Alternative Methods for Dissolution Profile Comparison in the Dissolution Test

Introduction. The article discusses the problem of assessing the similarity of the dissolution profiles of two batches of the nebivolol. The use of a generally accepted similarity factor for assessing equivalence is unacceptable in some cases, for example, for drugs with a high variability in the values of the release of the active substance from the formulation. At the same time, at present, there are no generally accepted approaches to comparing the profiles of the dissolution kinetics of drugs, with the exception of the method for assessing the comparability of profiles based on the mathematical calculation of the similarity factor f₂, which has certain criteria that limit its application.

Aim. To demonstrate alternative methods for assessing the similarity between the dissolution profiles of two drugs using a practical example.

Materials and methods. The results of the comparative dissolution test of two series of nebivolol at a dosage of 5 mg. Five model-independent methods for assessing the equivalence of drug dissolution were used. Statistical data processing was performed using Microsoft Excel software.

Results and discussion. The paper presents a practical example of using five alternative model-independent methods for assessing the equivalence of the dissolution profile. An example is used to illustrate the proposed equivalence limits and statistical methodology. Also, various approaches to determining the boundaries of equivalence have been proposed to assess the similarity of the dissolution profiles of an active substance.

Conclusion. According to the results of the comparative dissolution test of two batches of nebivolol, it was shown that the use of the similarity factor as a criterion for assessing dissolution profiles led to a false positive result. In such cases, the possibility of using alternative methods for assessing the equivalence of dissolution profiles described in the article, or other methods presented in the scientific literature, should be considered, with a justification of their acceptability in each specific case.

1. Mironov A. N., Romodanovsky D. P., Niyazov R. R., Goryachev D. V. Expert approaches to developing and analysing the results of comparative dissolution kinetics testing for generic medicines in solid dosage forms. Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya = Bulletin of the Scientific Center for Expertise of Medicinal Products. 2014;2:3–8. (In Russ.)

2. Chow S.-C., Fanny Y. C. K. Statistical comparison between dissolution profiles of drug products. Journal of Biopharmaceutical Statistics. 1997;7(2):241–258. DOI: 10.1080/10543409708835184.

3. Hoffelder T. Equivalence analyses of dissolution profiles with the Mahalanobis distance. Biometrical Journal. 2019;61(5):1120–1137. DOI: 10.1002/bimj.201700257.

4. Abend A., Curran D., Kuiper J., Lu X., Li H., Hermans A., Kotwal P., Diaz D. A., Cohen M. J., Zhang L., Stippler E., Drazer G., Lin Y., Raines K., Yu L., Coutant C. A., Grady H., Krämer J., Pope-Miksinski S., Suarez-Sharp S. Dissolution Testing in Drug Product Development: Workshop Summary Report. The AAPS Journal. 2019;21(2). DOI: 10.1208/s12248-018-0288-4.

5. Diaz D. A., Colgan S. T., Langer C. S., Bandi N. T., Likar M. D., Van Alstine L. Dissolution Similarity Requirements: How Similar or Dissimilar Are the Global Regulatory Expectations? The AAPS Journal. 2016;18(1):15–22. DOI: 10.1208/s12248-015-9830-9.

6. Shohin I. E., Bagaeva N. S., Malashenko E. A., Kuzina V. N. Method of Estimating the Equivalence of Dissolution Profiles: a Modern View. Razrabotka i registratsiya lekarstvennykh sredstv = Drug development & registration. 2020;9(2):145–150. (In Russ.) DOI: 10.33380/2305-2066-2020-9-2-145-150.

7. Suarez-Sharp S., Abend A., Hoffelder T., Leblond D., Delvadia P., Kovacs E., Diaz D. A. In Vitro Dissolution Profiles Similarity Assessment in Support of Drug Product Quality: What, How, When– Workshop Summary Report. The AAPS Journal. 2020;22(4):74. DOI: 10.1208/s12248-020-00458-9.

8. Schuirmann D. J. A comparison of the Two One-Sided Tests Procedure and the Power Approach for assessing the equivalence of average bioavailability. Journal of Pharmacokinetics and Biopharmaceutics. 1987;15(6):657–680. DOI: 10.1007/BF01068419.

9. Kirkwood T. B. L., Westlake W. J. Bioequivalence Testing - A Need to Rethink. Biometrics. 1981;37(3):589–594. DOI: 10.2307/2530573.

10. Noce L., Gwaza L., Mangas-Sanjuan V., Garcia-Arieta A. Comparison of free software platforms for the calculation of the 90% confidence interval of f2 similarity factor by bootstrap analysis. European Journal of Pharmaceutical Sciences. 2020;146:105259. DOI: 10.1016/j.ejps.2020.105259.