Effect of drug solubility, polymer, and filler on drug release from modified-release matrix tablets in hydroethanolic media

Abstract

This study aimed to develop strategies to prevent accelerated drug release (alcohol-induced dose dumping) from modified-release matrix tablets in hydroethanolic media. Drugs with different solubility profiles (theophylline, propranolol HCl, paracetamol, and carbamazepine) were formulated with water-soluble or water-insoluble matrix formers, with optional addition of soluble or insoluble fillers. Drug release, medium uptake, and leaching were evaluated in 0.1 N HCl containing 0, 20, or 40% (v/v) ethanol. No release acceleration was observed for theophylline and propranolol HCl, which showed low solubility ratios between hydroethanolic and aqueous media (approximately 2). In contrast, paracetamol and carbamazepine (solubility ratio approximately 20) required formulation adjustments. For paracetamol, comparable release profiles across media were achieved using matrix formers with low medium uptake (e.g., Klucel® MXF or Kollidon® SR) or by incorporating a soluble filler such as lactose. For carbamazepine, the increased solubility in hydroethanolic media shifted the release mechanism from erosion-dominated to diffusion-dominated; similar release profiles were only obtained with hydrophilic polymers exhibiting relatively high erosion rates.

Introduction

Alcohol-induced dose dumping remains an important concern for regulatory agencies and formulation scientists. In view of the risks associated with unintended rapid release after co-administration with alcoholic beverages, the FDA recommends additional in vitro testing of extended-release formulations in media containing 0–40% (v/v) ethanol, and profile similarity is commonly assessed using the f2 factor (FDA, 2022). The clinical relevance of this issue was highlighted in 2005, when markedly increased Cmax values were reported for extended-release hydromorphone capsules administered with ethanol (FDA, 2022). Since then, both commercial and non-commercial modified-release dosage forms have been investigated extensively (Jedinger et al., 2014).

Among oral extended-release systems, matrix tablets based on water-soluble or water-insoluble polymers are particularly common. It was showed that ethanol can accelerate or modify drug release from hydrophilic, lipophilic, and dual–matrix tablets depending on polymer type and formulation design. The study underscores the risk of alcohol–induced dose dumping in certain matrix systems (Rahim et al., 2013). For matrix tablets, hydroethanolic media can affect drug solubility, wettability, swelling, erosion, and mechanical properties (Jedinger et al., 2014). It was demonstrated that hydro–alcoholic media can significantly alter the hydration and gel–layer formation of hypromellose (HPMC) matrix tablets, potentially affecting drug–release performance (Levina et al., 2007).

Because drug diffusion and polymer swelling/erosion occur simultaneously in hydrophilic matrices (Rahim et al., 2013, Levina et al., 2007, Peppas, 1985, Bettini et al., 2001, Colombo et al., 1999, Siepmann et al., 1999, Siepmann and Siepmann, 2008, Peppas and Sahlin, 1989, Tahara et al., 1995, Larsson et al., 2010, Rosiaux et al., 2013), the net ethanol effect is often formulation specific. For example, acetylsalicylic acid release from HPMC K4M tablets was related to increased drug solubility in hydroalcoholic media and possibly to a larger diffusional contribution, whereas tablet swelling was greater in non-ethanolic media (Roberts et al., 2007). In addition, erosion strongly depends on gel strength, which has been reported to increase for swollen HPMC tablets in hydroethanolic media (Missaghi et al., 2009). Previous studies also showed broadly similar release behavior for some combinations of drugs, fillers, and HPMC grades (Levina et al., 2007), while other reports highlighted that soluble lactose may intensify ethanol effects compared with insoluble MCC (Avachat and Nandare, 2014), whereas soluble maltitol can slow release because of its lower solubility in 40% ethanol (Asare-Addo et al., 2013). Comparable questions have been addressed for other hydrophilic polymers: no release acceleration was reported for PEO tablets containing metformin or gliclazide (Palmer et al., 2010) or for HPC-based systems with tramadol (Ong, 2020). The abuse-resistant Guardian® technology issued by Egalet Corp. utilizes injection molding of PEO with morphine sulphate at high temperature and pressure to avoid preliminary drug release and accelerated release (Ahmad et al., 2018).

Theophylline tablets with xanthan gum were also studied with respect to polymer content and particle size; larger particles and lower polymer levels increased release in 40% ethanol, especially in mini-tablets because of the shorter diffusion pathway (Lazzari et al., 2018).

Water-insoluble polymers have been investigated less frequently for modified-release matrix tablets. For ethylcellulose, previous work mainly addressed films and demonstrated increased water permeation and swelling after ethanol addition (Larsson et al., 2010). Ethylcellulose in combination with guar gum was also used as a coating to obtain ethanol-resistant release from theophylline pellets (Rosiaux et al., 2013) and corn starch-codeine phosphate pellets (Jedinger et al., 2016). Likewise, tramadol tablets prepared with Kollidon® SR showed alcohol-resistant release behavior (Traynor et al., 2008, Husár et al., 2019). In such insoluble matrix systems, drug release is generally dominated by diffusion through the hydrated polymer network (Siepmann et al., 2010).

A mechanistic understanding of alcohol-related dose-dumping risks and highlights the need to evaluate ethanol effects during formulation development. It was demonstrated that ethanol affects key biopharmaceutical processes—namely drug solubility, supersaturation, and intestinal absorption. Using a combination of solubility measurements, dissolution experiments, and in silico absorption modelling, it was demonstrated that ethanol can markedly increase the apparent solubility of certain drugs, alter supersaturation profiles, and consequently modify the predicted absorption kinetics. Importantly, the study showed that these ethanol-induced changes are highly drug-dependent and can either enhance or reduce absorption, meaning that alcohol consumption has the potential to compromise the intended performance of controlled-release formulations (Fagerberg et al., 2015).

Taken together, the available literature does not yet provide broadly applicable formulation guidelines because most reports focus on specific drugs or individual formulations. The present study therefore goes beyond drug solubility alone and systematically examines how drug solubility, polymer type/viscosity, and filler properties jointly influence release from modified-release matrix tablets in hydroethanolic media. The specific aim was to identify combinations that are prone to ethanol-induced release changes and to derive practical formulation approaches to minimize or prevent such changes.

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Materials

Carbamazepine, paracetamol, and theophylline were obtained from BASF SE (Ludwigshafen, Germany), and propranolol HCl was obtained from IPCA Laboratories Limited (Mumbai, India). Hydroxypropylcellulose (HPC, Klucel® MXF, Ashland Inc., Wilmington, USA), ethylcellulose (EC, Ethocel® 10 FP), hypromellose (HPMC, Methocel® K100LV CR, K4M CR, and K100M CR; Colorcon Ltd., Dartford, UK), polyethylene oxide (PEO, Sentry Polyox® WSR 303 LEO NF Grade, Dow, Inc., Connecticut, USA), poly(vinyl acetate) and poly(vinyl pyrrolidone) (PVAc/PVP, Kollidon® SR, BASF SE, Ludwigshafen, Germany), poly(ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride) [1:2:0.1] (Eudragit® RS, Evonik Industries AG, Darmstadt, Germany), Patent Blue V (BASF SE, Ludwigshafen, Germany), lactose (Flowlac® 100, Meggle GmbH & Co. KG, Wasserburg am Inn, Germany), magnesium stearate (Baerlocher GmbH, Unterschleissheim, Germany), and ethanol (99.8%, Carl Roth GmbH + Co. KG, Karlsruhe, Germany) were used as received.

Tobias Heinrich, Roland Bodmeier, Andriy Dashevskiy, Effect of drug solubility, polymer, and filler on drug release from modified-release matrix tablets in hydroethanolic media, International Journal of Pharmaceutics, 2026, 126940, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.126940.

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