Introduction: The hydrolytic stability of the calcium channel blocker representative diltiazem hydrochloride in the presence of different polymeric entourage was quantitatively assessed using HPLC.
Aim: The experiment was performed in order to establish drug-excipients compatibility in Poloxamer 407 hydrogel formulations, where the drug was introduced either by a direct (conventional) approach or in the form of Eudragit RS microsponge-type particles with sustained drug release.
Materials and Methods: Samples of conventional diltiazem 2% hydrogel and microsponge-enriched diltiazem 2% hydrogel were stored at 25±2oC for 10 months, protected from light. Analysis of the chemical decomposition rate of diltiazem hydrochloride to its desacetyl degradant - O-desacetyl-diltiazem hydrochloride - was performed in the period between 4th and 10th month of storage.
Results and Discussion: It was hypothesized that a polymeric “shield” of Eudragit RS in the composition of diltiazem-loaded porous microspheres and/or the enhanced viscosity achieved by the addition of high-molecular gelling agent Poloxamer 407 to an aqueous drug dispersion will benefit the drug’s stability. Instead, a negative effect on the hydrolysis rate was found to be dominant for both polymers, likely due to an “unfavorable” shift in the dielectric conductivity of the media and/or suspected catalytic effect of quaternary ammonium groups of Eudragit RS.
Conclusion: These preliminary results led us to a deeper understanding of the polymeric impact on diltiazem hydrolytic behavior and a very useful foundation for a future preformulation stage in the development of diltiazem modified-release semisolid forms for the treatment of chronic anal fissure.
Yoshioka S, Stella VJ. Stability of drugs and dosage forms. Kluwer Academic Publishers; 2002. doi: 10.1007/0-306-46829-8_4.
Chafetz L, Shah KP. Stability of diltiazem in acid solution. J Pharm Sci. 1991;80(2):171–2. doi: 10.1002/jps.2600800218.
Sadeghi F, Navidpour L, Bayat S, Afshar M. Validation and uncertainty estimation of an ecofriendly and stability-indicating hplc method for determination of diltiazem in pharmaceutical preparations. J Anal Methods Chem. 2013;2013:1–10. doi: 10.1155/2013/353814.
Mazzo DJ, Obetz CL, Shuster J. Diltiazem Hydrochloride. In: Brittain HG, editor. Analytical profiles of drug substances and excipients. Elsevier: Academic Press, Inc; 1994. p. 53–98. doi: 10.1016/s0099-5428(08)60600-0.
Molden E, Johansen PW, Boe GH, Bergan S, Christensen H, Rugstad HE, et al. Pharmacokinetics of diltiazem and its metabolites in relation to CYP2D6 genotype. Clin Pharmacol Ther. 2002;72(3):333–42. doi: 10.1067/mcp.2002.127396.
Molden E. Desacetyl-diltiazem displays severalfold higher affinity to CYP2D6 compared with CYP3A4. Drug Metab Dispos. 2002;30(1):1–3. doi: 10.1124/dmd.30.1.1.
Muszalska I, Jamszol L, Grzeskowiak D. Kinetics of hydrolysis of diltiazem hydrochloride in aqueous solutions. Acta Pol Pharm. 2003;60(3):163-168. doi: 10.1111/j.1365-2710.1988.tb00215.x.
Ishii K, Minato K, Nakai H, Sato T. Simultaneous assay of four stereoisomers of diltiazem hydrochloride. Application to in vitro chiral inversion studies. Chromatographia. 1995;41(7-8):450–4. doi: 10.1007/bf02318621.
Ishii K, Wakamoto S, Nakai H, Sato T. Assay of four stereoisomers of desacetyl diltiazem hydrochloride. Application to in vitro chiral inversion studies. Chromatographia. 1996;43(7-8):413–8. doi: 10.1007/bf02271021.
Molden E, Christensen H, Sund RB. Extensive metabolism of diltiazem and P-Glycoprotein-mediated efflux of desacetyl-diltiazem (M1) by rat jejunum in vitro. Drug Metab Dispos. 1999; 28(2):107-109. doi: 10.1124/dmd.30.1.1.
Ivanova NA, Trapani A, Franco CD, Mandracchia D, Trapani G, Franchini C, et al. In vitro and ex vivo studies on diltiazem hydrochloride-loaded microsponges in rectal gels for chronic anal fissures treatment. Int J Pharm. 2019; 557:53–65. doi: 10.1016/j.ijpharm.2018.12.039.
Kolev IN, Ivanova NА, Marinov MK, Alexieva GE, Strashilov VL. A QCM-based assay of drug content in Eudragit RS 100-based delivery systems. Talanta. 2019;202:531–9. doi: 10.1016/j.talanta.2019.05.033.
Ivanova NA, Franco CD, Trapani A, Petkova V, Dimitrov M. Synthesis and characterization of diltiazem loaded Eudragit RS 100 “microsponges”. World J Pharm Pharm Sci. 2017;6(6):32–42. doi: 10.20959/wjpps20176-9275.
Council of Europe. European Pharmacopoeia 8th ed. Strasbourg: Council of Europe; Ammonio Methacrylate Copolymer Type B. 2008;1551-52.
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