Study of Dissolution Kinetics of Mefenamic Acid Solid Dispersion with Polyvinylpyrrolidone

The low solubility of a biologically active substance in an aqueous medium is often the main reason for the reduced therapeutic effect of drugs. The most common approach to solve this problem is to obtain a watersoluble salt of the active substance and an appropriate preparatory formulation based on it. In this case, the solubility of the obtained compound in hydrophobic systems decreases dramatically, which decreases the rate of transmembrane transport and changes the pharmacokinetic laws of the process. In practice, not only the dependence of the therapeutic effect on the salt compound properties, but also a complete loss of the drug active ingredient activity can be observed. The use of biologically active compound solid dispersions in watersoluble polymers is the most promising approach to increase the therapeutic effect of drugs while maintaining the hydrophobic nature of the active component, to reduce the dose load on the patient’s body and obtain prolonged action. In experiments we obtained solid dispersions of mefenamic acid in polyvinylpyrrolidone and studied kinetic regularities of solubility of this promising drug form in aqueous solution of phosphate buffer. By means of mathematical modelling it was found that the phenomenon under study is well described by Ritger --- Peppas model, which considers diffusion of biologically active component into solution according to Fick's law with possible influence on mass transfer at swelling and degradation of polymer matrix

Funding for this research was provided by the Ministry of Science and Higher Education of the Russian Federation (project no. 075-03-2020-223 (FSSF-2020-0017))

References

[1] Khadka P., Ro J., Kim H., et al. Pharmaceutical particle technologies: an approach to improve drug solubility, dissolution and bioavailability. Asian J. Pharm. Sci., 2014, vol. 9, iss. 6, pp. 304--316. DOI: https://doi.org/10.1016/j.ajps.2014.05.005

[2] Shokhin I.E., Kulinich Yu.I., Ramenskaya G.V., et al. Essential biopharmaceutical properties of drugs at the gastrointestinal absorption stage (review). Pharm. Chem. J., 2011, vol. 45, no. 7, pp. 415--418. DOI: https://doi.org/10.1007/s1109401106454

[3] Golovenko N.Ya., Borisyuk I.Yu. Biopharmaceutical classification system --- experimental model of the prediction of drug bioavailability. Biochem. M. Suppl. Ser. B, 2008, vol. 2, no. 3, pp. 235--244. DOI: https://doi.org/10.1134/S1990750808030037

[4] Yabbarov N.G., Posypanova G.A., Vorontsov E.A. Application prospects of multifunctional dendritic molecules in medicine and biology. Molekulyarnaya meditsina [Molecular Medicine], 2012, no. 6, pp. 37--45 (in Russ.).

[5] Alekseev K.V., Tikhonova N.V., Blynskaya E.V., et al. Technology of raising the avaliability of biologic and pharmaceutical drugs. Vestnik novykh meditsinskikh tekhnologiy [Journal of New Medical Technologies], 2012, vol. 19, no. 4, pp. 43--47 (in Russ.).

[6] Shokhin I.E., Ramenskaya G.V., Vasilenko G.F., et al. In vitro dissolution kinetic study of ibuprofen preparations. Vestnik VGU. Ser. Khimiya. Biologiya. Farmatsiya [Proceedings of Voronezh State University. Series: Chemistry. Biology. Pharmacy], 2009, no. 2, pp. 198--201 (in Russ.).

[7] Loftsson T., Brewster M.E. Pharmaceutical applications of cyclodextrins: basic science and product development. J. Pharm. Pharmacol., 2010, vol. 62, iss. 11, pp. 1607--1621. DOI: https://doi.org/10.1111/j.2042-7158.2010.01030.x

[8] Bonthagarala B., Dasari V., Kotra V. Enhancement of solubility and dissolution rate of BCS class II drug ritonavir using liquisolid technique. Int. J. Pharm. Sci. Res., 2019, vol. 10, iss. 5, pp. 2430--2438. DOI: https://doi.org/10.13040/IJPSR.0975-8232.10(5).2430-38

[9] Modica de Mohac L., Keating A.V., de Fatima Pina M., et al. Engineering of nanofibrous amorphous and crystalline solid dispersions for oral drug delivery. Pharmaceutics, 2019, vol. 11, iss. 7. DOI: https://doi.org/10.3390/pharmaceutics11010007

[10] Shmyreva Yu., Schmalz D., Brunemann J. Increasing solubility by solid dispersion using cellulose derivatives. Farmatsevticheskaya otrasl’, 2015, no. 6, pp. 52--55 (in Russ.).

[11] Tkachenko M.L., Zhnyakina L.E., Moshchenskiy Yu.V., et al. Ibuprofen hard dispersions research with trisamin as the hydrophilic carrier. Vestnik VGU. Ser. Khimiya. Biologiya. Farmatsiya [Proceedings of Voronezh State University. Series: Chemistry. Biology. Pharmacy], 2007, no. 1, pp. 53--60 (in Russ.).

[12] Kanikkannan N. Technologies to improve the solubility, dissolution and bioavailability of poorly soluble drugs. J. Anal. Pharm. Res., 2018, vol. 7, iss. 1, art. 00198. DOI: https://doi.org/10.15406/japlr.2018.07.00198

[13] Teslev A.A. On the use of solid dispersed systems to improve the biopharmaceutical characteristics of medic. Farmatsevticheskie tekhnologii i upakovka, 2014, vol. 3, no. 2, pp. 18--21 (in Russ.).

[14] Allawadi D., Singh N., Singh S., et al. Solid dispersions: a review on drug delivery system and solubility enhancement. Int. J. Pharm. Sci. Res., 2013, vol. 4, iss. 6, pp. 2094--2105. DOI: https://doi.org/10.13040/IJPSR.0975-8232.4(6).209405

[15] Nurhikmah W., Sumirtapura Y.C., Pamudji J.S. Dissolution profile of mefenamic acid solid dosage forms in two compendial and biorelevant (FaSSIF) media. Sci. Pharm., 2016, vol. 84, iss. 1, pp. 181--190. DOI: https://doi.org/10.3797/scipharm.ISP.2015.09

[16] Rao K.R., Nagabhushanam M.V., Chowdary K.P. In vitro dissolution studies on solid dispersions of mefenamic acid. Indian J. Pharm. Sci., 2011, vol. 73, no. 2, pp. 243--247.

[17] Singh A., Sharma P.K., Meher J.G., et al. Evaluation of enhancement of solubility of paracetamol by solid dispersion technique using different polymers concentration. Asian J. Pharm. Clin. Res., 2011, vol. 4, no. 1, pp. 117--119.

[18] Niebergall P.J., Milosovich G., Goyan J.E. Dissolution rate studies. II. Dissolution of particles under conditions of rapid agitation. J. Pharm. Sci., 1963, vol. 52, iss. 3, pp. 236--241. DOI: https://doi.org/10.1002/jps.2600520310

[19] Higuchi T. Mechanism of sustained-action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J. Pharm. Sci., 1963, vol. 52, iss. 12, pp. 1145--1149. DOI: https://doi.org/10.1002/jps.2600521210

[20] Ritger P.L., Peppas N.A. A simple equation for description of solute release I. Fickian and non-Fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs. J. Control Release, 1987, vol. 5, iss. 1, pp. 23--36. DOI: https://doi.org/10.1016/0168-3659(87)90034-4

[21] Peppas N.A., Sahlin J.J. A simple equation for the description of solute release. III. Coupling of diffusion and relaxation. Int. J. Pharm., 1989, vol. 57, iss. 2, pp. 169--172. DOI: https://doi.org/10.1016/0378-5173(89)903062

[22] Katti V.S., Kadam A.M., Honmane S.M., et al. Improvement of solubility and dissolution rate of candesartan cilexetil by solid dispersion in polyvinylpyrrolidone. Int. J. Pharm. Sci. Res., 2014, vol. 5, iss. 4, pp. 1550--1556. DOI: https://doi.org/10.13040/IJPSR.0975-8232.5(4).1550-56

[23] Guedes F.L., de Oliveira B.G., Hernandes M.Z., et al. Solid dispersions of imidazolidinedione by PEG and PVP polymers with potential antischistosomal activities. AAPS PharmSciTech, 2011, vol. 12, no. 1, pp. 401--410. DOI: https://doi.org/10.1208/s12249-0109556-z

[24] Zhao Y., Xin T., Ye T., et al. Solid dispersion in the development of a nimodipine delayed-release tablet formulation. Asian J. Pharm. Sci., 2014, vol. 9, iss. 1, pp. 35--41. DOI: https://doi.org/10.1016/j.ajps.2013.11.006

[25] Fadeev G.N., Ermolaeva V.I., Boldyrev V.S., et al. Destabilization kinetics of polyvinylpyrrolidone-iodine in a field of low frequency impacts. Russ. J. Phys. Chem., 2016, vol. 90, no. 9, pp. 1724--1728. DOI: https://doi.org/10.1134/S0036024416090077

[26] Boldyrev V.S., Ermolaeva V.I., Sinkevich V.V., et al. Destabilization of polyvinyl pyrrolidone-iodine chelate structure in lowfrequency field. Herald of the Bauman Moscow State Technical University, Series Natural Sciences, 2017, no. 4 (73), pp. 90--99 (in Russ.). DOI: https://doi.org/10.18698/18123368201749099

[27] Sharmal A., Jain C.P. Preparation and characterization of solid dispersions of carvedilol with PVP K30. Res. Pharm. Sci., 2010, vol. 5, no. 1, pp. 49--56.

[28] Varfolomeev S.D., Gurevich K.G. Biokinetika. Prakticheskiy kurs [Biokinetics: a practical course]. Moscow, Fair-press Publ., 1999.