IN VITRO EVALUATION OF NAPROXEN SODIUM AND ACETAMINOPHEN FROM FIXED-DOSE COMBINATION GENERIC DRUGS USING THE FLOW-THROUGH CELL METHOD

Abstract

Objective: The aim of this study was the in vitro evaluation of naproxen sodium and acetaminophen from fixed-dose combination generic drugs based on the hydrodynamic environment generated by the flow-through cell method (USP Apparatus 4).

Methods: Dissolution studies were carried out using a USP Apparatus 4 Sotax CE6 with 22.6 mm cells, laminar flow at 16 ml/min, and 0.1 M phosphate buffer pH 7.4 at 37.0±0.5 °C as dissolution medium. Both drugs were identified and quantified by a validated first-order derivative spectrophotometric method. Measurements were achieved at 243.26 and 297.0 nm for naproxen sodium and acetaminophen, respectively. Dissolution profiles of generic drugs were compared with similarity factor f₂, t_50%, t_85%, t_90% values as well as model-dependent and independent methods.

Results: According to f₂ values, dissolution profiles of all generic drugs were considered dissimilar to the dissolution profiles of the reference product (f₂<50). Significant differences in t_50%, t_85%, t_90%, mean dissolution time and dissolution efficiency values were found (*P<0.05). Dissolution data better adjusted to Makoid-Banakar and Weibull's kinetic models.

Conclusion: The flow-through cell method was adequate for the in vitro evaluation of fixed-dose combination generic drugs containing naproxen sodium and acetaminophen. It should be necessary to evaluate the in vivo performance of fixed-dose generic formulations that contain naproxen sodium and acetaminophen in order to assure bioequivalence.

Keywords: Naproxen sodium, Acetaminophen, Flow-through cell method, Fixed-dose combination generic drugs, First-order derivative spectrophotometry.

 

1.        Ruiz ME, Gregorini A, Talevi A, Volonté MG. Dissolution studies of generic medications: new evidence of deviations from the transitivity principle. Dissol Technol 2012;19:13−24.

2.        Shokin IE, Ramenskaya GV, Vasulenko GF, Malalshenko EA. Assessment of the possibility of using comparative in vitro dissolution kinetics (biowaiver) instead of in vitro bioequivalence evaluation for establishing the inter-changeability of generic drugs. Pharm Chem J 2011;45:107−9.

3.        Jayasheel BG. Regulatory requirements for marketing fixed dose combinations. Perspect Clin Res 2010;1:120−3.

4.        Mitra A, Wu Y. Challenges and opportunities in achieving bioequivalence for fixed-dose combination products. AAPS J 2012;14:646−55.

5.        Faasen F, Vromans H. Biowaivers for oral immediate-release products. Clin Pharmacokinet 2004;45:1117−26.

6.        Kalantzi L, Reppas C, Dressman JB, Amidon GL, Junginger HE, Midha KK, et al. Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol). J Pharm Sci 2006;95:4−14.

7.        Palma-Aguirre JA, Villalpando-Hernández J, Novoa-Heckel G, Oliva I, Cariño L, López-Bojórquez E, et al. Bioavailability of two oral tablet and two oral suspension formulations of naproxen sodium/paracetamol (acetaminophen): single dose, randomized, open-label, two-period crossover comparisons in healthy Mexican adult subjects. Clin Ther 2009;31:399−410.

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

9.        United States Pharmacopeia and National Formulary USP 38-NF 33: The United States Pharmacopeial Convention, Inc. Rockville, MD; 2015.

10.     US FDA. Dissolution methods. Available from URL: http://www.accessdata.fda.gov/scripts/cder/dissolution/. [Last accessed on 24 Sep 2015].

11.     Medina JR, López-Tableros CA, Hernández-Altamirano G, Alarcón-Ãngeles G, Hurtado M, Domínguez-Ramírez AM. Simultaneous determination of naproxen sodium and acetaminophen in fixed-dose combinations formulations by first-order derivative spectroscopy: application to dissolution studies. Int J Pharm Pharm Sci 2015;7:183−8.

12.     Chevalier E, Viana M, Artaud A, Chomette L, Haddouchi S, Devidts G, et al. Comparison of three dissolution apparatuses for testing calcium phosphate pellets used as ibuprofen delivery systems. AAPS PharmSciTech 2009:10:597−605.

13.     Greco K, Bergman TL, Bogner R. Design and characterization of a laminar flow-through dissolution apparatus: comparison of hydrodynamic conditions to those of common dissolution techniques. Pharm Dev Technol 2011;16:75−87.

14.     Shiko G, Gladden LF, Sederman AJ, Connolly PC, Butler JM. MRI studies of the hydrodynamics in a USP 4 dissolution testing cell. J Pharm Sci 2011;100:976−91.

15.     Szymanska E, Winnicka K. Comparison of flow-through cell and paddle methods for testing vaginal tablets containing a poorly water-soluble drug. Trop J Pharm Res 2013;12:39–44.

16.     Emara LH, Emam MF, Taha NF, El-Ashmawy AA, Mursi NM. In-vitro dissolution study of meloxicam immediate release products using flow-through cell (USP apparatus 4) under different operational conditions. Int J Pharm Pharm Sci 2014;6:254−60.

17.     Jinno J, Kamada N, Miyake M, Yamada K, Mukai T, Odomi M, et al. In vitro-in vivo correlation for a wet-milled tablet of poorly water-soluble cilostazol. J Controlled Release 2008;130:29−37.

18.     Jantratid E, De Maio V, Ronda E, Mattavelli V, Vertzoni M, Dressman JB. Application of bio-relevant dissolution tests to the prediction of in vivo performance of diclofenac sodium from an oral modified-release pellet dosage form. Eur J Pharm Sci 2009;37:434−41.

19.     Hurtado M, Vargas Y, Domínguez-Ramírez AM, Cortés AR. Comparison of dissolution profiles for albendazole tablets using USP apparatus 2 and 4. Drug Dev Ind Pharm 2003;29:777-83.

20.     Medina JR, Salazar DK, Hurtado M, Cortés AR, Domínguez-Ramírez 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;22:141−7.

21.     Relación de Medicamentos de Referencia. Comisión Federal para la Protección contra Riesgos Sanitarios. México. Available from: URL: http://www.cofepris.gob.mx/AS/Documents/ Registro Sanitario Medicamentos/Rel_med_de_ref_15-08-2013. pdf. [Last accessed on 21 Nov 2015].

22.     ICH, Q2B Validation of Analytical Procedures: Methodology, International Conference on Harmonization; 1996. Available from: URL: http://www.fda.gov/downloads/drugs/ guidance-complianceregulatoryinformation/guidances/ucm073384.pdf. [Last accessed on 24 Oct 2015].

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

24.     Gao Z. In vitro dissolution testing with the flow-through method: a technical note. AAPS Pharm Sci Tech 2009;10:1401–5.

25.     Qui S, Wang K, Li M. In vitro dissolution studies of immediate-release and extended release formulations using flow-through cell apparatus 4. Dissolution Technol 2014;21:6−15.

26.     Yuksel N, Kanik AE, Baykara T. Comparison of dissolution profiles by ANOVA-based, model-dependent and independent methods. Int J Pharm 2000;209:57−67.

27.     Zhang Y, Huo M, Zhou J, Zou A, Li W, Yao C, et al. DD Solver: an add-in program for modeling and comparison of drug dissolution profiles. AAPS J 2010;12:263−71.

28.     Langenbucher F, Benz D, Kurth W, Moller H, Otz M. Standardized flow-cell method as an alternative to existing pharmacopoeial dissolution testing. Pharm Indian 1989; 51:1276−81.

29.     Steffansen B, Brodin B, Und Nielsen C. editors. Molecular Biopharmaceutics. ULLA Pharmacy Series. Pharmaceutical Press; 2010.

30.     Sunesen VH, Pedersen BL, Kristensen HG, Müller A. In vitro in vivo correlations for a poorly soluble drug, danazol, using the flow-through dissolution method with relevant dissolution media. Eur J Pharm Sci 2005;24:305−13.

31.     Demirtürk E, Öner L. In vitro-in vivo correlations. FABAD J Pharm Sci 2003;28:215−24.

32.     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.

33.     Anand O, Yu LX, Conner DP, Davit BM. Dissolution testing of generic drugs: and FDA perspective. AAPS J 2011;13:328−35.