This study aimed to simulate the in vivo behavior of indomethacin suppositories (reference and a generic formulation) using in vitro dissolution data and a numerical convolution method. The United States Pharmacopeia (USP) basket apparatus (USP apparatus I) at 100 rpm and the flow-through cell method (USP apparatus IV) with laminar flow at 16 ml/min were used. The dissolution medium phosphate buffer (0.1 M, pH 7.4) with or without 1% sodium dodecyl sulfate (SDS) was used. The dissolution profiles were compared with model-dependent and independent methods. For the reference drug product, tested with the USP apparatus IV and without 1% SDS, predicted Cmax and AUC0–inf were 2.39 and 8.46 μgh/ml, respectively; for the generic formulation, same medium but with the USP apparatus I, values of 0.73 and 3.11 μgh/ml were calculated. When comparing predicted pharmacokinetic parameters with in vivo data prediction errors <10% for Cmax and AUC0–inf were only found with the reference drug product and the flow-through cell method. USP apparatus IV and phosphate buffer (0.1 M, pH 7.4) without 1% SDS were the ideal dissolution conditions to test multisource formulations and generate hypothetical in vivo behavior. To confirm these results, human studies using indomethacin suppositories should be conducted.
Medina-Lopez JR, Reyes-Ramirez FD, Cedillo-Diaz LA, Contreras-Jimenez JM. Hypothetical in vivo behavior of semisolid dosage forms: indomethacin suppositories. J Appl Pharm Sci. 2025. Online First. https://doi.org/10.7324/JAPS.2025.223837
1. Thakur S, Riyaz B, Patil A, Kaur A, Kapoor B, Mishra V. Novel drug delivery systems for NSAIDs in management of rheumatoid arthritis: an overview. Biomed Pharmacother. 2018;106:1011–23. doi: https://doi.org/10.1016/j.biopha.2018.07.027
2. Patai A, Solymosi N, Mohácsi L, Patai AV. Indomethacin and diclofenac in the prevention of post-ERCP pancreatitis: a systematic review and meta-analysis of prospective controlled trials. Gastrointest Endosc. 2017;85(6):1144–56e1. doi: https://doi.org/10.1016/j.gie.2017.01.033
3. Yang C, Zhao Y, Li W, Zhu S, Yang H, Zhang Y, et al. Rectal nonsteroidal anti-inflammatory drugs administration is effective for the prevention of post-ERCP pancreatitis: an update meta-analysis of randomized controlled trials. Pancreatology 2017;17(5):681–8. doi: https://doi.org/10.1016/j.pan.2017.07.008
4. Nascimento ALCS, Fernandes RP, Charpentier M, Ter Horst JH, Caires FJ, Chorillo M. Co-crystals of non-steroidal anti-inflammatory drugs (NSAIDs): insight toward formation, methods, and drug enhancement. Particuology 2021;58(3):227–41. doi: https://doi.org/10.1016/j.partic.2021.03.015
5. Nascimento ALCS, Martins ICB, Spósito L, Morais-Silva G, Duarte JL, Rades T, et al. Indomethacin-omeprazole as therapeutic hybrids? Salt and co-amorphous systems enhancing physicochemical and pharmacological properties. Int J Pharm. 2024;653:123857. doi: https://doi.org/10.1016/j.ijpharm.2024.123857
6. Mohammed A, Elshaer A, Sareh P, Elsayed M, Hassanin H. Additive manufacturing technologies for drug delivery applications. Int J Pharm. 2020;580:119245. doi: https://doi.org/10.1016/j.ijpharm.2020.119245
7. Aiache JM, Islasse M, Beyssac E, Aiache S, Renoux R, Kantelip JP. Kinetics of indomethacin release from suppositories. In vitro-in vivo correlation. Int J Pharm. 1987;39(3):235–42. doi: https://doi.org/10.1016/0378-5173(87)90221-3
8. De Muynck C, Remon JP. Influence of fat composition on the melting behavior and on the in vitro release of indomethacin suppositories. Int J Pharm. 1992;85(1–3):103–12. doi: https://doi.org/10.1016/0378-5173(92)90139-S
9. Uzunkaya G, Bergi?adi N. In vitro drug liberation and kinetics of sustained release indomethacin suppository. Il Farmaco. 2003;58(7):509–12. doi: https://doi.org/10.1016/S0014-827X(03)00070-3
10. United States Pharmacopeia 47/National Formulary 42. United States Pharmacopoeial Convention, Inc; 2024.
11. Hassan HA, Charoo NA, Ali AA, Alkhatem SS. Establishment of a bioequivalence-indicating dissolution specification for candesartan cilexetil tablets using a convolution model. Dissol Technol. 2015;22(2):36–43. doi: https://doi.org/10.14227/DT220115P36
12. Emara LH, El-Menshawi BS, Estefan MY. In vitro-in vivo correlation and comparative bioavailability of vincamine in prolonged-release preparations. Drug Dev Ind Pharm. 2000;26(3):243–51. doi: https://doi.org/10.1081/ddc-100100352
13. Jinno J, Kamada N, Miyake M, Yamada K, Mukai T, Odomi M, et al. In vitro-in vivo correlation for wet-milled tablet of poorly water-soluble cilostazol. J Control Rel. 2008;130(1):29–37. doi: https://doi.org/10.1016/j.jconrel.2008.05.013
14. Xie F, Ji S, Cheng Z. In vitro dissolution similarity factor (f2) and in vivo bioequivalence criteria, how and when do they match? Using a BCS class II drug as a simulation example. Eur J Pharm Sci. 2015;66:163–72. doi: https://doi.org/10.1016/j.ejps.2014.10.002
15. Zhang Y, Huo M, Zhou J, Zou A, Li W, Yao C, et al. DDSolver: an add-in program for modeling and comparison of drug dissolution profiles. AAPS J. 2010;12(3):263–71. doi: https://doi.org/10.1208/s12248-010-9185-1
16. 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: https://doi.org/10.1016/s0378-5173(00)00554-8
17. 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: https://doi.org/10.1016/j.cmpb.2010.01.007
18. 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;4:38–47. doi: https://doi.org/10.2174/1874126601004010038
19. Rastogi V, Yadav P, Lal N, Rastogi P, Singh BK, Verma N, et al. 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: https://doi.org/10.1016/j.fjps.2018.003.001
20. Efentakis M, Al-Hmoud H, Buckton G, Rajan Z. The influence of surfactants on drug release from a hydrophobic matrix. Int J Pharm. 1991;70(1–2):153–8. doi: https://doi.org/10.1016/0378-5173(91)90175-N
21. Lootvoet G, Beyssac E, Shiu GK, Aiache JM, Ritschel WA. Study on the release of indomethacin from suppositories: in vitro-in vivo correlation. Int J Pharm. 1992;85(1–3):113–20. doi: https://doi.org/10.1016/0378-5173(92)90140-W
22. Azarmi S, Roa W, Löbenberg R. Current perspectives in dissolution testing of conventional and novel dosage forms. Int J Pharm. 2007;328(1):12–21. doi: https://doi.org/10.1016/j.ijpharm.2006.10.001
23. Podczeck F. Comparison of in vitro dissolution profiles by calculating mean dissolution time (MDT) or mean residence time (MRT). Int J Pharm. 1993;97(1–3):93–100. doi: https://doi.org/10.1016/0378-5173(93)90129-4
24. Archondikis A, Papaioannou G. Comparative study of two dissolution methods for indomethacin suppositories from fatty and water-soluble bases. Int J Pharm. 1989;55:217–20. doi: https://doi.org/10.1010/0378-5173(89)90044-6
25. Ilango KB, Kavimani S. A systematic review of the mathematical models of pharmaceutical dosage forms. Int J Curr Pharm Rev Res. 2015;6(1):59–70.
26. Medina JR, Salazar K, Hurtado M, Cortés AR, Domínguez-Ramírez AM. Comparative in vitro dissolution study of carbamazepine immediate-release products using the US paddles method and the flow-through cell system. Saudi Pharm J. 2014;22:141–7. doi: https://doi.org/j.jsps.2013.02.001
27. Fang JB, Robertson VK, Rawat A, Flick T, Tang ZJ, Cauchon NS, et al. Development and application of a biorelevant dissolution method using USP apparatus 4 in early phase formulation development. Mol Pharmaceut. 2010;7(5):1466–77. doi: https://doi.org/10.1021/MP100125B
28. De Muynck C, Lefebvre RA, Remon JP. Study of the bioavailability of four indomethacin suppository formulations in healthy volunteers. Int J Pharm. 1994;104(1):87–91. doi: https://doi.org/10.1016/0378-5173(94)90339-5
29. Xu J, Zhang L, Shao X. Application of bio-predictive dissolution tools for the development of solid oral dosage forms: current industrial experience. Drug Dev Ind Pharm. 2022;48(3):79–97. doi: https://doi.org/10.1018/03639045.2022.2098315
30. Paprská?ová A, Možná 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):1261–5. doi: https://doi.org/10.1208/s12249-015-0444-4
31. Fotaki N. Flow-through cell apparatus (USP apparatus 4): operation and features. Dissolut Technol. 2011;18(4):46–9. doi: https://doi.org/10.14227/DT180411P46
32. Todaro V, Persoons T, Grove G, Healy MA, D’Arcy DM. Characterization and simulation of hydrodynamics on the paddle, basket and flow-through dissolution testing apparatuses – a review. Dissolut Technol. 2017;24(3):24–36. doi: https://doi.org/10.14227/DT240317P24
33. Abdelfattah F, Taha N, Abdou A, Mursi N, Emara L. Prediction of in vivo performance of ibuprofen immediate-release products using different dissolution models. J App Pharm Sci. 2022;12(8):193–201. doi: https://doi.org/10.7324/JAPS.2022.120820
34. Medina-López JR, Lugo-Ortíz R, Contreras-Jiménez JM, Hurtado M, Helmy SA. Dissolution performance of verapamil-HCl tablets using USP Apparatus 2 and 4: prediction of in vivo plasma profiles. Dissol Technol. 2023;30(4):230–7. doi: https://doi.org/10.14227/DT300423P230
35. Medina-López R, Vera-Ángeles YA, Reyes-Ramírez 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.
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