• Jose Raúl Medina-López Departamento Sistemas Biologicos, Universidad Autonoma Metropolitana-Xochimilco, Mexico City http://orcid.org/0000-0002-4159-8403
  • Joaquín Alexandro Soto-Juha Departamento Sistemas Biologicos, Universidad Autonoma Metropolitana-Xochimilco, Mexico City
  • Juan Manuel Contreras-Jiménez Departamento Sistemas Biologicos, Universidad Autonoma Metropolitana-Xochimilco, Mexico City


determinations for the simultaneous quantification of ibuprofen (IBU) and caffeine (CAF) in fixed-dose combination formulations (soft gelatin capsules). The proposed method was validated, and it was applied to determine the in vitro dissolution performance of IBU and CAF from a commercial formulation.

Methods: The method is based on the use of the second-derivatives of the zero-order spectra and measurement at zero-crossing wavelengths. Linearity, accuracy, precision, stability, and influence of the filter were evaluated. Dissolution profiles of IBU and CAF were obtained with the USP Apparatus 2 at 100 rpm and 900 ml of 0.1 M phosphate buffer pH 7.4 as dissolution medium. Dissolution samples were treated with the proposed UV-derivative method and results were compared with data previously published.

Results: The zero-crossing points for determination of IBU and CAF were found at 235.6 nm and 218.8 nm, respectively. The method was linear in the range of 7.5-15 µg/ml for IBU and 5-25 µg/ml for CAF (R2>0.999, *P<0.05). The precision and accuracy of the method were within acceptable criteria (CV<0.99% and recovery 97.97% for IBU and CV<1.76% and recovery 99.05% for CAF). Fiberglass filters were the best option to filter samples and stability of all drugs was adequate when solutions were stored at 25ºC during 24 h. Dissolution of IBU and CAF at 60 min was 99-100% with dissolution profiles of sigmoidal S-shape. Weibull function and logistic were the best-fit models that describe the in vitro dissolution performance of both drugs.

Conclusion: The proposed UV-derivative method allows the simultaneous determination of IBU and CAF in fixed-dose combination formulations. The method generates reliable information that can be compared with published data. The proposed UV-derivative method is rapid and simple and can be easily adopted for routine analysis of IBU and CAF.

Keywords: caffeine, derivative spectroscopy, ibuprofen, USP Apparatus 2


1. Bell DSH. Combine and conquer: advantages and disadvantages of fixed-dose combination therapy. Diabetes Obes Metab 2013;15:291?300.
2. Potthast H, Dressman JB, Junginger HE, Midha KK, Oeser H, Shah VP, Vogelpoel H, Barends DM. Biowaiver monographs for immediate-release solid oral dosage forms: ibuprofen. J Pharm Sci 2005;94:2121?31.
3. Tavares C, Sakata RK. Caffeine in the treatment of pain. Rev Bras Anestesiol 2012;62:387?401.
4. Grama P, Oltea MP, Zah CA. Effect of caffeine in pain management. Acta Marisiensis-Seria Medica 2020;66:127?31.
5. Williams HD, Barrett DA, Ward R, Hardy IJ, Melia CD. A liquid chromatography method for quantifying caffeine dissolution from pharmaceutical formulations into colloidal, fat-rich media. J Chromatogr B Analyt Technol Biomed Life Sci 2010;878:1739?45.
6. Polski A, Kasperek R, Sobotka-Polska K, Poleszak E. Review on analgesic effect of co-administrated ibuprofen and caffeine. Curr Issues Pharm Med Sci 2014;27:10?3.
7. Medina JR, Domínguez-Ramírez AM, Jung H, Bravo G, Díaz-Reval MI, Déciga-Campos M, López-Muñoz FJ. Enhancement of antinociception by co-administration of ibuprofen and caffeine in arthritic rats. Eur J Pharmacol 2006;544:31?8.
8. Medina R, Hurtado M, Soria-Arteche O, Moreno-Rocha LA, Jung H, López-Muñoz FJ. PK/PD of rac-ibuprofen co-administered with caffeine: a preclinical study using PIFIR model. Lat Am J Pharm 2018;37:1638?45.
9. Bergese S, Castellon-Larios K. The effectiveness of a single dose of oral ibuprofen plus caffeine in acute postoperative pain in adults. BMJ Evid Based Med 2016;21:24.
10. Forbes JA, Beaver WT, Jones KF, Kehm CJ, Smith WK, Gongloff CM, Zeleznock JR, Smith JW. Effect of caffeine on ibuprofen analgesia in postoperative oral surgery pain. Clin Pharmacol Ther 1991;49:674?84.
11. McQuay HJ, Angell K, Carroll D, Moore RA, Juniper RP. Ibuprofen compared with ibuprofen plus caffeine after third molar surgery. Pain 1996;66:247?51.
12. Weiser T, Richter E, Hegewisch A, Muse DD, Lange R. Efficacy and safety of a fixed-dose combination of ibuprofen and caffeine in the management of moderate to severe dental pain after third molar extraction. Eur J Pain 2018;22:28?38.
13. Förderreuther S, Lampert A, Hitier S, Lange R, Weiser T. The impact of baseline pain intensity on the analgesic efficacy of ibuprofen/caffeine in patients with acute postoperative dental pain: post hoc subgroup analysis of a randomized controlled trial. Adv Ther 2020;37:2976?87.
14. Amidon GL, Lennernäs H, Shah VP, Crison JRA. Theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 1995;12:413?20.
15. Lindenberg M, Kopp S, Dressman JB. Classification of orally administered drugs on the World Health organization model list of essential medicines according to the biopharmaceutics classification system. Eur J Pharm Biopharm 2004;58:265?78.
16. Kasim NA, Whitehouse M, Ramachandran C, Bermejo M, Lennernäs H, Hussain AS, Junginger HE, Stavchansky SA, Midha KK, Shah VP, Amidon GL. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Mol Pharm 2004;1:85?96.
17. Food and Drug Administration. Guidance for Industry: Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutics Classification System; 2017. Available from: https://www.fda.gov/media/70963/download. [Last Accessed on 1 Feb 2021]
18. United States Pharmacopeia and National Formulary USP43-NF38; The United States Pharmacopeial Convention, Inc: Rockville MD; 2020.
19. Martín MJ, Pablos F, González AG. Simultaneous determination of caffeine and non-steroidal anti-inflammatory drugs in pharmaceutical formulations and blood plasma by reverse-phase HPLC from linear gradient elution. Talanta 1999;49:453?9.
20. Khoshayand MR, Abdollahi H, Shariatpanahi M, Saadatfard S, Mohammadi A. Simultaneous spectrophotometric determination of paracetamol, ibuprofen and caffeine in pharmaceuticals by chemometric methods. Spectrochim Acta A 2008;70:491?9.
21. Dang HV, Thi Thu HT, Thi Ha LD, Mai HN. RP-HPLC and UV spectrophotometric analysis of paracetamol, ibuprofen, and caffeine in solid pharmaceutical dosage forms by derivative, Fourier, and wavelet transforms: a comparison study. J Anal Methods Chem 2020, article ID 8107571, 13 pages.
22. Serrano N, Castilla O, Ariño C, Diaz-Cruz MS, Díaz-Cruz JM. Commercial screen-printed electrodes based on carbon nanomaterials for a fast and cost-effective voltametric determination of paracetamol, ibuprofen and caffeine in water samples. Sensors 2019;19:4039.
23. Zambakjian C, Sakur AA. A new gas chromatographic method development and validation for the simultaneous determination of ibuprofen and caffeine in bulk and pharmaceutical dosage form. Future J Pharm Sci 2020;6:110.
24. Lemos de Souza M, Otero JC, López-Tocón I. Comparative performance of citrate, borohydride, hydroxylamine and ?-cyclodextrin silver solos for detecting ibuprofen and caffeine pollutants by means of surface-enhanced Raman spectroscopy. Nanomaterials 2020;10:2339.
25. Mohammadnejad M. Simultaneous determination of ibuprofen and caffeine in urine samples by combining MCR-ALS and excitation-emission data. Anal Bioanal Chem Res 2016;3:123?30.
26. Podczeck F. Comparison of in vitro dissolution profiles by calculating mean dissolution time (MDT) or mean residence time (MRT). Int J Pharm 1993;97:93?100.
27. 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 Ana 1998;17:811?22.
28. Cardot JM, Beyssac E, Alrici M. In vitro-in vivo correlation: importance of dissolution in IVIVC. Dissolut Technol 2007;14:15?9.
29. Yuksel N, Kanik AE, Baykara T. Comparison of in vitro dissolution profiles by ANOVA-based, model-dependent and -independent methods. Int J Pharm 2000;209:57?67.
30. Zhang Y, Huo M, Zhou J, Zou A, Li W, Yao C, Xie S. DDSolver: an add-in program for modeling and comparison of drug dissolution profiles. AAPS J 2010;12:263?71.
31. Ilango KB, Kavimani S. A systematic review of mathematical models of pharmaceutical dosage forms. Int J Curr Pharm Rev Res 2015;6:59?70.
32. Langenbucher F. Linearization of dissolution rate curves by the Weibull distribution. J Pharm Pharmacol 1972;24:979?81.
33. Medina JR, Cortés M, Romo E. Comparison of the USP Apparatus 2 and 4 for testing the in vitro release performance of ibuprofen generic suspensions. Int J Appl Pharm 2017;9:90?5.
34. Medina R, Cázares IS, Hurtado M, Domínguez-Ramírez AM. Estimation of acetaminophen and ibuprofen in tablets by a derivative UV method: characterization of in vitro release using USP Apparatuses 2 and 4. Lat Am J Pharm 2017;36:706?15.
35. Liu X, Liu S, Wu J, Fang Z. Simultaneous monitoring of aspirin, phenacetin and caffeine in compound aspirin tablets using a sequential injection drug-dissolution testing system with partial least squares calibration. Anal Chim Acta 1999;392:273?81.
36. Franek F, Holm P, Larsen F, Steffansen B. Interaction between fed gastric media (Ensure Plus®) and different hypromellose based caffeine controlled release tablets: comparison and mechanistic study of caffeine release in fed and fasted media versus water using the USP dissolution apparatus 3. Int J Pharm 2014;461:419?26.
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Medina-López, J. R., Soto-Juha, J. A., & Contreras-Jiménez, J. M. (2021). RAPID AND SIMPLE DETERMINATION OF IBUPROFEN AND CAFFEINE IN FIXED-DOSE COMBINATION FORMULATIONS: APPLICATION TO DISSOLUTION STUDIES. International Journal of Applied Pharmaceutics, 13(3). https://doi.org/10.22159/ijap.2021v13i3.40975
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