title: A potentiometric titration method for the crystallization of drug-like organic molecules.
abstract: It is generally accepted, that crystalline solids representing a low energy polymorph should be selected for development of oral dosage forms. As a consequence, efficient and robust procedures are needed at an early stage during drug discovery to prepare crystals from drug-like organic molecules. In contrast to the use of supersaturated solutions, we present a potentiometric crystallization procedure where saturated solutions are prepared in a controlled manner by pH-titration. Crystallization is carried out under defined conditions using the sample concentration and experimental pK(a) values as input parameters. Crystals of high quality were obtained for 11 drugs selected to demonstrate the efficiency and applicability of the new method. Technical improvements are suggested to overcome practical limitations and to enhance the possibility of obtaining crystals from molecules in their uncharged form.
authors.affiliation: F. Hoffmann-La Roche Ltd., Discovery Chemistry, Molecular Properties & Structure Property Correlation, Grenzacherstrasse, CH-4070 Basel, Switzerland.
authors.forename: Lei
authors.initials: L
authors.lastname: Du-Cuny
authors.forename: Jörg
authors.initials: J
authors.lastname: Huwyler
authors.forename: Holger
authors.initials: H
authors.lastname: Fischer
authors.forename: Manfred
authors.initials: M
authors.lastname: Kansy
mesh_terms: D000465:Algorithms; D002021:Buffers; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003460:Crystallization; D018360:Crystallography, X-Ray; D006859:Hydrogen / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000032:analysis*; D011199:Potentiometry; D012995:Solubility
chemical_list: D002021:Buffers; D004364:Pharmaceutical Preparations; D006859:Hydrogen