Drug release from magnesium aluminium silicate-polyethylene oxide (PEO) nanocomposite matrices: An investigation using the USP III apparatus

https://doi.org/10.1016/j.ejps.2020.105474Get rights and content

Highlights

  • ITC results show binding between DILT and PEO was enthalpy and entropy driven.

  • Binding between veegum and DILT in the presence of PEO shown to be enthalpy driven and entropically unfavourable.

  • ITC results successfully explain drug release from veegum-PEO matrices.

  • USP III used to successfully simulate fed and fasted states with matrices robust in up to 0.2 M ionic strength.

Abstract

This work investigated the use of the USP III apparatus in discriminating simulated fed and fasted conditions as well as ionic strength on veegum-polyethylene (PEO) (called clay-PEO matrices hereafter) matrices. The successful formulations were characterised using differential scanning calorimetry (DSC) and evaluated for their physical properties. Isothermal calorimetry (ITC) was used to evaluate the thermodynamics of the complexation processes. The effect of agitation sequences on the matrices as evaluated from the USP III suggested an increase in polymer content to significantly decrease the burst release experienced using diltiazem hydrochloride (DILT) as a model cationic drug. The manufacturing methods showed superior performance in relation to a decrease in burst release over the physical manufactured counterparts. The clay-PEO matrices also showed robustness (no matrix failure) in up to 0.2 M ionic strength solutions mimicking the upper limit experienced in the GI tract. ITC results revealed that the binding between DILT and PEO was enthalpy and entropy-driven. Furthermore, the binding between veegum and DILT in the presence of PEO was shown to be enthalpy-driven and entropically unfavourable, which was also the case for the binding between veegum and PEO thus giving insights to how the matrices were performing on a molecular level.

Introduction

Polyethylene oxide (PEO) (Fig. 1a) is a synthetic polymer obtained commercially upon the catalytic polymerisation of ethylene oxide. It has the same chemical structure as polyethylene glycol (PEG) but a higher molecular weight, usually over 100,000. PEO is also soluble in a wide variety of solvents (ethanol, acetone, toluene, chloroform) and in water. When dissolved in water, PEO tablets hydrate, swell and form a gel layer outside the dry core. As with hydrophilic matrices, this gel layer controls the release of an active pharmaceutical ingredient (API) as the polymeric chains unfold and disentangle in the dissolution medium (Ward et al., 2019; Nokhodchi et al., 2012; Ma et al., 2014). Its physicochemical properties such as rapid hydration and high water solubility, non-toxicity, pH insensitivity to physiological fluids and easy manufacturability make PEO an attractive polymer and as such it is widely used in the formulation of controlled drug release systems (Ma et al., 2014; Kim et al., 1995; Maggi et al., 2002; Shojaee et al., 2013a, b, 2015; Kaialy et al., 2016). Palmer et al. (2013) used PEO in combination with other matrix-forming polymers such as sodium carboxymethylcellulose (NaCMC), to control the release of chlorpheniramine maleate, venlafaxine hydrochloride, propranolol hydrochloride and verapamil hydrochloride (Palmer et al., 2013). The authors found that a synergistic interaction between PEO and NaCMC in the tablets significantly slowed drug release when compared to the tablets containing a single polymer component (PEO or NaCMC) (Palmer et al., 2013; Nokhodchi et al., 2015).

Veegum also known as magnesium aluminium silicate (MAS) (Fig. 1b and c) is a mixture of natural smectite montmorillonite and saponite clays. Veegum has a layered silicate structure, formed of one alumina or magnesia octahedral sheet, sandwiched between two tetrahedral silicate sheets (Vanderbilt 2014a, b; Kanjanakawinkul et al., 2013; Totea et al., 2020). MAS has become a material for the use in drug formulation due to its high surface area and good affinity with cationic drugs which has been well documented and exploited (Rojtanatanya and Pongjanyakul, 2010; Pongjanyakul and Rojtanatanya, 2012Adebisi et al., 2015; Okeke and Boateng, 2016, 2017; Totea et al., 2019). Several polymers including quaternary polymethacrylates, chitosan and alginate have also been successfully crosslinked with veegum to produce coatings, films or matrices for the successful delivery of drugs (Rongthong et al., 2013, 2020; Khuathan and Ponjanyakul, 2014, 2016; Khlibsuwan et al., 2017). Pappa et al. reported the intercalation of PEO between nanolayers of sodium montmorillonite to formulate nanostructured composites, intended for the dissolution modulation of aprepitant. The authors found the PEO and clay nanocomposites were highly effective as drug carriers for sustained release (Pappa et al., 2018).

Diltiazem hydrochloride (DILT) (Fig. 1d) is a non-dihydropyridine calcium channel blocker with molecular weight and pKa of 450.98 g/mol and 7.8 respectively. DILT inhibits the calcium channels in the blood vessels which leads to vasodilatation and, hence lower blood pressure (Padial et al., 2016). DILT has an elimination half-life of 3.2 ± 1.3 h following oral administration with a bioavailability of 42 ± 18% following first-pass metabolism (Hermann et al., 1983) therefore making it an ideal candidate for extended release (Qazi et al., 2013; Li et al., 2016) hence its use as the model cationic drug.

Although multiple studies have reported the efficient use of PEO as an excipient in the formulation of controlled release systems on its own or in combination with other polymers or materials such as clay, the effect of the polymer on the clay adsorption capacity has not been previously explored at a molecular level. This experiment therefore aims to understand the interactions between the model drug DILT, PEO and veegum at the molecular level and how the interaction can potentially impact on the drug release from the clay-PEO matrices. This is primarily investigated using isothermal calorimetry (ITC). Secondly, a more biorelevant dissolution methodology (USP III) is utilised in conducting the dissolution studies using a range of dip per minute (dpm) as well as dpm in ascending and descending order as reported elsewhwere (Asare-Addo et al., 2013a and b) to mimic the potential effect of food as well as ionic strength on DILT release from the manufactured matrices. To the best of the author's knowledge, this is the first of such a study. Hence, the information reported in this study will allow a formulator to draw conclusions on parameters that may need to be manipulated in order to improve drug release modulation.

Section snippets

Materials

The hydrophilic matrix tablets were prepared using DILT as the model drug. DILT was purchased from TCI chemicals, UK. The PEO (Polyox WSR 301, with a molecular 4000,000) polymer was a kind gift from Colorcon, Ltd, UK. Veegum F was a kind gift from Lake Chemical UK. The dissolution media used was prepared according to the USP 2003 method of preparing buffers using potassium chloride (Acros Organic, UK), hydrochloric acid (Fisher Scientific, UK) for pH 1.2 and 2.2, and potassium phosphate

Solid-state properties and physical properties of the starting materials and formulated blends

The DSC thermograph of the pure drug DILT exhibited a sharp endothermic melting peak at ~ 209 °C (Table 3). Prasad et al. (2013), however, reported the melting peak of DILT to be around ~ 215 °C. This difference may have to do with the manufacturing and purity of the drug as they were sourced from different suppliers. The veegum exhibited a broad endothermic peak at ~ 70 °C, which was attributed to the dehydration of free water residues within the clay (Fig. 3a) which has also reported

Conclusions

Veegum-PEO matrices were successfully manufactured using different manufacturing techniques. The effect of agitation sequences on the matrices suggested an increase in polymer content to significantly decrease the burst release experienced using diltiazem hydrochloride as a model cationic drug. The manufacturing methods showed superior performance in relation to a decrease in burst release over the physical manufactured counterparts. The veegum-PEO matrices also showed resilience or robustness

CRediT authorship contribution statement

Kofi Asare-Addo: Conceptualization, Writing - original draft, Writing - review & editing, Data curation. Ana-Maria Totea: Data curation, Formal analysis, Methodology, Investigation. Ali Nokhodchi: Conceptualization, Data curation, Methodology, Investigation, Writing - review & editing.

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgements

The authors are grateful to the Universities of Huddersfield and Sussex for funding. The authors also thank Laura Waters of the University of Huddersfield, Irina Dorin formerly of Malvern Panalytical, UK and Juan Sabin of AFFINImeter, Spain for useful discussions and help with the ITC experiments.

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