Theoretical and experimental assessment of the solubility advantage of glassy pharmaceuticals over their corresponding crystalline counterparts

Amorphous pharmaceuticals are markedly more soluble than their crystalline counterparts and this difference is due to the amorphous form having higher free energy. But there is difficulty in measuring true equilibrium solubility of amorphous materials due to solvent mediated crystallization that can occur during experimental measurement of its solubility. Thermodynamic predictions can provide a useful indication of the theoretical maximum solubility advantage for amorphous pharmaceuticals and quantitative estimation of free energy will be an appropriate technique to achieve that goal. A quantitative thermodynamic relationship is developed to estimate the solubility advantage of amorphous pharmaceutical over its crystalline counterpart and applied to a model drug (indomethacin). This relationship provides maximum solubility enhancement that can be achieved by amorphous form of the drug prior to solid dispersion formulation development is undertaken to realize biopharmaceutic benefit of amorphous form of drug. ^ Application of this relationship of estimation of theoretical maximum solubility benefit of amorphous counterpart of crystalline drug has been further evaluated for additional eight compounds that differ in their physico-chemical properties. Pharmaceuticals that differ in melting point (and heats of fusion) and lipophilicity or both and belong to various states of ionization (acid, base and neutral) are investigated to ascertain the general applicability of this approach. For 67% (six out of nine) of compounds the prediction of solubility advantage of amorphous drug form was within 2-fold however for the remaining 33% (3 out of 9) of compounds the predictions were between 7 to 11-fold higher than experimental results. ^ The ability to measure the solubility of amorphous form of a compound experimentally often times is difficult or impossible due to the rapid conversion to the crystalline state. Therefore we have investigated an approach of identifying crystallization/nucleation inhibitor in solution that may experimentally allow attainment of maximum solubility advantage of amorphous pharmaceutical.