Drug-Polymer Solubility Determination: A New Thermodynamic Model Free from Lattice Theory Assumptions.

PURPOSE: Traditional methods for estimating drug-polymer solubility either require fast dissolution in the polymeric matrix, rapid re-crystallization kinetics from supersaturated states or derive from regular solution theories. In this work, we present a new method for determining drug solubility, purely based on thermodynamic considerations, that uses only experimental data from DSC for calculations. METHODS: The new thermodynamic model presented combines DSC analysis and application of Hess's law to determine free energies of conversion of binary mixtures to amorphous solid dispersions, free energies of mixing as well as solubility as a function of temperature. The model drug indomethacin and polymers HPMCAS LF, PVP K29/32 and Eudragit EPO were used in these studies. RESULTS: Free energies were calculated as a function of temperature, for different drug-polymer compositions and the results show that HPMCAS LF solid dispersion with high drug content are less thermodynamically favorable compared to other polymer systems. Solubility of indomethacin in HPMCAS LF, PVP K29/32 and Eudragit EPO was 24, 55 and 56% w/w, respectively, at 25°C. CONCLUSIONS: The thermodynamic model presented has great advantages over traditional methods. It does not require estimation of any interaction parameters, it is almost assumption-free and uses only thermal data for calculations.

Assessment of the amorphous "solubility" of a group of diverse drugs using new experimental and theoretical approaches.

The supersaturation potential of poorly water-soluble compounds is of interest in the context of solubility enhancing formulations for enhanced bioavailability. In this regard, the amorphous "solubility", i.e., the maximum increase in solution concentration that can be obtained relative to the crystalline form, is an important parameter, albeit a very difficult one to evaluate experimentally. The goal of the current study was to develop new approaches to determine the amorphous "solubility" and to compare the experimental values to theoretical predictions. A group of six diverse model compounds was evaluated using the solvent exchange method to generate an amorphous phase in situ, determining the concentration at which the amorphous material was formed. The theoretical estimation of the amorphous "solubility" was based on the thermal properties of the crystalline and amorphous phases, the crystalline solubility, and the estimated concentration of water in the water-saturated amorphous phase. The formation of an amorphous precipitate could be captured transiently for all six compounds and hence the amorphous "solubility" determined experimentally. A comparison of the experimental amorphous "solubility" values to those calculated theoretically showed excellent agreement, in particular when the theoretical estimate method treated the precipitated phase as a supercooled liquid, and took into account heat capacity differences between the two forms. The maximum supersaturation ratio in water was found to be highly compound dependent, varying between 4 for ibuprofen and 54 for sorafenib. This information may be useful to predict improvements in biological exposure for poorly water-soluble compounds formulated as amorphous solid dispersions or other formulations that rely on supersaturation.

Calorimetric determination of rate constants and enthalpy changes for zero-order reactions.

Calorimetry is a general method for determination of the rates of zero-order processes, but analysis of the data for the rate constant and reaction enthalpy is difficult because these occur as a product in the rate equation so evaluation of one requires knowledge of the other. Three methods for evaluation of both parameters, without prior knowledge, are illustrated with examples and compared with literature data. Method 1 requires the reaction to be studied in two buffers with different enthalpies of ionization. Method 2 is based on calculation of reaction enthalpy from group additivity functions. Method 3 applies when reaction progresses to completion. The methods are applied to the enzymatic hydrolysis of urea, the hydrolysis of acetylsalicylic acid, and the photodegradation of nifedipine, respectively.