In vitro bioequivalence of psychotherapeutics acquired by the Peruvian state: case, Carbamazepine and Diazepam
DOI:
https://doi.org/10.18004/mem.iics/1812-9528/2025.e23122510Keywords:
Bioavailability, biowaiver, dissolution profile, validationAbstract
Bioequivalence assessment plays a fundamental role in determining the quality and efficacy of generic drugs. In the specific case of psychotropic drugs, such as carbamazepine (CBZ) and diazepam (DZP), their in vitro biopharmaceutical equivalence is a priority. The objective was to determine the in vitro bioequivalence of carbamazepine and diazepam purchased by the Peruvian government. Quality control, method validation, and determination of dissolution profiles compared to the innovator drug were performed using the similarity factor (f₂). Significant differences were found in quality controls; the method was successfully validated; and there are more significant differences in the dissolution profile of carbamazepine than diazepam. In vitro bioequivalence with the innovator was only demonstrated by the multisource batch of diazepam acquired by EsSalud.
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References
1. World Health Organization (WHO). WHO Expert Committee on Specifications for Pharmaceutical Preparations: Forty-second report. Geneva: WHO; 2008. (WHO Technical Report Series; No 948).
2. Amidon GL, Lennernäs H, Shah VP, Crison JR. A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability. Pharm Res. 1995; 12(3): 413-20.
3. Davit BM, Nwakama PE, Buehler GJ, et al. Comparing Generic and Innovator Drugs: A Review of 12 Years of Bioequivalence Data from the United States Food and Drug Administration. Ann Pharmacother. 2009; 43(10): 1583-97.
4. Ministerio de Salud, MINSA. Decreto Supremo N° 024-2018-SA que Aprueba el Reglamento que regula la intercambiabilidad de medicamentos. El Peruano. setiembre de 2018.
5. Organización Panamericana de la Salud, OPS. Evaluación del desempeño de los sistemas de salud: Un marco para el análisis de políticas. Washington: PAHO; 2023.
6. British Pharmacopoeia Commission. British Pharmacopoeia. London: The Stationery Office; 2023.
7. US Pharmacopeia (USP). USP 43/NF 38. The United States Pharmacopeial Convention. Baltimore: United Book Press; 2020.
8. Cytiva. Quantitative ashless filter paper. Lab filtration products - Cellulose filter papers. 2025.
9. World Health Organization (WHO). Fifty-first report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. Geneva: WHO; 2017. (WHO Technical Report Series; No. 1003).
10. U.S. Department of Health and Human Services, FDA, CDER. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a BCS Guidance for Industry. 2017.
11. Alarcón A. Evaluación de los perfiles de disolución de carbamazepina en tabletas de liberación inmediata de tres productos comercializados en Guatemala. Universidad del Valle de Guatemala; 2005.
12. Pringels E, Vervaet C, Verbeeck R, Foreman P, Remon JP. The addition of calcium ions to starch/Carbopol® mixtures enhances the nasal bioavailability of insulin. Eur J Pharm Biopharm. 2008; 68(2): 201-6.
13. Van Der Merwe J, Steenekamp J, Steyn D, Hamman J. The Role of Functional Excipients in Solid Oral Dosage Forms to Overcome Poor Drug Dissolution and Bioavailability. Pharmaceutics. 2020; 12(5): 393.
14. Narro C, Ramos A. Características Fisicoquímicas De Tabletas De Diazepam 10 mg Adquiridas Por El Estado Peruano. Universidad Nacional de Trujillo; 2020.
15. World Health Organization (WHO). List of Essential Medicines. Geneva: WHO; 2019.
16. Bermejo M, Meulman J, Davanço MG, et al. In Vivo Predictive Dissolution (IPD) for Carbamazepine Formulations. Pharmaceutics. 2020; 12(6): 558.
17. Sangnim T, Zandu SK, Kaur S, et al. Development and Evaluation of MCC-SiO2/CMC-SiO2 Conjugates as Tablet Super-Disintegrants. Polymers. 2022; 14(5): 1035.
18. Agencia Española de Medicamentos y Productos Sanitarios. Ficha Técnica Tegretol 200 mg comprimidos. AEMPS; 2025.
19. Fortunato D. Dissolution Method Development for Immediate Release Solid Oral Dosage Forms. Dissolution Technol. 2005; 12(3): 12-4.
20. Salehi N, Kuminek G, Al-Gousous J, et al. Improving Dissolution Behavior and Oral Absorption of Drugs with pH-Dependent Solubility Using pH Modifiers. Mol Pharm. 2021; 18(9): 3326-41.
21. Silva JRD, Lemes EDO, Vargem DDS. Influência dos excipientes na dissolução in vitro dos fármacos a partir de cápsulas gelatinosas duras contendo cetoprofeno 50 mg. Rev Eletrônica Farmácia. 2016; 13(4): 176.
22. Correa T, Rodríguez I, Salas A, Milán R, Romano C, Romano S. Farmacocinética poblacional de carbamazepina en niños epilépticos. Revista Mexicana de Ciencias Farmacéuticas. 2009; 40(1): 9.
23. Johannessen S, Johannessen Landmark C. Antiepileptic Drug Interactions - Principles and Clinical Implications. Curr Neuropharmacol. 2010; 8(3): 254-67.
24. Dávila G. Cinética y perfiles de disolución de especialidades farmacéuticas de marca y de fuentes múltiples conteniendo Carbamazepina. Vérit J. 2006; 10(1).
25. Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). Ficha Técnica Valium 10 mg comprimidos. AEMPS; 2025.
26. Rowe RC, Sheskey PJ, Quinn ME. Handbook of Pharmaceutical Excipients. 6° edition. London: Pharmaceutical Press; 2009.
27. Saavedra-Suárez S, Alva-Plasencia P, Gutiérrez-Ramos M, et al. Estudio comparativo de la calidad biofarmacéutica de Diazepam 10 mg comercializados en el mercado peruano. Ars Pharm. 2022; 63(1): 45-55.
28. Alva R, Lecca N. Comparación de perfiles de disolución de Diazepam en tabletas genéricas 10 mg y el producto innovador. Universidad Nacional de Trujillo; 2009.
29. Yu L, Jiang W, Zhang X, et al. Novel bioequivalence approach for narrow therapeutic index drugs. Clin Pharmacol Ther. 2015; 97(3): 286-91.
30. Lindenberg M, Kopp S, Dressman JB. Classification of orally administered drugs on the WHO Model list of Essential Medicines according to the biopharmaceutics classification system. Eur J Pharm Biopharm. 2004; 58(2): 265-78.
