(644b) Comparative Evaluation of Dissolution Behavior and Bioequivalence of Various Capsules

Two-piece hard capsules continuously serve as widely used oral drug and dietary supplement dosage forms. Hard gelatin capsules are used in 20% of all oral dosage forms but have numerous shortcomings especially with potential crosslinking with the active ingredient, the growing consumer preference for non-animal products and concerns about bovine spongiform encephalopathy (BSE or mad cow disease). The most common polymer used to replace gelatin in hard capsules is hydroxypropyl methylcellulose (HPMC) or hypromellose. In this study, Propranolol HCl was used to evaluate dissolution behavior and bioequivalence of various capsules especially between gelatin and various types of HPMC capsules.

DuPont’s FloVitro ^TM technology is a flow through approach utilizing a series of solid transfer cells which incorporates drug pharmacokinetic characteristics to simulate a biomimetic system. It is a biorelevant in vitro test that reflects physiological environment in the test conditions with a purpose of correlating in vitro drug release with in vivo drug absorption. FloVitro ^TM has the unique ability to generate dissolution curves that match plasma profiles directly without the need for mathematical modeling. This study will use Modified USPII and FloVitro ^TM technology to study dissolution behavior of Propranolol HCl in various commercial gelatin and HPMC capsules.

Using USP II method, there was approximately 5 to 6 min delayed release of Propranolol HCl from HPMC capsules without gelling agent, and approximately 2 to 23 min delayed release of Propranolol HCl from HPMC capsules with gelling agent. Using FloVitro ^TM technology, it was found that the key pharmacokinetic parameters, C_max and T_max, of HPMC capsules without gelling agent were not statistically different to that of gelatin capsules. Additionally, HPMC capsules without gelling agent showed more consistent dissolution performance (less coefficient of variation) than that of HPMC capsules with gelling agents (see Table 1).

In summary, dissolution of an active in the dosage form is critical for absorption and bioavailability, and for product quality and consistency assessments during drug product life cycle. It was found that the key pharmacokinetic parameters, C_max and T_max, of HPMC capsules without gelling agent were not statistically different to that of gelatin capsules using FloVitro ^TM technology. Using DuPont’s FloVitro ^TM technology, pharmaceutical scientists can relatively quickly assess biorelevant information on specific APIs and dosage forms. The prediction of in vivo performance of Propranolol HCl in various commercial gelatin and HPMC capsules will help formulation scientists gaining insights on key factors that impact the drug efficacy and safety in the patients.

Acknowledgement

We would like to thank Alejandro Carbo, Jonathan Gilinski of CapsCanada for their discussion and support of this report.

References

1. AAPS 2008 Poster Presentation: Exploring Suitability and Feasibility of a Novel In Vitro Dissolution System A. Selen, L. F. Buhse, E. G. Chikhale, W. H. Doub, S. K. De, Z. Gao, A. S. Gehris, L. Hughes, R. Lu, H. Mahayni, P. K. Maturu, T. D. Mehta

2. Eddington ND, Rekhi GS, Lesko LJ, Augsburger LL. Scale-Up Effects on Dissolution and Bioavailability of Propranolol Hydrochloride and Metoprolol Tartrate Tablet Formulations. AAPS PharmSciTech. 2000; 1(2): article

3. AAPS 2010 Poster Presentation: Evaluation of Suitability, Transferability, and Bio-relevance of a Novel In-Vitro Dissolution Technique (Rohm & Haas Dissolution System, i.e. FloVitroâ„¢ Technology*) A. Selen, L. F. Buhse, E. G. Chikhale, W. H. Doub, S. K. De, Z. Gao, A. S. Gehris, L. Hughes, R. Lu, H. Mahayni, P. K. Maturu, T. D. Mehta

4. AAPS 2011 Poster Presentation: Application of FloVitroâ„¢ Technology to Evaluate Dissolution of Furosemide and Danazol in Simulated Media at Fed and Fasted Conditions A. Selen, W.J. Rodriguez, W. H. Doub, L. F. Buhse, E. G. Chikhale, S. K. De, Z. Gao, A. S. Gehris, L. Hughes, R. Lu, H. Mahayni, P.K. Maturu, T. D. Mehta 13

5. Hughes, Lyn, Dissolution Test Equipment and Method. US Patent No. 2004/US6799123B2, Sept 28th, 2004