Supersaturation Potential of Salt, Co-Crystal, and Amorphous Forms of a Model Weak Base

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• 作者：Luis Almeida e Sousa ; Susan M. Reutzel-Edens ; Gregory A. Stephenson ; Lynne S. Taylor
• 刊名：Crystal Growth & Design
• 出版年：2016
• 出版时间：February 3, 2016
• 年：2016
• 卷：16
• 期：2
• 页码：737-748
• 全文大小：631K
• ISSN：1528-7505

文摘

High energy solids, such as salts, co-crystals, or amorphous solid dispersions, have been widely used to generate supersaturated aqueous solutions and improve drug bioavailability. However, most research on solubility enhancing strategies has focused on the kinetics of dissolution, and there is relatively little comparison of the different degrees of supersaturation achieved by using different solid state forms of the same compound. Recent studies from our group have demonstrated that the maximum achievable supersaturation is dictated by the aqueous solubility of the amorphous form of the drug. Liquid–liquid phase separation (LLPS) occurs at concentrations above this value. Herein, it was hypothesized that the upper limit of supersaturation that can be achieved from dissolution of various high energy solids is also governed by the amorphous solubility. To test this hypothesis, the dissolution and supersaturation behavior of different solid forms of a model compound, CRH1, were investigated using a variety of techniques. With the exception of CRH1 crystalline free base, all solid forms generated supersaturated solutions. The extent of supersaturation, onset of crystallization time, and area under the curve increased significantly when a polymer with crystallization inhibitory properties was present in the dissolution medium or incorporated in the formulation (in the case of amorphous solid dispersions). In the presence of the polymeric crystallization inhibitor, several solid state forms, including the amorphous solid dispersion and the salts, dissolved to concentrations above the amorphous free form solubility and underwent LLPS, generating a drug-rich phase. Other solid state forms underwent crystallization prior to attaining the amorphous solubility and showed no evidence of LLPS (co-crystal and glass forms). These studies should aid in solid state form selection and formulation and help to understand how to achieve maximized supersaturation in vivo.