Preformulation Studies To Meet The Challenges In The Manufacture Of Betaine Solid Dosage Form

摘要

The objectives were (ⅰ) to perform solid-state characterization of anhydrous betaine (A)rnand betaine monohydrate (M), (ⅱ) to develop a pressure differential scanning calorimetric (DSC)rntechnique for the quantification of M when present as a minor component in a mixture with Arnand, (ⅲ) to study the effect of annealing of A on the kinetics of A→ M transition. X-rayrnpowder diffractometer (XRD), DSC, thermogravimetric analyzer (TGA) and an automatedrnmoisture sorption apparatus were used to characterize the phases. DSC at an elevated pressure ofrn200 psi enabled quantification of M in mixtures of A and M. Humidity controlled TGA allowedrnstudy of the kinetics of A→M transition. Automated moisture studies showed that A has arnstrong tendency to sorb water (at RH ?20 %, 25℃) and convert to M. When M was subjected tornDSC at ambient pressure, the endotherms due to dehydration and vaporization of waterrnoverlapped. Pressure DSC enabled separation of these two thermal events. In mixtures of A andrnM, the enthalpy of dehydration (△H_d) of M could be used for its quantification. A linearrnrelationship was obtained when △H_d was plotted as a function of the weight fraction of M in thernmixture. The limits of detection and quantification of M in A were 0.15% and 1.5% w/wrnrespectively. The kinetics of water uptake by the annealed as well as the unannealed A, could bernbest described by the Avrami-Erofeev model (three-dimensional nucleation and growth). Therncalculated rate constant (k) of unannealed A (0.075 ± 0.002 min~(-1)) was significantly higher thanrnthat of annealed A (0.052 ± 0.004 min~(-1)). DSC at elevated pressure was a sensitive technique forrnquantification of M when present as a mixture with A. Annealing of A decelerated the A→Mrnphase transition reaction, possibly by increasing the degree of crystallinity of A.