Unraveling Complexity in the Solid Form Screening of a Pharmaceutical Salt: Why so Many Forms? Why so Few?

Doris E Braun,Peter Müller,Sreenivas R Lingireddy,Rui Guo,Susan M Reutzel-Edens,Sarah L Price,Mark D Beidelschies

doi:10.1021/acs.cgd.7b00842

Abstract

The solid form landscape of 5-HT2a antagonist 3-(4-(benzo[d]isoxazole-3-yl)piperazin-1-yl)-2,2-dimethylpropanoic acid hydrochloride (B5HCl) proved difficult to establish. Many crystalline materials were produced by solid form screening, but few forms readily grew high quality crystals to afford a clear picture or understanding of the solid form landscape. Careful control of crystallization conditions, a range of experimental methods, computational modeling of solvate structures, and crystal structure prediction were required to see potential arrangements of the salt in its crystal forms. Structural diversity in the solid form landscape of B5HCl was apparent in the layer structures for the anhydrate polymorphs (Forms I and II), dihydrate and a family of solvates with alcohols. The alcohol solvates, which provided a distinct packing from the neat forms and the dihydrate, form layers with conserved hydrogen bonding between B5HCl and the solvent, as well as stacking of the aromatic rings. The ability of the alcohol hydrocarbon moieties to efficiently pack between the layers accounted for the difficulty in growing some solvate crystals and the inability of other solvates to crystallize altogether. Through a combination of experiment and computation, the crystallization problems, form stability, and desolvation pathways of B5HCl have been rationalized at a molecular level.

Highlights

The oral delivery of a drug from a solid dosage form depends on the properties of its solid state
As crystallinity usually confers upon the drug substance advantages, such as impurity rejection, improved handling characteristics, and generally greater physical and chemical stability, the selection of a crystalline form is one of the first steps taken in drug development to transform a molecule to a safe and efficacious medicine
The solid form screen of B5HCl comprised more than 450 experiments, most of which were solution-based recrystallizations designed around the overall poor solubility of the HCl salt

Summary

Introduction

The oral delivery of a drug from a solid dosage form depends on the properties of its solid state. As crystallinity usually confers upon the drug substance advantages, such as impurity rejection, improved handling characteristics, and generally greater physical and chemical stability, the selection of a crystalline form is one of the first steps taken in drug development to transform a molecule to a safe and efficacious medicine. The pharmaceutical industry must have a thorough knowledge of the solid-state forms of the drug substance and their properties in order to identify one that is developable, and potentially commercializable, for a drug product.[1] Both the form of interest, usually that which has the lowest free energy (i.e., is thermodynamically stable), and other competitive forms (those to avoid) are necessary inputs to designing downstream crystallization and formulation processes.

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