Development of a solvate as an active pharmaceutical ingredient: Developability, crystallisation and isolation challenges
- 作者：Julien Douillet ; julien.b.douillet@gsk.com ; Neil Stevenson ; Mei Lee ; Franck Mallet ; Richard Ward ; Peter Aspin ; Daniel Robert Dennehy ; Laure Camus
- 关键词：A1. Phase diagrams ; A2. Pharmaceutical crystallisation ; A2. Seed crystals ; A2. Cake washing ; B1. Solvate ; B1. Organic compounds
- 刊名：Journal of Crystal Growth
- 出版年：2012
- 期刊代码：49_00220248
- 类别：ch
- 出版时间：1 March, 2012
- 卷：342
- 期：1
- 页码：2-8
- 文件大小：763 K
摘要
The preclinical development of an active pharmaceutical ingredient (API) begins with the selection of a solid state form. A solvate may be selected for development if it is sufficiently stable and if the solvent quantity administered to the patient is lower than the tolerated potential daily exposure (PDE). The selection and process development of a solvate is presented here. The initial crystallisation process gave poor control over the particle size distribution (PSD) and inclusion of additional crystallisation solvent in the crystal lattice. These two API attributes were controlled using micronised seeds and optimising the crystallisation conditions. After filtration, slurry washing with a second solvent was used to replace the high boiling point crystallisation solvent to improve the drying efficiency. The slurry washing was modelled and studied in the laboratory to control the level of unbound crystallisation solvent in the API. The API desolvation during slurry washing was studied by considering thermodynamics, by construction of the ternary phase diagram, and kinetics aspects. This work provides useful approaches and considerations to assess the risks specific to the controlled production of a solvate that are rarely presented in the literature.