• JOSE RAUL MEDINA-LOPEZ Departamento Sistemas Biologicos, Universidad Autonoma Metropolitana Xochimilco, Mexico City, Mexico http://orcid.org/0000-0002-4159-8403
  • JOAQUIN ALEXANDRO SOTO-JUHA Departamento Sistemas Biologicos, Universidad Autonoma Metropolitana Xochimilco, Mexico City, Mexico
  • JUAN MANUEL CONTRERAS-JIMÉNEZ Departamento Sistemas Biologicos, Universidad Autonoma Metropolitana Xochimilco, Mexico City, Mexico




Caffeine, Derivative spectroscopy, Ibuprofen, USP Apparatus 2


Objective: To develop a UV-derivative spectrophotometric method with zero-crossing 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 the 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 25 °C 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.


Bell DSH. Combine and conquer advantages and disadvantages of fixed-dose combination therapy. Diabetes Obes Metab 2013;15:291‒300.

Potthast H, Dressman JB, Junginger HE, Midha KK, Oeser H, Shah VP, et al. Biowaiver monographs for immediate-release solid oral dosage forms: ibuprofen. J Pharm Sci 2005;94:2121‒31.

Tavares C, Sakata RK. Caffeine in the treatment of pain. Rev Bras Anestesiol 2012;62:387‒401.

Grama P, Oltea MP, Zah CA. Effect of caffeine in pain management. Acta Marisiensis Seria Med 2020;66:127‒31.

Shah KM, Dadhaniya P, Trivedi VT. Effect of caffeine in an experimental model of rheumatoid arthritis in rats. Int J Pharm Pharm Sci 2015;7:364‒7.

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: Anal Technol Biomed Life Sci 2010;878:1739‒45.

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.

Medina JR, Dominguez Ramirez AM, Jung H, Bravo G, Diaz Reval MI, Deciga Campos M, Lopez Muñoz FJ. Enhancement of antinociception by co-administration of ibuprofen and caffeine in arthritic rats. Eur J Pharmacol 2006;544:31‒8.

Medina R, Hurtado M, Soria Arteche O, Moreno Rocha LA, Jung H, Lopez Munoz FJ. PK/PD of rac-ibuprofen co-administered with caffeine: a preclinical study using PIFIR model. Latt Am J Pharm 2018;37:1638‒45.

Bergese S, Castellon Larios K. The effectiveness of a single dose of oral ibuprofen plus caffeine in acute postoperative pain in adults. Br Med J Evid Based Med 2016;21:24.

Forbes JA, Beaver WT, Jones KF, Kehm CJ, Smith WK, Gongloff CM, et al. Effect of caffeine on ibuprofen analgesia in postoperative oral surgery pain. Clin Pharmacol Ther 1991;49:674‒84.

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.

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.

Forderreuther 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.

Amidon GL, Lennernas 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.

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.

Kasim NA, Whitehouse M, Ramachandran C, Bermejo M, Lennernäs H, Hussain AS, et al. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Mol Pharm 2004;1:85‒96.

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 01 Feb 2021]

United States Pharmacopeia and National Formulary USP43-NF38; The United States Pharmacopeial Convention, Inc: Rockville MD; 2020.

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.

Muchlisyam AYS, Sinaga SM. Application and validation of derivative spectrophotometric for determination levels of ternary mixtures of paracetamol, propyphenazone, and caffeine in tablet dosage form. Asian J Pharm Clin Res 2018;11:8‒11.

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.

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. DOI:10.1155/2020/8107571

Serrano N, Castilla O, Arino C, Diaz Cruz MS, Diaz 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.

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.

Lemos de Souza M, Otero JC, Lopez Tocon I. Comparative performance of citrate, borohydride, hydroxylamine and β-cyclodextrin silver sols for detecting ibuprofen and caffeine pollutants by means of surface-enhanced Raman spectroscopy. Nanomaterials 2020;10:2339.

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.

Lofty HM, Saleh SS. Recent development in ultraviolet spectrophotometry through the last decade (2006-2016): a review. Int J Pharm Pharm Sci 2016;8:40‒56.

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.

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;17:811‒22.

Cardot JM, Beyssac E, Alrici M. In vitro-in vivo correlation: importance of dissolution in IVIVC. Dissolut Technol 2007;14:15‒9.

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.

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.

Ilango KB, Kavimani S. A systematic review of mathematical models of pharmaceutical dosage forms. Int J Curr Pharm Rev Res 2015;6:59‒70.

Langenbucher F. Linearization of dissolution rate curves by the weibull distribution. J Pharm Pharmacol 1972;24:979−81.

Medina JR, Cortes 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.

Medina R, Cazares IS, Hurtado M, Domínguez Ramirez AM. Estimation of acetaminophen and ibuprofen in tablets by a derivative UV method: characterization of in vitro release using USP apparatuses 2 and 4. Latt Am J Pharm 2017;36:706‒15.

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.

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.



How to Cite




Short Communication(s)

Most read articles by the same author(s)