Mechanistic insights into the influence of aqueous ethanolic media on the permeability of HPMC phthalate-based isolated films

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Abstract
Alcohol-induced dose dumping is a significant concern for modified-release oral dosage forms, as it can compromise the intended release behaviour. For enteric-coated formulations, alcohol exposure may lead to loss of enteric functionality and unintended premature drug release in the stomach. Although previous studies have mainly assessed the loss of enteric performance in delayed-release dosage forms, the mechanisms underlying alcohol-induced changes remain poorly understood. In this study, the behaviour of isolated hydroxypropyl methylcellulose phthalate (HPMC-P) films was investigated in aqueous ethanolic media containing 0-40% v/v ethanol. Film permeability was evaluated using paracetamol, nicotinamide and tritiated water as model permeants. No significant change in permeability was observed at ethanol concentrations up to 20% v/v. However, exposure to 40% v/v ethanol significantly increased permeability. Under these conditions, permeability differences between paracetamol (4.4±0.6 E-05 cm/s) and nicotinamide (2.4±0.3 E-05 cm/s) were observed and were initially attributed to differences in drug solubility in hydroalcoholic medium. However, studies with tritiated water eliminated solubility-related effects and provided direct evidence of ethanol-induced changes in film permeability. Microscopic imaging revealed ethanol concentration dependent pore formation within the films. Mass loss study showed negligible film erosion even at 40% v/v ethanol, despite the substantial increase in permeability. These findings demonstrate that increased film permeability originates primarily from ethanol-induced microstructural changes rather than polymer erosion. Overall, this work provides mechanistic insights into the effects of ethanol exposure on HPMC-P films and improves understanding of alcohol-induced alterations in enteric-coated formulations.

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