Tong W Q, Whitesell G
Glaxo Wellcome Inc., Department of Pharmaceutics, Research Triangle Park, North Carolina 27709, USA.
Pharm Dev Technol. 1998 May;3(2):215-23. doi: 10.3109/10837459809028498.
The purpose of this paper was to present an in situ salt screening technique which is applicable to most basic compounds. The theoretical aspects, experimental details, applications, and significance of this technique are illustrated through in situ salt screening studies performed on GW1818, an alpha 1A andrenergic receptor antagonist intended for treatment of benign prostatic hyperplasia (BPH). Generally, the in situ salt screening technique includes (i) acid selection, (ii) a solubility study, (iii) characterization of residual solids, and (iv) calculation of the Ksp and solubility of the salts. Six acids were screened for salt formation with GW1818. Excellent agreement was found between the solubility results determined using the authentic salts and solubility results obtained through in situ screening. Additional evidence of salt formation and some solid state properties of the salts formed in situ were obtained through microscopic examinations, differential scanning calorimetry (DSC), and x-ray powder diffraction studies. Four salts of GW1818, the phosphate, succinate, mesylate, and hydrochloride, were crystalline and demonstrated adequate solubility. These were selected for further evaluation. Adequate solubility was also observed in the case of citrate and tartrate salts, but these were considered only as potential backup candidates because they were difficult to crystallize. The results of the in situ salt screening experiments also led to the development of an IV formulation for use in pilot toxicological studies and pharmacological studies. In conclusion, the in situ salt screening technique offers a time- and compound-conserving approach for prioritizing salt selection and for providing solubility and stability information useful for formulation development both in the research and the development stages.
本文的目的是介绍一种适用于大多数碱性化合物的原位盐筛选技术。通过对GW1818进行的原位盐筛选研究，阐述了该技术的理论方面、实验细节、应用及意义。GW1818是一种用于治疗良性前列腺增生（BPH）的α1A肾上腺素能受体拮抗剂。一般来说，原位盐筛选技术包括：（i）酸的选择；（ii）溶解度研究；（iii）残余固体的表征；（iv）盐的溶度积（Ksp）和溶解度的计算。筛选了六种酸与GW1818形成盐。使用真实盐测定的溶解度结果与通过原位筛选获得的溶解度结果之间发现了极好的一致性。通过显微镜检查、差示扫描量热法（DSC）和X射线粉末衍射研究，获得了盐形成的额外证据以及原位形成的盐的一些固态性质。GW1818的四种盐，即磷酸盐、琥珀酸盐、甲磺酸盐和盐酸盐，是结晶性的，并且表现出足够的溶解度。选择这些盐进行进一步评估。柠檬酸盐和酒石酸盐也观察到了足够的溶解度，但由于它们难以结晶，因此仅被视为潜在的备用候选物。原位盐筛选实验的结果还促成了一种用于先导毒理学研究和药理学研究的静脉注射制剂的开发。总之，原位盐筛选技术提供了一种节省时间和化合物的方法，用于优先选择盐，并提供对研究和开发阶段的制剂开发有用的溶解度和稳定性信息。
