Evaluation of amorphous solid dispersion properties using thermal analysis techniques

Abstract

Amorphous solid dispersions are an increasingly important formulation approach to improve the dissolution rate and apparent solubility of poorly water soluble compounds. Due to their complex physicochemical properties, there is a need for multi-faceted analytical methods to enable comprehensive characterization, and thermal techniques are widely employed for this purpose. Key parameters of interest that can influence product performance include the glass transition temperature (T_g), molecular mobility of the drug, miscibility between the drug and excipients, and the rate and extent of drug crystallization. It is important to evaluate the type of information pertaining to the aforementioned properties that can be extracted from thermal analytical measurements, in addition to considering any inherent assumptions or limitations of the various analytical approaches. Although differential scanning calorimetry (DSC) is the most widely used thermal analytical technique applied to the characterization of amorphous solid dispersions, there are many established and emerging techniques which have been shown to provide useful information. Comprehensive characterization of fundamental material descriptors will ultimately lead to the formulation of more robust solid dispersion products.

Introduction

Poor aqueous solubility of active pharmaceutical ingredients (API) is an enduring problem in pharmaceutical development and is becoming increasingly more prevalent among new drug candidates[1], [2]. As a result, advanced formulation strategies are of interest in order to improve the dissolution rate and/or apparent solubility of poorly soluble APIs. While there are several available approaches, including salt formation [3], particle size reduction [4], prodrug formation [5], and complexation [6], rendering the drug amorphous is an attractive option [7]. However, this approach is tempered by a number of potentially severe drawbacks. These can include poor chemical and physical stability as well as difficulties in processing the amorphous material. In an attempt to overcome some of these issues, in particular the tendency of amorphous solids to crystallize to a more thermodynamically stable crystalline phase (i.e. the dosage form has poor physical stability), amorphous drugs are typically formulated as solid dispersions whereby the addition of excipients is used to enhance the properties of the formulation. In many respects, the resultant multi-component blends are fundamentally much more complex than formulations containing the crystalline API, and the advanced characterization of such systems is currently an extremely active area of research. The goal of the present review is to establish how thermal analysis techniques can be applied to provide insight into the properties of amorphous materials, with an emphasis on amorphous solid dispersions.

In order to appreciate how thermal analysis can be instrumental in aiding the characterization of amorphous solid dispersions, it is first necessary to briefly describe the terms solid dispersion and amorphous solid dispersion. The term solid dispersion has been applied to a wide variety of formulations where the drug is finely dispersed in an excipient, historically termed a “carrier”. Crystalline solid dispersions are systems in which the crystalline drug is dispersed within a crystalline or semi-crystalline carrier [e.g. polyethylene glycol (PEG), mannitol] forming a eutectic or monotectic mixture[8], [9]. In contrast to crystalline solid dispersions, amorphous solid dispersions contain a carrier which is amorphous rather than crystalline, and these dispersions can be further delineated into amorphous single phase blends, amorphous two phase systems, and crystalline-amorphous two phase dispersions. In amorphous one phase blends (sometimes termed amorphous solid solutions) the drug-carrier interactions are significant, resulting in complete miscibility of the two components, forming a one-phase system which is homogeneous at the molecular level [10], [11]. Two phase blends (sometimes termed solid suspensions), on the other hand, occur when the drug has limited miscibility in the carrier and undergoes phase separation [7], [9]. These systems consist of two phases, either two amorphous phases of different composition, or a fine dispersion of crystalline drug particles in an amorphous matrix. For a more comprehensive descriptions of these various types of systems, the readers are encouraged to read the classic review of Chiou and Riegelman [9] as well as the review by Vasconcelos et al [7]. In recent years, there has been intense interest in using amorphous solid dispersions to deliver poorly water soluble drugs, and it is this type of solid dispersion that will be the focus of this review. Amorphous solid dispersions are typically produced commercially either through spray drying of an organic solution of the formulation, or by melt extrusion of a powder blend. The desired end state is an amorphous form of the drug with improved dissolution characteristics relative to its crystalline counterpart, and which is physically stable over the shelf life of the product. In order to achieve physical stability, pharmaceutically acceptable polymers are normally incorporated into the formulation, usually at high concentrations (of the order of 50% by weight or higher). Thus most of the research carried out on amorphous solid dispersions using thermal analysis techniques aims to characterize the amorphous properties of the solid dispersion, as well as the crystallization behavior of the API. These topics are therefore addressed in this review.