In situ salt screening--a useful technique for discovery support and preformulation studies.
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.
Tong
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WQ
Glaxo Wellcome Inc., Department of Pharmaceutics, Research Triangle Park, North Carolina 27709, USA. WT14313@glaxo.com
Whitesell
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D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000737:chemistry*; D000465:Algorithms; D002626:Chemistry, Pharmaceutical; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D010080:Oxazoles / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry*; D011199:Potentiometry; D012995:Solubility; D014961:X-Ray Diffraction
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; C114263:GW 1818; D010080:Oxazoles; D010880:Piperidines