Dynamic Dissolution Testing To Establish In Vitro/In Vivo Correlations for Montelukast Sodium, a Poorly Soluble Drug
The objectives of the study was to develop a dissolution test method that can be used to predict the oral absorption of montelukast sodium, and to establish an in vitro/in vivo correlation (IVIVC) using computer simulations.
Drug solubility was measured in different media. The dissolution behaviour of montelukast sodium 10 mg film coated tablets was studied using the flow-through cell dissolution method following a dynamic pH change protocol, as well as in the USP Apparatus 2. Computer simulations were performed using GastroPlus™. Biorelevant dissolution media (BDM) prepared using bile salts and lecithin in buffers was used as the dissolution media, as well as the USP simulated intestinal fluid (SIF) pH 6.8 and blank FaSSIF pH 6.5. Dissolution tests in the USP Apparatus 2 were performed under a constant pH condition, while the pH range used in the flow through cells was pH 2.0 to 7.5. The in vitro data were used as input functions into GastroPlus™ to simulate the in vivo profiles of the drug.
The solubility of montelukast sodium was low at low pH, but increased as the pH was increased. There was no significant difference in solubility in the pH range of 5.0 to 7.5 in blank buffers, but the drug solubility was higher in biorelevant media compared with the corresponding blank buffers at the same pH. Using the flow through cells, the dissolution rate was fast in simulated gastric fluid containing 0.1% SLS. The dissolution rate slowed down when the medium was changed to FaSSIF pH 6.5 and increased when the medium was changed to FaSSIF medium at pH 7.5. In the USP Apparatus 2, better dissolution was observed in FaSSIF compared with the USP buffers and blank FaSSIF with similar pH values. Dissolution was incomplete with less than 10% of the drug dissolved in the USP-SIF, and was practically non existent in blank FaSSIF pH 6.5. The in vitro results of the dynamic dissolution test were able to predict the clinical data from a bioavailability study best.
Dynamic dissolution testing using the flow through cell seems to be a powerful tool to establish in vitro/in vivo correlations for poorly soluble drugs as input function into GastroPlus.
KEY WORDSACAT BCS dynamic dissolution IVIVC
This work was supported by a collaborative research grant from NSERC and Merck Frosst Canada Inc. We would like to thank Simulations Plus for their support.
- 1.T. R. Jones, M. Labelle, M. Belley, E. Champion, L. Charette, J. Evans, A. W. Ford-Hutchinson, J. Y. Gauthier, A. Lord, P. Masson et al. Pharmacology of montelukast sodium (Singulair), a potent and selective leukotriene D4 receptor antagonist. Can. J. Physiol. Pharmacol. 73:191–201 (1995).PubMedGoogle Scholar
- 4.FDA-CDER. Guidance for Industry, Dissolution Testing of Immediate release Solid Oral Dosage Forms, U.S. Department of Health and Human Services, Food and Drug Administration, 1997.Google Scholar
- 6.V. P. Shah, and L. J. Lesko. Current challenges and future regulatory directions in in vitro dissolution. Drug Inform. J. 29:885–891 (1995).Google Scholar
- 12.H. Cai, C. Stoner, A. Reddy, S. Freiwald, D. Smith, R. Winters, C. Stankovic, and N. Surendran. Evaluation of an integrated in vitro-in silico PBPK (physiologically based pharmacokinetic) model to provide estimates of human bioavailability. Int. J. Pharm. 308:133–139 (2006) DOI 10.1016/j.ijpharm.2005.11.002.PubMedCrossRefGoogle Scholar
- 15.SimulationsPlus. GastroPlus Manual. Lancaster, USA, 2006.Google Scholar
- 16.USP. United States Pharmacopeia 29/National Formulary 24. The USP, Rockville, MD, 2006.Google Scholar
- 18.K. Thoma, and I. Ziegler. Development of an automated flow-through dissolution system for poorly soluble drugs with poor chemical stability in dissolution media. Pharmazie. 53:784–790 (1998).Google Scholar
- 19.M. Marques. Dissolution Media Simulating fasted and Fed States, Dissolution Technologies Vol. 16, 2004.Google Scholar
- 21.L. V. Allen, N. G. Popovich, and H. C. Ansel. Ansel’s Pharmaceutical Dosage Forms and Drug Delivery systems. Lippincott Williams and Wilkins, Philadelphia, 2005.Google Scholar
- 27.H. Cheng, J. A. Leff, R. Amin, B. J. Gertz, M. De Smet, N. Noonan, J. D. Rogers, W. Malbecq, D. Meisner, and G. Somers. Pharmacokinetics, bioavailability, and safety of montelukast sodium (MK-0476) in healthy males and females. Pharm. Res. 13:445–448 (1996) DOI 10.1023/A:1016056912698.PubMedCrossRefGoogle Scholar
- 28.L. Shargel, and A. B. C. Yu. Applied Biopharmaceutics and Pharmacokinetics. McGraw-Hill, New York, 1999.Google Scholar
- 29.J. W. Moore, H. H, Flanner. Mathematical Comparison of Dissolution Profiles, Pharmaceutical Technology, Vol. 6, 1996, pp. 64–74.Google Scholar
- 30.FDA-CDER. Guidance for Industry Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations. In U.S. Department of Health and Human Services Food and Drug Administration (ed.), 1997.Google Scholar
- 33.J. R. Crison, N. D. Weiner, and G. L. Amidon. Dissolution media for in vitro testing of water-insoluble drugs: effect of surfactant purity and electrolyte on in vitro dissolution of carbamazepine in aqueous solutions of sodium lauryl sulfate. J. Pharm. Sci. 86:384–388 (1997) DOI 10.1021/js960105t.PubMedCrossRefGoogle Scholar
- 36.C. Y. Perng, A. S. Kearney, N. R. Palepu, B. R. Smith, and L. M. Azzarano. Assessment of oral bioavailability enhancing approaches for SB-247083 using flow-through cell dissolution testing as one of the screens. Int. J. Pharm. 250:147–156 (2003) DOI 10.1016/S0378-5173(02)00521-5.PubMedCrossRefGoogle Scholar
- 37.V. H. Sunesen, B. L. Pedersen, H. G. Kristensen, and A. Mullertz. In vivo in vitro correlations for a poorly soluble drug, danazol, using the flow-through dissolution method with biorelevant dissolution media. Eur. J. Pharm. Sci. 24:305–313 (2005) DOI 10.1016/j.ejps.2004.11.007.PubMedCrossRefGoogle Scholar
- 38.J. J. Zhao, J. D. Rogers, S. D. Holland, P. Larson, R. D. Amin, R. Haesen, A. Freeman, M. Seiberling, M. Merz, and H. Cheng. Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers. Biopharm. Drug Dispos. 18:769–777 (1997) DOI 10.1002/(SICI)1099-081X(199712)18:9<769::AID-BDD60>3.0.CO;2-K.PubMedCrossRefGoogle Scholar
- 39.S. K. Balani, X. Xu, V. Pratha, M. A. Koss, R. D. Amin, C. Dufresne, R. R. Miller, B. H. Arison, G. A. Doss, M. Chiba, A. Freeman, S. D. Holland, J. I. Schwartz, K. C. Lasseter, B. J. Gertz, J. I. Isenberg, J. D. Rogers, J. H. Lin, and T. A. Baillie. Metabolic profiles of montelukast sodium (Singulair), a potent cysteinyl leukotriene1 receptor antagonist, in human plasma and bile. Drug Metab. Dispos. 25:1282–1287 (1997).PubMedGoogle Scholar