Formulation Optimization for Gastroretentive Drug Delivery System of Carvedilol Cocrystals Using Design of Experiment

Gasper J. Fernandes, Mahalaxmi Rathnanand

Research output: Contribution to journalArticle

Abstract

Objectives: The objective of this study was to develop a gastroretentive dosage form (GRDF) of carvedilol cocrystals that were prepared utilizing hot-melt extrusion (HME) in order to prolong its gastric residence time. GRDF was optimized using Box-Behnken Design. Methods: The carvedilol nicotinamide cocrystals prepared in the ratio of 1:2 (drug:coformer) utilizing hot-melt extrusion (Omega10). The tablets were prepared by direct compression using cocrystals along with remaining excipients that include HPMC K4M, HPMC E50, Carbopol 934P, sodium bicarbonate, microcrystalline cellulose, talc, and magnesium stearate. Concentrations of HPMC E50, HPMC K4M, and Carbopol 934P were selected as independent factors while the gastroretentive parameters such as floating lag time (FLT), percentage of drug release in 2 h, and percentage of cumulative drug release in 12 h were selected as dependent variables in optimizing GRDF of carvedilol cocrystals. Test such as total floating time (TFT), floating lag time (FLT), swelling studies, dissolution studies, and precompression parameters such as bulk density (BD), tapped density (TD), compressibility index (CI), Hausner’s ratio (HR), and angle of repose were carried out on the optimized formulation. Results: The optimized tablets (F2) prepared by direct compression showed FLT of 11 s after placing the tablets in 0.1 N HCl (pH 1.2) with controlled drug release for 12 h where the mechanism of drug release was found to be Non-Fickian type of diffusion (swelling, erosion, and diffusion). The in vitro drug release profile of the optimized formulation (F2) was found to be 81.4% at 12 h in comparison with a formulation containing only carvedilol (65.55% drug release at 12 h). Conclusion: The study concluded that the cocrystals of carvedilol that were successfully prepared by HME could be used to prepare and optimize the floating tablets to achieve desired gastroretentive performance with good drug release profile for carvedilol. The results of the comparison of drug release profile between optimized formulation and formulation containing pure drug stressed the importance of preparing cocrystals. The formulation scientist in the future may adopt these strategies in developing GRDF for cocrystals of any drug.

Original languageEnglish
JournalJournal of Pharmaceutical Innovation
DOIs
Publication statusAccepted/In press - 01-01-2019

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Drug Delivery Systems
Dosage Forms
Tablets
Pharmaceutical Preparations
Talc
Sodium Bicarbonate
Niacinamide
Drug Liberation
carvedilol
Excipients
Stomach

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science
  • Drug Discovery

Cite this

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title = "Formulation Optimization for Gastroretentive Drug Delivery System of Carvedilol Cocrystals Using Design of Experiment",
abstract = "Objectives: The objective of this study was to develop a gastroretentive dosage form (GRDF) of carvedilol cocrystals that were prepared utilizing hot-melt extrusion (HME) in order to prolong its gastric residence time. GRDF was optimized using Box-Behnken Design. Methods: The carvedilol nicotinamide cocrystals prepared in the ratio of 1:2 (drug:coformer) utilizing hot-melt extrusion (Omega10). The tablets were prepared by direct compression using cocrystals along with remaining excipients that include HPMC K4M, HPMC E50, Carbopol 934P, sodium bicarbonate, microcrystalline cellulose, talc, and magnesium stearate. Concentrations of HPMC E50, HPMC K4M, and Carbopol 934P were selected as independent factors while the gastroretentive parameters such as floating lag time (FLT), percentage of drug release in 2 h, and percentage of cumulative drug release in 12 h were selected as dependent variables in optimizing GRDF of carvedilol cocrystals. Test such as total floating time (TFT), floating lag time (FLT), swelling studies, dissolution studies, and precompression parameters such as bulk density (BD), tapped density (TD), compressibility index (CI), Hausner’s ratio (HR), and angle of repose were carried out on the optimized formulation. Results: The optimized tablets (F2) prepared by direct compression showed FLT of 11 s after placing the tablets in 0.1 N HCl (pH 1.2) with controlled drug release for 12 h where the mechanism of drug release was found to be Non-Fickian type of diffusion (swelling, erosion, and diffusion). The in vitro drug release profile of the optimized formulation (F2) was found to be 81.4{\%} at 12 h in comparison with a formulation containing only carvedilol (65.55{\%} drug release at 12 h). Conclusion: The study concluded that the cocrystals of carvedilol that were successfully prepared by HME could be used to prepare and optimize the floating tablets to achieve desired gastroretentive performance with good drug release profile for carvedilol. The results of the comparison of drug release profile between optimized formulation and formulation containing pure drug stressed the importance of preparing cocrystals. The formulation scientist in the future may adopt these strategies in developing GRDF for cocrystals of any drug.",
author = "Fernandes, {Gasper J.} and Mahalaxmi Rathnanand",
year = "2019",
month = "1",
day = "1",
doi = "10.1007/s12247-019-09393-5",
language = "English",
journal = "Journal of Pharmaceutical Innovation",
issn = "1872-5120",
publisher = "Springer New York",

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AU - Fernandes, Gasper J.

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Y1 - 2019/1/1

N2 - Objectives: The objective of this study was to develop a gastroretentive dosage form (GRDF) of carvedilol cocrystals that were prepared utilizing hot-melt extrusion (HME) in order to prolong its gastric residence time. GRDF was optimized using Box-Behnken Design. Methods: The carvedilol nicotinamide cocrystals prepared in the ratio of 1:2 (drug:coformer) utilizing hot-melt extrusion (Omega10). The tablets were prepared by direct compression using cocrystals along with remaining excipients that include HPMC K4M, HPMC E50, Carbopol 934P, sodium bicarbonate, microcrystalline cellulose, talc, and magnesium stearate. Concentrations of HPMC E50, HPMC K4M, and Carbopol 934P were selected as independent factors while the gastroretentive parameters such as floating lag time (FLT), percentage of drug release in 2 h, and percentage of cumulative drug release in 12 h were selected as dependent variables in optimizing GRDF of carvedilol cocrystals. Test such as total floating time (TFT), floating lag time (FLT), swelling studies, dissolution studies, and precompression parameters such as bulk density (BD), tapped density (TD), compressibility index (CI), Hausner’s ratio (HR), and angle of repose were carried out on the optimized formulation. Results: The optimized tablets (F2) prepared by direct compression showed FLT of 11 s after placing the tablets in 0.1 N HCl (pH 1.2) with controlled drug release for 12 h where the mechanism of drug release was found to be Non-Fickian type of diffusion (swelling, erosion, and diffusion). The in vitro drug release profile of the optimized formulation (F2) was found to be 81.4% at 12 h in comparison with a formulation containing only carvedilol (65.55% drug release at 12 h). Conclusion: The study concluded that the cocrystals of carvedilol that were successfully prepared by HME could be used to prepare and optimize the floating tablets to achieve desired gastroretentive performance with good drug release profile for carvedilol. The results of the comparison of drug release profile between optimized formulation and formulation containing pure drug stressed the importance of preparing cocrystals. The formulation scientist in the future may adopt these strategies in developing GRDF for cocrystals of any drug.

AB - Objectives: The objective of this study was to develop a gastroretentive dosage form (GRDF) of carvedilol cocrystals that were prepared utilizing hot-melt extrusion (HME) in order to prolong its gastric residence time. GRDF was optimized using Box-Behnken Design. Methods: The carvedilol nicotinamide cocrystals prepared in the ratio of 1:2 (drug:coformer) utilizing hot-melt extrusion (Omega10). The tablets were prepared by direct compression using cocrystals along with remaining excipients that include HPMC K4M, HPMC E50, Carbopol 934P, sodium bicarbonate, microcrystalline cellulose, talc, and magnesium stearate. Concentrations of HPMC E50, HPMC K4M, and Carbopol 934P were selected as independent factors while the gastroretentive parameters such as floating lag time (FLT), percentage of drug release in 2 h, and percentage of cumulative drug release in 12 h were selected as dependent variables in optimizing GRDF of carvedilol cocrystals. Test such as total floating time (TFT), floating lag time (FLT), swelling studies, dissolution studies, and precompression parameters such as bulk density (BD), tapped density (TD), compressibility index (CI), Hausner’s ratio (HR), and angle of repose were carried out on the optimized formulation. Results: The optimized tablets (F2) prepared by direct compression showed FLT of 11 s after placing the tablets in 0.1 N HCl (pH 1.2) with controlled drug release for 12 h where the mechanism of drug release was found to be Non-Fickian type of diffusion (swelling, erosion, and diffusion). The in vitro drug release profile of the optimized formulation (F2) was found to be 81.4% at 12 h in comparison with a formulation containing only carvedilol (65.55% drug release at 12 h). Conclusion: The study concluded that the cocrystals of carvedilol that were successfully prepared by HME could be used to prepare and optimize the floating tablets to achieve desired gastroretentive performance with good drug release profile for carvedilol. The results of the comparison of drug release profile between optimized formulation and formulation containing pure drug stressed the importance of preparing cocrystals. The formulation scientist in the future may adopt these strategies in developing GRDF for cocrystals of any drug.

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