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Ethanol-based solubility-enabling oral drug formulation development: Accounting for the solubility-permeability
1Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.
International Journal of Pharmaceutics
|February 12, 2024
Summary
Developing oral drug formulations with ethanol requires balancing drug solubility and intestinal permeability. Using the minimum effective ethanol concentration maximizes absorption by avoiding unnecessary permeability reduction.
Area of Science:
- Pharmaceutical Sciences
- Drug Delivery Systems
- Formulation Development
Background:
- Ethanol is frequently used in oral drug formulations to enhance the solubility of poorly soluble compounds.
- Understanding the complex interplay between ethanol concentration, drug solubility, and intestinal permeability is crucial for successful formulation design.
- Carbamazepine (CBZ), a BCS class II antiepileptic drug, serves as a model compound to investigate these effects.
Purpose of the Study:
- To investigate the key factors influencing the success of ethanol-based oral drug formulations.
- To evaluate the concentration-dependent effects of ethanol on drug solubility, intestinal permeability, and dissolution.
- To develop a predictive model for the solubility-permeability relationship in ethanol-containing systems.
Main Methods:
- Assessed carbamazepine (CBZ) solubility across varying ethanol concentrations.
- Evaluated in-vitro Caco-2 cell permeability and in-vivo rat perfusion studies with different ethanol levels.
- Conducted biorelevant dissolution studies to determine the minimum ethanol concentration for complete drug dissolution.
- Developed a predictive model incorporating ethanol absorption to describe the solubility-permeability interplay.
Main Results:
- Ethanol significantly increased CBZ solubility in a concentration-dependent manner.
- A concomitant decrease in intestinal permeability (both in-vitro and in-vivo) was observed with increasing ethanol concentrations.
- An excellent agreement between predicted and experimental permeability was achieved when ethanol absorption was considered.
- Minimal ethanol concentrations (30-50%) were sufficient for complete dissolution of low CBZ doses (1-5 mg) without precipitation.
Conclusions:
- Successful development of ethanol-based formulations necessitates careful consideration of drug solubility, permeability, their interplay, and the intended drug dose.
- The optimal strategy involves using only the minimal ethanol amount required to solubilize the drug throughout the gastrointestinal tract.
- This approach aims to mitigate unnecessary permeability loss and maximize overall drug absorption.
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