 2016
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA. and Macromolecular Science and Engineering, University of Michigan, 48109-1055, USA.
This report highlights the discovery of a new polymorph of the anticonvulsant drug phenobarbital (PB) using polymer-induced heteronucleation (PIHn) and unravelling the crystal structure of the elusive form V. Both forms are characterized by structural, thermal and VT-Raman spectroscopy methods to elucidate phase transformation behavior and shed light on stability relationships.
View Article and Find Full Text PDFThe Bioenhancer Piperine is at Least Trimorphic.
Cryst Growth Des
May 2015
Department of Chemistry and the Macromolecular Science and Engineering Program, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States.
Polymer-induced heteronucleation (PIHn), a powerful crystalline polymorph discovery method, has revealed two novel polymorphs of the low solubility bioenhancer piperine. Both of these forms exhibit enhanced solubility when compared to the commercial polymorph, thereby potentially improving the efficacy of piperine as a bioenhancer. Structural comparison of the three forms reveals that π-π interactions are only present in the two newly discovered forms.
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