Alcohol dose dumping: The influence of ethanol on hot-melt extruded pellets comprising solid lipids.
The objective of the present study was to investigate interactions between alcohol and hot-melt extruded pellets and the resulting drug release behavior. The pellets were composed of vegetable calcium stearate as matrix carrier and paracetamol or codeine phosphate as model drugs. Two solid lipids (Compritol® and Precirol®) were incorporated into the matrix to form robust/compact pellets. The drug release characteristics were a strong function of the API solubility, the addition of solid lipids, the dissolution media composition (i.e., alcohol concentration) and correspondingly, the pellet wettability. Pellets comprising paracetamol, which is highly soluble in ethanol, showed alcohol dose dumping regardless of the matrix composition. The wettability increased with increasing ethanol concentrations due to higher paracetamol solubilities yielding increased dissolution rates. For pellets containing codeine phosphate, which has a lower solubility in ethanol than in acidic media, the wettability was a function of the matrix composition. Dose dumping occurred for formulations comprising solid lipids as they showed increased wettabilities with increasing ethanol concentrations. In contrast, pellets comprising calcium stearate as single matrix component showed robustness in alcoholic media due to wettabilities that were not affected by the addition of ethanol. The results clearly indicate that the physico-chemical properties of the drug and the matrix systems are crucial for the design of ethanol-resistant dosage forms. Moreover, hydrophobic calcium stearate can be considered a suitable matrix system that minimizes the risk of ethanol-induced dose dumping for certain API's.
Research Center Pharmaceutical Engineering, Graz, Austria.
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Jedinger
Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology, University of Graz, Graz, Austria.
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Schrank
Research Center Pharmaceutical Engineering, Graz, Austria.
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Mohr
Research Center Pharmaceutical Engineering, Graz, Austria.
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Feichtinger
Research Center Pharmaceutical Engineering, Graz, Austria; Institute for Process and Particle Engineering, Graz University of Technology, Graz, Austria.
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Khinast
Research Center Pharmaceutical Engineering, Graz, Austria; Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology, University of Graz, Graz, Austria. Electronic address: eva.roblegg@uni-graz.at.
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Roblegg
D000082:Acetaminophen / Q000008:administration & dosage* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003061:Codeine / Q000008:administration & dosage* / Q000737:chemistry; D004075:Diglycerides / Q000737:chemistry; D004339:Drug Compounding / Q000379:methods; D065546:Drug Liberation; D000431:Ethanol / Q000737:chemistry*; D005227:Fatty Acids / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D008055:Lipids / Q000737:chemistry*; D012995:Solubility; D013229:Stearic Acids / Q000737:chemistry; D017155:Wettability
D004075:Diglycerides; D005227:Fatty Acids; D008055:Lipids; D013229:Stearic Acids; C086409:glyceryl behenate; D000082:Acetaminophen; D000431:Ethanol; C031183:stearic acid; C009032:precirol; D003061:Codeine
Alcohol dose dumping; Calcium stearate; Controlled-release; Hot-melt extrusion; Solid lipids