Preparation and characterization of amorphous pharmaceuticals

This thesis work focuses on the preparation and characterization of amorphous pharmaceuticals. Dehydration and melt-quenching were the two techniques used to prepare amorphous phases. Based on the solid-state of the dehydration products, the ten selected model hydrates can be divided into two groups. In one group, which includes oxytetracycline dihydrate and sodium ibuprofen dihydrate, a crystalline anhydrate was formed. The other group, which includes carbamazepine dihydrate, nitrofurantoin monohydrate, oxyphenbutazone monohydrate, ampicillin trihydrate, calcium fenoprofen dihydrate, loperamide hydrochloride tetrahydrate, lidocaine hydrochloride monohydrate, and cetylpyridium chloride monohydrate, the product was an amorphous anhydrate. The glass transition temperatures (T_g) of the amorphous anhydrates were found to be in the temperature range of 28 to 107°C. Amorphous carbamazepine was characterized in situ in the sample chamber of a differential scanning calorimeter (DSC) and a variable temperature X-ray powder diffractometer (VTXRD). It has a T_g of 56°C and is a relatively strong glass with a strength parameter of 37. The kinetics of crystallization of amorphous carbamazepine was studied by VTXRD under two sets of conditions. In the first set of studies, a 22-fold increase in the magnitude of the reaction rate constant was found as the temperature increased from 35 to 75°C in the absence of water vapor. The relationship between the reaction rate constant and temperature followed the Williams-Landel-Ferry equation. In the second set of studies, as water vapor pressure increased from 0 to 31.8 Torr at 40°C, the kinetics of crystallization was accelerated. The amount of water sorbed was <1% w/w even at 31.8 Torr. Amorphous sulfapyridine was prepared by melt quenching and characterized in situ. It has a T_g of 58°C and is a relatively fragile glass with a strength parameter of 21. Under isothermal conditions, amorphous sulfapyridine crystallized into a mixture of two polymorphs, while under nonisothermal conditions, only one polymorph was formed. The nucleation process was found to be predominately bulk rather than surface nucleation. VTXRD in combination with DSC were found to be excellent techniques to study the crystallization of amorphous phases both as a function of temperature and water vapor pressure.