Comparison of the effects of two drying methods on polymorphism of theophylline

Processing-induced transformations in drug formulation may induce adverse biopharmaceutical changes in the finished product. During the drying phase of wet granulation, theophylline monohydrate transforms either the stable (form I), ora polymorphic, metastable (form I*) form of anhydrous theophylline. We investigated the effect of two drying methods (multichamber microscale fluid bed dryer MMFD) or variable temperature X-ray powder diffractometer (VT-XRPD) on the relative amounts of the different theophylline forms remaining in the dried granules. Granules were analyzed using XRPD and near-infrared spectroscopy. Form I* was the predominant form of theophylline after drying at 40-50degreesC with both drying techniques. Although drying at temperatures over 50degreesC produced mostly form I, more than 20% of form I-* remained even at 90degreesC when drying in MMFD. In these conditions, humidity had little influence on the amount of form I* in the granules. In contrast, drying in a VT-XRPD at 60degreesC produced form I already during the first 15 min. Using additional drying methods, including MMFD, during the preformulation stage can be more informative about the possible polymorphic transformations and their underlying mechanisms, such as triboelectrification or recrystallization, in drug ingredients during the manufacturing process. (C) 2004 Elsevier B.V. All rights reserved.