POLYMORPHISM IN ANHYDROUS THEOPHYLLINE - IMPLICATIONS ON THE DISSOLUTION RATE OF THEOPHYLLINE TABLETS

The objects of this investigation were (i) to prepare and characterize a new anhydrous theophylline phase that is metastable under ambient c onditions, and (ii) to prepare model tablet formulations containing ei ther this metastable anhydrate (I) or stable anhydrous theophylline ( I), store them under different relative humidity (RH) conditions, and compare their dissolution behavior. I was prepared by dehydration of theophylline monohydrate (II). Variable temperature Xray powder diffra ctometry of li[ revealed the following series of transitions: II --> I --> I. The metastable anhydrate, I*, which has not yet been reported in the literature, appears to be related monotropically to I. It was characterized by ambient and variable temperature X-ray powder diffrac tometry, Karl Fischer titrimetry, and thermoanalytical techniques (dif ferential scanning calorimetry and thermogravimetric analysis). Tablet formulations containing either I or I were prepared and stored at 33 and 52% RH (room temperature). The solid state of the drug was monito red by X-ray powder diffractometry and the tablets were subjected to t he USP dissolution test. In tablets, I completely converted to I in l ess than or equal to 10 days when stored at either 33 or 52% RH. Scann ing electron microscopy provided direct visual evidence of recrystalli zation, This recrystallization was accompanied by a decrease in the di ssolution rate of the stored formulations that was so pronounced in th e formulations stored at 52% RH that they failed the USP dissolution t est. The in situ solid state transition appears to be responsible for the decrease in dissolution rate observed following storage. Stored ta blets containing I showed neither a phase transition nor an alteration in their dissolution behavior.