Evaluation of crystallinity and drug release stability of directly compressed theophylline hydrophilic matrix tablets stored under varied moisture conditions

The effects of relative humidity (RH) and compression pressure on drug/excipient crystal changes or drug release of theophylline tablets were studied using X-ray diffractometry (X-RD), differential scanning calorimetry (DSC) and dissolution analysis. A tablet formulation, containing hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose (MCC) and anhydrous magnesium stearate was compressed at pressures such as 194.8 and 274.4 MPa, and stored at 23°C for 3 months under different RH values, ranging from 31 to 100%. Moisture sorption isotherms of all the tablets studied indicated sorption of large amounts of moisture at RH > 52%. Powder X-RD patterns of tablets stored at RH < 52% indicated no change in crystallinity after 3 months, while in tablets stored at RH > 52%, theophylline monohydrate peaks were observed within 1 month and characteristic anhydrous theophylline peaks decreased. Peaks corresponding to pseudopolymorphs of magnesium stearate were also observed. DSC analysis of tablets stored at ≤ 52% revealed only the endothermic peak of theophylline at 277°C, while in tablets stored at > 52% RH, the endothermic peak of theophylline, and that of magnesium stearate pseudopolymorphs at 72°C were observed. Moisture sorption or crystal form was not affected by compression pressure. Drug release decreased as the compression pressure increased, and/or becomes inconsistent as a result of the formation of the less soluble theophylline monohydrate, partial hydration of the MCC and gelation of the HPMC. The drug dissolution data at the onset did not fit the Higuchi square-root model, but rather revealed a biphasic release pattern, indicative of faster, initial surface erosion followed by a slower diffusion-based mechanism from the gelled matrix. Higher RH resulted in a tendency towards a diffusion-only mechanism.