A potentiometric titration method for the crystallization of drug-like organic molecules

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...

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Bibliographic Details
Published in:International journal of pharmaceutics 2007-09, Vol.342 (1), p.161-167
Main Authors: Du-Cuny, Lei, Huwyler, Jörg, Fischer, Holger, Kansy, Manfred
Format: Article
Language:English
Subjects:
Algorithms
Biological and medical sciences
Buffers
Chemical Phenomena
Chemistry, Physical
Crystal
Crystallization
Crystallography, X-Ray
General pharmacology
Hydrogen - chemistry
Hydrogen-Ion Concentration
Medical sciences
Models, Molecular
Pharmaceutical Preparations - analysis
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Potentiometric titration
Potentiometry
Solubility
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Summary: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 p K 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.
ISSN:0378-5173
1873-3476
DOI:10.1016/j.ijpharm.2007.05.030