Interrogating erosion-based drug liberation phenomena from hydrophilic matrices using near infrared (NIR) spectroscopy

Abstract

The present work explores the application of in situ near infrared (NIR) imaging to determine the drug release mechanisms from hydrophilic matrices containing a low solubility model drug (Compound A, with aqueous solubility at 37 °C ∼0.05 mg/mL). Correlation maps generated from the NIR data determined the extent drug and HPMC co-localisation. Judicious thresholding facilitated band separation of low drug/HPMC ratio and high drug/HPMC ratio. A pseudo-image time-series confirmed the dominant erosion release mechanisms. The gel layer region showed low drug concentration with progressive dissolution. However, large drug aggregates remained unchanged even when fully “immersed” within the gel layer. From the correlation maps, further discrimination was possible for the pure drug signal, generating a highly contrasted image that enabled individual particle tracking. These contrasted images also revealed the evolution of single or clusters of drug particles. Initially, an aggregative process involving the drug particles occurred, with a subsequent migration process of such particles. This second process dominated the subsequent 90 min before significant erosion. In summary, this study has provided tentative confirmation that NIR imaging has the potential to afford insights into drug liberation phenomena where erosion is the predominant release mechanism.

Introduction

Achieving reproducible extended release oral drug delivery remains a key goal for many therapeutic areas. Substantial resources have been employed to investigate the reproducible and robust achievement of this goal. One example technology is the hydrophilic matrix, an approach which has been in use since the first patents were filed in the 1960s (Alderman, 1984, Melia, 1991, Li et al., 2005) and has resulted in several marketed products such as Glucophage SR, Morphgesic SR and Phyllocontin Continus.

The hydrophilic matrix tends to be single-unit dosage form, comprising of physical mixtures of drugs and swellable excipients, typically manufactured into tablets by compression (Melia, 1991, Li et al., 2005). The excipients need to be capable of hydrating to form a matrix which (a) is erodible and can release drug by this mechanism and/or (b) forms a polymeric network enabling the drug to be released by diffusion.

There is a wide range of polysaccharides and synthetic and semi-synthetic water-soluble polymers used in such devices and include: (i) xanthan gum (Cox et al., 1999), (ii) sodium alginate (Sriamornsak et al., 2007), (iii) chitosan (Phaechamud and Ritthidej, 2007), (iv) polyethylene oxide (PEO) (Wu et al., 2005) and (v) the ether derivatives of cellulose, including hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose and methylcellulose (MC) (Alderman, 1984, Li et al., 2005, Nair et al., 2007). The modus operandi of such systems is through the formation of a viscous “pseudo-gel” layer upon contact with aqueous fluids, which consequently controls the rate of water ingress and subsequent drug egress (Alderman, 1984, Melia, 1991, Li et al., 2005). As hydration proceeds, extended release is achieved by diffusion through and/or erosion of the expanding “pseudo-gel” layer on the surface of the tablet (Li et al., 2005). Various factors influence the drug release mechanism, including both the drug solubility and the physicochemical properties of the polymer (Fig. 1) (Ford et al., 1991). The drug release from hydrophilic matrices is time-dependent and results from the complex interplay of various factors, owing to the microstructure and macrostructure of HPMC exposed to water (Siepmann and Peppas, 2001).

During the formulation development of hydrophilic matrices, extensive screening of formulation iterations is usually necessary to achieve a desired in vitro dissolution profile. In the industrial context, the USP dissolution test and discernment of drug release kinetics remains the universal tool for development, production and quality control (QC) of oral solid dosage forms. However, the dissolution test does not provide microscopic temporal and spatial information and its use in elucidating the underlying mechanism of drug liberation is limited.

Some work has been carried out to address this issue. At the fundamental molecular level, understanding drug release mechanisms from hydrophilic matrices has been the subject of an extended body of work from both practical and theoretical levels (Bajwa et al., 2006, Ferrero et al., 2008, Pygall et al., 2009). Several important correlations have been established between the tablet hydration and drug release in solution based on hydration kinetic models (Gao and Meury, 1996, Colombo et al., 1999, Bettini et al., 2001). However, such theoretical approaches are often incomplete and may not always facilitate the understanding of the interplay of water-permeation and drug release.

Attempts to understand dosage form performance beyond the dissolution test initially involved the use of ex situ bulk characterisation techniques. Subsequently, the research has been driven towards developing robust in situ methods that are more indicative of the in vitro and in vivo situation. Demands for in situ analysis include (i) non-destructive dosage form testing, (ii) a sampling set-up that does not interfere with the dissolution medium flow, (iii) an ability to obtain data in the presence of dissolution media and (iv) sufficient temporal and spatial resolution. In fact, a critical feature of desirable in situ characterisation is the capability of resolving microscopic phenomena temporally and spatially. Specific to HPMC hydrophilic matrices, various image modalities have been used to investigate and characterise drug release mechanisms such as (i) magnetic resonance imaging (MRI) (Richardson et al., 2005, Zhang et al., 2011), (ii) confocal imaging (Pygall et al., 2007, Williams et al., 2009, Williams et al., 2010), (iii) ultrasound (Konrad et al., 1998), (iv) texture analysis (Jamzad et al., 2005), (v) FTIR spectroscopy imaging (Kazarian and Van der Weerd, 2008) and (vi) Near infrared Imaging (Li et al., 2010, Avalle et al., 2011).

Spectroscopic and microscopic techniques provide surface and internal chemical imaging and observations of the whole dosage form or of individual components on a macro-, micro- or nano-scale. In recent years, there has been a significant rise in interest in the use of spectroscopic techniques to interrogate the behaviour of solid dosage forms. Such spectroscopic methods offer the potential advantages of characterisation on the molecular level coupled with non-invasive, non-destructive component imaging of ingredients and behaviour. Spectroscopic imaging based on terahertz, mid and near-IR and Raman spectroscopy are routinely used to provide information on e.g. tablet composition, drug phase and the distribution of components within a tablet, and are also becoming increasingly used for the in situ investigations of drug release processes (Kazarian and Van der Weerd, 2008). The dependence of vibrational spectroscopy on the chemical properties of the sample allows both facets to be explored in a single measurement. The near infrared (NIR) region has been shown to be a potentially powerful tool in the analysis of controlled release pharmaceutical samples e.g. (Hardy et al., 2007). This offers advantages over terahertz and IR, which are strongly absorbed by water, and also Raman, which is disadvantaged by its typically longer acquisition time and possible interference owing to unwanted fluorescence (Fechner et al., 2005).

The drug release from polymeric matrices occurs predominantly by diffusion in cases the drug possesses good aqueous solubility (Melia, 1991, Li et al., 2005). However, the increasing number of drug candidates with poor aqueous solubility (Lipinski, 2000) that requires dedicated formulation strategies is becoming an increasingly prevalent problem. Achieving controlled release for such molecules is particularly problematic and the hydrophilic matrix with an erosion-based mechanism can provide a simple and elegant methodology. In the case of low solubility drugs the release mechanism occurs predominantly through erosion of the gel layer resulting from the disentanglement and dissolution of individual polymer chains.

This work aims to explore the application of NIR imaging to a hydrating solid oral controlled release dosage form containing a low solubility drug. The work illustrates the procedure for mapping the drug release and water penetration as a function of time and position within the tablet matrix, offering previous unobtainable insights into the mechanistic phenomena underpinning the release.