Biorelevant dissolution

Nicolaides E, Hempenstall JM, Reppas C. Biorelevant dissolution tests with the flow-through apparatus. Dissolution Technol 2000 7(1) 8—11. 

In this case, the solubility is extremely poor, even at pH 7, which is considerably above the pKa of troglitazone and corresponds to pH values commonly found in the mid section of the small intestine. Other well-known compounds with analogous behavior are mefenamic acid, glyburide, and phe-nytoin. For troglitazone, the presence of bile salts improves the solubility quite dramatically and lipophilic constituents in the dissolution medium (e.g., in full-fat milk) lead to better dissolution, and in turn better absorption when troglitazone is administered in the fed than the fasted state, as reported by Nicolaides (13). Use of biorelevant dissolution testing permitted these authors not only to qualitatively predict the food effect, but also to predict relative bioavailability of three test formulations. 

In such cases, it is obviously advantageous to use biorelevant dissolution tests to characterize the drug substance, to compare formulations and to make a preliminary assessment of possible food effects. However, for routine quality control work, the manufacture of media containing bile components is not only rather time-consuming but may also present difficulties in terms of quality assurance and validation of the raw materials, as is the case with many chemicals obtained from natural sources. 

FUTURE DIRECTIONS OF BIORELEVANT DISSOLUTION TEST DESIGN... 

Nicolaides E, Symillides M, Dressman JB, Reppas C. Biorelevant dissolution testing to predict the plasma profile of highly lipophilic drugs after oral administration. Pharm Res 2001 18(3) 380-388. 

In this chapter, the emphasis is on producing physiologically relevant dissolution data sets. Compared to dissolution profiles obtained according to relevant compendia requirements for quality control purposes, biorelevant dissolution data sets collected in closed systems often do not reach 100% dissolved and frequently are associated with higher variability (22). 

The FDA guidance on IVIVC development and validation defines a number of circumstances where an IVIVC can be used to justify a biowaiver request in support of (1) level 3 process changes, (2) complete removal or replacement of non-release-controlling excipients, (3) level 3 changes in release-controlling excipients, (4) approval of lower strengths, and (5) approval of new strengths. Additionally, use of the IVIVC to justify biorelevant dissolution specifications is cited as the optimal approach. 

Stippler E. Biorelevant Dissolution Test Methods to Asses Bioequivalence of Drug Products. Frankfurt Institute for Pharmaceutical Technology, J. W. Goethe University, 2004 414. 

Westerhoff K, Kaunzinger A, Wurglics M, Dressman J, Schubert-Zsilavecz M. Biorelevant dissolution testing of St. John s wort products. J Pharm Pharmacol 2002 54 1615-1621. 

In order to establish an appropriate acceptance criterion, the additional dissolution studies with biorelevant dissolution media FaSSIF in Table 6.1 were conducted, and the results are shown in Figure 6.5. Figure 6.5 indicates that the dissolution rate has been uniformly increased, and all three lots pass the acceptance criterion of 80% in 30 min. On the basis of these biorelevant dissolution results along with the bioequivalence study data, the acceptance criterion was reduced to 70% in 30 min. 

In addition to selection of a suitable type of dissolution apparatus, the dissolution media is another critical element in generating IVIVCs. Besides the compendial dissolution media, proper selection and use of biorelevant dissolution media to mimic Gl biological conditions can be of beneLt as has been reported, especially for dosage forms containing poorly water-soluble drugs [10-16], The commonly used dissolution media are ... 

Whilst the applicability of the flow through apparatus to biorelevant dissolution tests still requires further investigation and optimization, an in vitro-in vivo correlation (TVrVC) has been reported with this apparatus using physiologically relevant flow rates and media. ... 

Sunesen, V.H. Pedersen, B.L. Kristensen, H.G. Mullertz, A. 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. 2005, 24 (4), 305-313. 

Stippler E, [Dissertation], Biorelevant Dissolution Test Methods to Assess Bioequivaience of Drug Products. Germany, Johann-Wolfgang von Goethe University Frankfurt, 2004. 

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