Investigation of drug–polymer interaction in solid dispersions by vapour sorption methods

Abstract

The objective of this study was to investigate the effect of different polymeric carriers in solid dispersions with an active pharmaceutical ingredient (API) on their water vapour sorption equilibria and the influence of the API–polymer interactions on the dissolution rate of the API. X-ray diffraction, scanning electron microscopy (SEM), moisture sorption analysis, infrared (IR) spectroscopy and dissolution tests were performed on various API–polymer systems (Valsartan as API with Soluplus, PVP and Eudragit polymers) after production of amorphous solid dispersions by spray drying. The interactions between the API and polymer molecules caused the water sorption isotherms of solid dispersions to deviate from those of ideal mixtures. The moisture sorption isotherms were lower in comparison with the isotherms of physical mixtures in all combinations with Soluplus and PVP. In contrast, the moisture sorption isotherms of solid dispersions containing Eudragit were significantly higher than the corresponding physical mixtures. The nature of the API–polymer interaction was explained by shifts in the characteristic bands of the IR spectra of the solid dispersions compared to the pure components. A correlation between the dissolution rate and the water sorption properties of the API–polymer systems has been established.

Introduction

A significant portion of recently developed pharmaceutical molecules suffer from poor solubility and consequently low bioavailability, i.e., they belong to the biopharmaceutics classification system (BCS) class II. A popular approach to increase the rate of dissolution and thus improve the drug bioavailability is to prepare dispersions of the active pharmaceutical ingredient (API) in water-soluble polymers. The dissolution rate of a solid dispersion is enhanced due to the formation of high-energy metastable forms of the API, including amorphous form. The small particle size and better wettability of the drug–polymer solid dispersion are also important reasons that contribute to the observed improvements in bioavailability (Alam et al., 2012, Craig, 2002, Serajuddin, 1999). The wettability improvement in a solid dispersion is related to the enhancement of drug solubility. Poorly soluble drugs are generally also hydrophobic. Improving of wetting properties due to the presence of a hydrophilic polymer may lead to enhancing the diffusion of water to the solid powder and consequently to increased dissolution rate (Craig and Newton, 1992, Frizon et al., 2013).

In a solid dispersion, the API and the polymer may interact by a number of mechanisms, including hydrogen bonds (Taylor et al., 2001). The formation of hydrogen bonds between the drug and the polymer can lead to their higher miscibility and effectively improves the physical stability of the solid dispersion. However, the intermolecular interactions may also cause changes in the orientations of the molecules, the angles in functional groups or the number of available hydrogen bond donors and acceptors (Reed et al., 1988).

Water vapour sorption is an established method, used to study the affinity of powders and their physical mixtures towards water. A water sorption isotherm reflects the interaction between a powder material and water by relating the humidity of air in equilibrium with water content of the solid material at a constant temperature and pressure (Chang et al., 1997). The water sorption isotherm of binary physical mixtures can be predicted by assuming additivity of the individual component isotherms. Assuming that there is no interaction between the components, the moisture isotherm of a binary mixture can be calculated using the equation:

$$W_{\text{mixture}}=\frac{{(W}_{\text{API}}·m_{\text{API}}+W_{\text{polymer}}·m_{\text{polymer}})}{(m_{\text{API}}+m_{\text{polymer}})}$$

where W is the mass of absorbed water per dry mass of solid and m is the component mass in the mixture (Crowley and Zografi, 2002, Kachel et al., 2013, Sanzgiri et al., 2003). On the other hand, if the API and the polymer interact with each other, a deviation from the ideal behaviour implied by Eq. (1) would be observed and the extent of the deviation can be regarded as a measure of the strength of the API–polymer interaction.

Water sorption into a solid dispersion has been predicted by the additivity of the individual component isotherms in (Crowley and Zografi, 2002). The findings indicate that interactions through hydrogen bonding between two components in an amorphous dispersion form do not significantly affect the interaction between each component and water (Zhang and Zografi, 2001). Contrary to that study, amorphous sugar–protein dispersions revealed an influence of intermolecular interactions in the dispersion and a deviation from the additivity of water sorption isotherms of the individual components has been observed (Constantino et al., 1998, Shamblin et al., 1998).

The goal of the present study was to investigate the use of water sorption method for the evaluation of the ability of different polymers to influence the water affinity of solid dispersions of an API, to probe the extent of API–polymer interaction and to relate these interactions to the dissolution rate of the API. The extent of the API–polymer interaction in a solid dispersion was studied using infrared (IR) spectroscopy as a technique sensitive to changes in the local chemical environment (Koleva, 2005, Rumondor, 2009, Taylor, 1997). By correlating water sorption data with dissolution rate constants evaluated from dissolution curves, the possible applicability of dynamic vapour sorption as a screening method for assessing the suitability of different polymer matrices for solid dispersions of poorly soluble APIs has been investigated.