Solution mediated phase transformation: Investigating using a novel flow-through dissolution apparatus

Drugs that are poorly soluble in water often have low or variable absorption after oral administration. Soluble salts and amorphous solids can be formed to increase the solubility of these poorly soluble pharmaceutical compounds. Solution mediated transformation (SMPT) is the precipitation of the less soluble solid form during dissolution of the more soluble form. SMPT can decrease the dissolution rate during in vitro evaluations, and ultimately in vivo resulting in lower bioavailability and therapeutic effectiveness. In this study we investigated the SMPT of amorphous solids and soluble salt forms during dissolution in a novel flow-through apparatus. ^ The apparatus was designed to utilize small samples sizes and enable viewing of solids during dissolution. Intrinsic dissolution rates of the solids were measured under well-defined hydrodynamic conditions. In all cases studied, changes in hydrodynamics did not affect the time course of SMPT. The flow-through configuration enabled measurement of dissolution rate rather than the traditional cumulative amount dissolved. A decrease in dissolution rate with time occurred immediately upon exposure to aqueous medium, indicating SMPT occurred immediately on exposure to aqueous solution. ^ The amorphous form of the drug, indomethacin, was prepared by several methods. SMPT of the higher solubility amorphous form to the lower solubility crystalline form was confirmed by in situ Raman microscopy and polarized light microscopy. The kinetics of transformation of amorphous indomethacin was found to be highly dependant on the processing method and presence of crystalline impurity. Dissolution appears to be more sensitive to differences in solid form than many of the traditional solids characterization techniques. ^ The solution mediated phase transformation of two salts, haloperidol mesylate and haloperidol chloride, to the free base form was found to be dependant on the buffer concentration at pH 7. As buffer concentration increased, the dissolution rates and time of conversion decreased. Additionally, the SMPT of haloperidol mesylate, at pH 7 exhibited complex behavior as a function of the concentration of an ionic surfactant, sodium lauryl sulfate. ^ Solution composition and solid characteristics, not hydrodynamics, affect the time course of SMPT.