Development, characterization and stabilization of amorphous form of a low Tg drug

Abstract

The objective of the present study was to develop a stable amorphous form of model drug carvedilol (CAR). The amorphous material produced by melt quench technique was subjected to physico-chemical characterization. Chemical stability of the drug during preparation of glass was tested by HPLC and IR spectroscopy and presence of amorphous form was confirmed by DSC and XRPD. The rate of dissolution and magnitude of the apparent solubility were found to be significantly higher for amorphous CAR than for crystalline CAR, at 25 °C. However at 37 °C, it was observed that dissolution of the amorphous form did not show a noticeable improvement over pure CAR over the period of 60 min, due to formation of cohesive supercooled liquid state. This observation was supported by enthalpy relaxation study, which indicated increase in enthalpy recovery and structural relaxation of amorphous form towards the supercooled liquid region. This indicated the functional inability of amorphous CAR from stability point of view and suggested the need for elevation of T g. Hence combination of solid dispersion (SD) and surface adsorption techniques was attempted to overcome the functional limitations of amorphous CAR. SD in the ratio of 1:2:2 parts by weight of CAR, PVP (for elevation of T g) and Aerosil ® 200 (as adsorbent) respectively presented dramatic improvement in rate and extent of drug dissolution. During accelerated stability studies with SD 1:2:2 the dissolution characteristics were slightly decreased over the period of 3 months and no crystallization events were observed. Thus, to exploit the functional advantage of amorphous form of low T g drugs, formation of ternary SD system is recommended.