Development, characterization and stabilization of amorphous form of a low T g drug Varsha B. Pokharkar, Leenata P. Mandpe, Mahesh N. Padamwar, Anshuman A. Ambike, Kakasaheb R. Mahadik, Anant Paradkar ⁎ Department of Pharmaceutics, Bharati Vidyapeeth Deemed University, Poona College of Pharmacy, Erandwane, Pune-411 038, Maharashtra, India Received 22 May 2005; received in revised form 4 January 2006; accepted 30 May 2006 Available online 21 July 2006 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. © 2006 Elsevier B.V. All rights reserved. Keywords: Carvedilol; Amorphous; Enthalpy relaxation; Solid dispersion; Stability 1. Introduction Most of the drug candidates entering the pharmaceutical development process are in their highly pure and thermody- namically stable crystalline state, wherein the molecules have regular and well-defined molecular packing. However, it has also been recognized that upon isolation the material may be obtained in a fully or partially amorphous state, which exhibits short-range order over a few molecular dimensions and possesses physical properties quite different from those of their corresponding crystalline state [1]. Intentional solid state modification (crystalline to amorphous) can be a viable and promising approach for enhancing drug dissolution and in turn bioavailability [2,3]. However, the high internal energy and specific volume of amorphous state relative to crystalline state can create a possibility that during processing (mechanical stress) or storage (temperature and humidity stress) the amorphous state may undergo devitrification. Hence, exploita- tion of full potential of amorphous solids requires their stabilization in solid state as well as during performance. The common techniques for producing an amorphous state are quench-cooling of a melt (laboratory scale) and spray drying (large-scale). Even though the former technique yields an amorphous product, which is brittle in nature and poses handling difficulties during further processing. This is the only available technique to produce the amorphous form of drugs with relatively lower glass transition temperature (T g ) [4]. Powder Technology 167 (2006) 20 – 25 www.elsevier.com/locate/powtec ⁎ Corresponding author. Tel.: +91 20 25437237; fax: +91 20 25439383. E-mail addresses: vbpokharkar@rediffmail.com (V.B. Pokharkar), arparadkar@rediffmail.com (A. Paradkar). 0032-5910/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2006.05.012