Co-amorphous solids of dasatinib and olanzapine by saccharin with promising physicochemical properties

Abstract

Two co-amorphous compounds of poorly water-soluble drugs dasatinib (DAS) and olanzapine (OLA) were formed, dasatinib-saccharin (DAS-SAC), and olanzapine-saccharin (OLA-SAC) with saccharin (SAC) as the co-former through liquid assisted grinding method, and at large scale, by rapidly evaporating the solvent (ethanol) from a rota-vapor at 60 °C under vacuum. The co-amorphous solids showed improved dissolution rates in phosphate-buffered saline (PBS, pH 7.2) and glycine-HCl buffer (pH 3.6) at 37 °C compared to the freeform. For example, the dissolution rate of DAS-SAC in PBS in first 10 min was 0.12 mg/mL (30-times faster than DAS) compared to 0.004 mg/mL of DAS. The dissolution rate of OLA-SAC in PBS in 10 min was 1.72 mg/mL and more than OLA (~21 times faster) as opposed to 0.08 mg/mL of OLA. Thermal analysis of the DAS-SAC and OLA-SAC showed single glass transition temperature (Tg) with the onsets of 132.8 °C and 161.7 °C, respectively indicating the amorphous nature of solids. The co-amorphous forms were stable at various temperatures (6 °C, 25 °C and 40 °C) and relative humidity (11%, 75% and dry condition) for up to eight weeks. Importantly, no amorphous forms were able to produce with DAS and OLA through grinding or quick evaporation without the use of SAC.