An investigation into the crystallization tendency/kinetics of amorphous active pharmaceutical ingredients: A case study with dipyridamole and cinnarizine Shrawan Baghel a,⇑ , Helen Cathcart a , Wynette Redington b , Niall J. O’Reilly a a Pharmaceutical and Molecular Biotechnology Research Centre (PMBRC), Waterford Institute of Technology, Cork Road, Waterford, Ireland b Materials and Surface Science Institute, University of Limerick, Castletroy, Co. Limerick, Ireland article info Article history: Received 16 February 2016 Revised 6 April 2016 Accepted in revised form 20 April 2016 Available online 21 April 2016 Keywords: Amorphous Fragility Glass forming ability Molecular mobility Mean relaxation time Crystallization kinetics Stability abstract Amorphous drug formulations have great potential to enhance solubility and thus bioavailability of BCS class II drugs. However, the higher free energy and molecular mobility of the amorphous form drive them towards the crystalline state which makes them unstable. Accurate determination of the crystallization tendency/kinetics is the key to the successful design and development of such systems. In this study, dipyridamole (DPM) and cinnarizine (CNZ) have been selected as model compounds. Thermodynamic fragility (m T ) was measured from the heat capacity change at the glass transition temperature (T g ) whereas dynamic fragility (m D ) was evaluated using methods based on extrapolation of configurational entropy to zero ðm D CE Þ, and heating rate dependence of T g ðm D Tg Þ . The mean relaxation time of amorphous drugs was calculated from the Vogel–Tammann–Fulcher (VTF) equation. Furthermore, the correlation between fragility and glass forming ability (GFA) of the model drugs has been established and the relevance of these parameters to crystallization of amorphous drugs is also assessed. Moreover, the crystallization kinetics of model drugs under isothermal conditions has been studied using Johnson– Mehl–Avrami (JMA) approach to determine the Avrami constant ‘n’ which provides an insight into the mechanism of crystallization. To further probe into the crystallization mechanism, the non-isothermal crystallization kinetics of model systems were also analysed by statistically fitting the crystallization data to 15 different kinetic models and the relevance of model-free kinetic approach has been established. The crystallization mechanism for DPM and CNZ at each extent of transformation has been predicted. The calculated fragility, glass forming ability (GFA) and crystallization kinetics are found to be in good corre- lation with the stability prediction of amorphous solid dispersions. Thus, this research work involves a multidisciplinary approach to establish fragility, GFA and crystallization kinetics as stability predictors for amorphous drug formulations. Ó 2016 Elsevier B.V. All rights reserved. 1. Introduction The solid state is preferred for drug formulations due to reasons of stability and ease of handling at different stages of drug product manufacture. The majority of drugs can exist in different solid- state forms such as amorphous or crystalline (hydrates, solvates and polymorphs) or both [1]. The amorphous form has the advan- tage of a higher apparent aqueous solubility compared to their crystalline counterpart [2]. However, inherently lower physical and chemical stability poses challenges in view of product performance and efficacy [3]. Phase transitions such as conversion of amorphous to crystalline forms are thermodynamically and kinetically driven by higher free energy and molecular mobility, respectively [4]. Given the increasing importance being attached to the stability of amorphous drug products during unit operations such as spray drying and melt extrusion (non-ambient conditions) or upon normal storage (where the conditions remain more or less constant), a robust crystallization prediction protocol may facili- tate the prompt development of amorphous drug formulations with better life expectancy [5]. Crystallization tendency describes the properties related to crystallization behaviour of amorphous drugs. Different factors such as chemical structure, molecular weight, number of aromatic rings, symmetry of the structure, number of rotatable bonds, pres- ence of intermolecular interactions, number of electronegative atoms and number of branches have been suggested to affect crys- tallization tendency [6]. In addition, physicochemical properties such as glass transition and melting temperature, melting and http://dx.doi.org/10.1016/j.ejpb.2016.04.017 0939-6411/Ó 2016 Elsevier B.V. All rights reserved. ⇑ Corresponding author. E-mail address: 20065131@mail.wit.ie (S. Baghel). European Journal of Pharmaceutics and Biopharmaceutics 104 (2016) 59–71 Contents lists available at ScienceDirect European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb