HYPOTHETICAL IN VIVO BEHAVIOR OF CARBAMAZEPINE TABLETS FROM IN VITRO RELEASE DATA OF USP APPARATUS II AND IV AND DISSOLUTION MEDIA OF PHYSIOLOGICAL RELEVANCE

FELIPE DINO REYES RAMIREZ; YAMIR ALI VERA ANGELES; JOSE RAUL MEDINA LOPEZ

doi:10.22159/ijap.2025v17i4.53916

Authors

FELIPE DINO REYES RAMIREZ Departamento Sistemas Biologicos, Universidad Autónoma Metropolitana Xochimilco, Calzada del Hueso 1100 Colonia Villa Quietud Alcaldía Coyoacán, CP-04960 Mexico City, Mexico
YAMIR ALI VERA ANGELES Departamento Sistemas Biologicos, Universidad Autónoma Metropolitana Xochimilco, Calzada del Hueso 1100 Colonia Villa Quietud Alcaldía Coyoacán, CP-04960 Mexico City, Mexico https://orcid.org/0009-0004-0830-4903
JOSE RAUL MEDINA LOPEZ Departamento Sistemas Biologicos, Universidad Autónoma Metropolitana Xochimilco, Calzada del Hueso 1100 Colonia Villa Quietud Alcaldía Coyoacán, CP-04960 Mexico City, Mexico https://orcid.org/0000-0002-4159-8403

DOI:

https://doi.org/10.22159/ijap.2025v17i4.53916

Keywords:

Carbamazepine, Convolution, Flow-through cell method, Multisource formulations, USP apparatus IV

Abstract

Objective: To estimate the hypothetical in vivo behavior of carbamazepine tablets (immediate-release, 200 mg) with dissolution data and a convolutional approach.

Methods: USP apparatus II and IV and media at pH 1.2, 4.5, and 6.8 (all containing 1% sodium lauryl sulfate) were used. The dissolved drug was calculated from 10 to 60 min. The dissolution profiles were compared with f₂data and some dissolution parameters. In vitro release data were adjusted using several mathematical models. Predicted plasma levels were calculated using dissolution data and published pharmacokinetic information. A criterion for prediction error<10% for peak plasma concentration and area under the curve is considered suitable.

Results: After 60 min, with both USP apparatuses, all formulations released>75%. Similar dissolution profiles, with all formulations using USP apparatus II at pH 4.5 and 1.2 and with USP apparatus IV at pH 1.2, were found (f₂>50). In almost all the comparisons, dissolution parameters were statistically significant different (*P<0.05). Due to the diversity of the fitting results, no comparisons were made. Prediction errors<10% were found for all formulations using USP apparatus II at pH 4.5 and reference using USP apparatus IV at pH 6.8 and 4.5.

Conclusion: USP apparatus IV showed good discriminatory capacity; however, better in vivo predictions were obtained with USP apparatus II. Corroborating our findings from human studies using the formulations used is necessary.

References

Lake OA, Olling M, Barends DM. In vitro/in vivo correlations of dissolution data of carbamazepine immediate-release tablets with pharmacokinetic data obtained in healthy volunteers. Eur J Pharm Biopharm. 1999;48(1):13-9. doi: 10.1016/s0939-6411(99)00016-8, PMID 10477323.

Garcia MA, Cristofoletti R, Abrahamsson B, Groot DW, Parr A, Polli JE. Biowaiver monograph for immediate release solid oral dosage forms: carbamazepine. J Pharm Sci. 2021;110(5):1935-47. doi: 10.1016/j.xphs.2021.02.019, PMID 33610571.

Bell WL, Crawford IL, Shiu GK. Reduced bioavailability of moisture exposed carbamazepine resulting in status epilepticus. Epilepsia. 1993;34(6):1102-4. doi: 10.1111/j.1528-1157.1993.tb02140.x, PMID 8243363.

United States Pharmacopeia and National Formulary USP 47-NF 42. MD Inc. The United States of America Pharmacopeial Convention. Rockville; 2024.

Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation and Research (CBER). Food and Drug Administration guidance for industry: M9 biopharmaceutics classification system-based biowaivers; 2021. Available from: https://www.chromeextension://efaidnbmnnnibpcajpcglclefindmkaj/fda.gov/media/148472/download. [Last accessed on 15 May 2025].

Mc Pherson S, Perrier J, Dunn C, Khadra I, Davidson S, Ainousah B. Small scale design of experiment investigation of equilibrium solubility in simulated fasted and fed intestinal fluid. Eur J Pharm Biopharm. 2020 May;150:14-23. doi: 10.1016/j.ejpb.2020.01.016, PMID 32035969.

Davidson AG. A multinational survey of the quality of carbamazepine tablets. Drug Dev Ind Pharm. 1995;21(19):2167-86. doi: 10.3109/03639049509065899.

Gao Z. In vitro dissolution testing with flow through method: a technical note. AAPS PharmSciTech. 2009;10(4):1401-5. doi: 10.1208/s12249-009-9339-6, PMID 19937283.

Singh I, Aboul Enein HY. Advantages of USP apparatus IV (flow-through cell apparatus) in dissolution studies. J Iran Chem Soc. 2006;3(3):220-2. doi: 10.1007/BF03247211.

Fotaki N, Reppas C. The flow through cell methodology in the evaluation of intralumenal drug release characteristics. Dissolution Technol. 2005;12(2):17-21. doi: 10.14227/DT120205P17.

Medina JR, Salazar DK, Hurtado M, Cortes AR, Dominguez Ramirez AM. Comparative in vitro dissolution study of carbamazepine immediate release products using the USP paddles method and the flow through cell system. Saudi Pharm J. 2014;22(2):141-7. doi: 10.1016/j.jsps.2013.02.001, PMID 24648826.

Hassan HA, Charoo NA, Ali AA, Alkhatem SS. Establishment of a bioequivalenceindicating dissolution specification for candesartan cilexetil tablets using a convolution model. Dissolution Technol. 2015;22(1):36-43. doi: 10.14227/DT220115P36.

Moore JW, Flanner HH. Mathematical comparison of dissolution profiles. Pharm Technol. 1996;20(6):64-74.

Zhang Y, Huo M, Zhou J, Zou A, Li W, Yao C. DDSolver: an add-in program for modeling and comparison of drug dissolution profiles. AAPS J. 2010;12(3):263-71. doi: 10.1208/s12248-010-9185-1, PMID 20373062.

Yuksel N, Kanik AE, Baykara T. Comparison of in vitro dissolution profiles by ANOVA based model dependent and independent methods. Int J Pharm. 2000;209(1-2):57-67. doi: 10.1016/s0378-5173(00)00554-8, PMID 11084246.

Qureshi SA. In vitro-in vivo correlation (IVIVC) and determining drug concentrations in blood from dissolution testing – a simple and practical approach. Open Drug Deliv J. 2010;4(2):38-47. doi: 10.2174/1874126601004020038.

Zhang Y, Huo M, Zhou J, Xie S. PKSolver: an add-in program for pharmacokinetic and pharmacodynamic data analysis in microsoft excel. Comput Methods Programs Biomed. 2010;99(3):306-14. doi: 10.1016/j.cmpb.2010.01.007, PMID 20176408.

Jankovic SM, Jovanovic D, Milovanovic JR. Pharmacokinetic modeling of carbamazepine based on clinical data from serbian epileptic patients. Methods Find Exp Clin Pharmacol. 2008;30(9):707-13. doi: 10.1358/mf.2008.30.9.1303589, PMID 19229380.

Rastogi V, Yadav P, Lal N, Rastogi P, Singh BK, Verma N. Mathematical prediction of pharmacokinetic parameters an in vitro approach for investigating pharmaceutical products for IVIVC. Future J Pharm Sci. 2018;4(2):175-84. doi: 10.1016/j.fjps.2018.03.001.

Paprskarova A, Mozna P, Oga EF, Elhissi A, Alhnan MA. Instrumentation of flow through USP IV dissolution apparatus to assess poorly soluble basic drug products: a technical note. AAPS PharmSciTech. 2016;17(5):1261-6. doi: 10.1208/s12249-015-0444-4, PMID 26573157.

Medina Lopez JR, Cedillo Diaz LA, Hurtado M. In vitro equivalence study of different doses of carbamazepine reference tablets using USP apparatuses 2 and 4. Int J App Pharm. 2019;11(4):291-5. doi: 10.22159/ijap.2019v11i4.33174.

Kumar Das S, Chakraborty S, Bose A, Rajabalaya R, Khanam J. Effects of the preparation technique on the physicochemical characteristics and dissolution improvement of ketoprofen-SDE7-β-CD binary inclusion complexes. Colloids Surf A Physicochem Eng Asp. 2021;611(2):125775. doi: 10.1016/j.colsurfa.2020.125775.

Anderson NH, Bauer M, Boussac N, Khan Malek R, Munden P, Sardaro M. An evaluation of fit factors and dissolution efficiency for the comparison of in vitro dissolution profiles. J Pharm Biomed Anal. 1998;17(4-5):811-22. doi: 10.1016/S0731-7085(98)00011-9, PMID 9682166.

Podczeck F. Comparison of in vitro dissolution profiles by calculating mean dissolution time (MDT) or mean residence time (MRT). International Journal of Pharmaceutics. 1993;97(1-3):93-100. doi: 10.1016/0378-5173(93)90129-4.

Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2001;13(2):123-33. doi: 10.1016/S0928-0987(01)00095-1, PMID 11297896.

Demirturk E, Oner L. In vitro-in vivo correlations. Fabad J Pharm Sci. 2003;28:215-24.

Marroum P. Role of in vitro-in vivo correlations in drug development. Dissolution Technol. 2015;22(2):50-6. doi: 10.14227/DT220215P50.

Ojstersek T, Vrecer F, Hudovornik G. Comparative fitting of mathematical models to carvedilol release profiles obtained from hypromellose matrix tablets. Pharmaceutics. 2024;16(4):498. doi: 10.3390/pharmaceutics16040498, PMID 38675159.

El Zein H, Riad L, El Bary AA. Enhancement of carbamazepine dissolution: in vitro and in vivo evaluation. International Journal of Pharmaceutics. 1998;168(2):209-20. doi: 10.1016/S0378-5173(98)00093-3.

Jung H, Milan RC, Girard ME, Leon F, Montoya MA. Bioequivalence study of carbamazepine tablets: in vitro/in vivo correlation. International Journal of Pharmaceutics. 1997;152(1):37-44. doi: 10.1016/S0378-5173(97)04910-7.

Kovacevic I, Parojcic J, Homsek I, Tubic Grozdanis M, Langguth P. Justification of biowaiver for carbamazepine a low soluble high permeable compound in solid dosage forms based on IVIVC and gastrointestinal simulation. Mol Pharm. 2009;6(1):40-7. doi: 10.1021/mp800128y, PMID 19248231.

Kulthanan K, Nuchkull P, Varothai S. The pH of water from various sources: an overview for recommendation for patients with atopic dermatitis. Asia Pac Allergy. 2013;3(3):155-60. doi: 10.5415/apallergy.2013.3.3.155, PMID 23956962.

Sowmya C, Abrar Ahmed H, Suriya Prakaash KK. Virtual bioequivalence in pharmaceuticals: current status and future prospects. Int J App Pharm. 2023;15(5):1-9. doi: 10.22159/ijap.2023v15i5.48589.

Sarkar P, Das S, Majee SB. Biphasic dissolution model: novel strategy for developing discriminatory in vivo predictive dissolution model for BCS class II drugs. Int J Pharm Pharm Sci. 2022;14(4):20-7. doi: 10.22159/ijpps.2022v14i4.44042.

Okumu A, DiMaso M, Lobenberg R. Computer simulations using gastroplus to justify a biowaiver for etoricoxib solid oral drug products. Eur J Pharm Biopharm. 2009;72(1):91-8. doi: 10.1016/j.ejpb.2008.10.019, PMID 19056493.

JR ML, A RL, FD RR. Convolution approach to estimate the in vivo behavior of ibuprofen soft gelatin capsules from in vitro release data of USP apparatus 4. Int J Res Pharm Sci. 2024;15(4):88-94. doi: 10.26452/ijrps.v15i4.4727.

Medina Lopez R, Vera Angeles YA, Reyes Ramirez FD. Simulation of indomethacin plasma levels: influence of the hydrodynamics of the USP basket apparatus and flow through cell system to evaluate capsules. Lat Am J Pharm. 2025;44(2):182-8.