Freeze-Drying of Thermosensible Pharmaceuticals with Organic Co-solvent + Water Formulations

Abstract

The organic co-solvent + water formulations present many interesting advantages for the freeze-drying of thermosensible drugs to produce stabilized and elegant powders of marketed pharmaceuticals products: high freezing temperatures, very short sublimation times, low sublimation enthalpies, high equilibrium vapour/frozen solid pressures and low toxicity of the residual solvent contents. The formulations that have been the most investigated have concerned certainly tert-butanol (TBA) + water mixtures. Thus, some main characteristics of the water + TBA formulations have been reviewed, especially its interesting thermodynamical properties (sublimation enthalpies; equilibrium vapour pressures), the impact of freezing conditions on morphological properties of frozen formulations (nucleation, crystals size and shape), the influence of operating parameters (total pressure, temperature) on sublimation times and finally on organic co-solvent and water residual contents. The crystals morphology of frozen formulations prepared with tert-butanol (TBA) revealed unexpected results compared with the results reported in the literature for water-based formulations, pointing the complex relationships between freezing rates, supercooling, nucleation temperatures and solvent crystals morphology (size and shape). To illustrate the functional relationships between the sublimation rates, the mean product temperatures and the two principal independent process variables, namely the shelf heat transfer fluid temperature and the total gas pressure, we used the Design Space concept presented as an envelope in a graph with sublimation rates and total gas chamber pressures on main (x, y) axis. The limits of this Design Space are determined by the influence of product and process variables on main quality attributes of the freeze-dried drug, more precisely by the failure of these attributes under aggressive cycle conditions. In the case of large industrial freeze-dryers, other limits are also imposed by freeze-dryer performances. Next, as an illustration of this concept, we have presented a case study concerning methodology of construction of the Design Space for an ibuprofen organic co-solvent (TBA)-based formulation determined with a pilot laboratory freeze-dryer. It proved that the setting up of optimum freeze-drying cycles has to be realized by taking into account simultaneously the impact of formulation variables, especially the tert-butanol content and the classical freeze-drying variables at the freezing step (nucleation temperatures, freezing rates) and at the two drying steps (shelf temperature, total gas pressure) to maximize the drying rates and to minimize the residual solvent levels while preserving the main quality attributes of the freeze-dried powder.