A fully automated sequential injection system was tested in terms of its application in liberation testing, and capabilities and limitations were discussed for clotrimazole liberation from three semisolid formulations. An evaluation based on kinetic profiles obtained in short and longer sampling intervals and steady-state flux values were applied as traditional methods. The obtained clotrimazole liberation profile was faster in the case of Delcore and slower for Clotrimazol AL and Canesten cream commercial formulations. The steady-state flux values for the tested formulations were 52 µg cm-2 h-1 for Canesten, 35 µg cm-2 h-1 for Clotrimazol AL, and 7.2 µg cm-2 h-1 for Delcore measured in 4 min sampling intervals. A simplified approach for the evaluation of the initial rate based on the gradient between the second and third sampling points was used for the first time and was found to correspond well with the results of the conventional methods. A comparison based on the ratio of the steady-state flux and the initial rate values for Canesten and Clotrimazol AL proved the similarity of the obtained results. The proposed alternative was successfully implemented for the comparison of short-term kinetic profiles. Consequently, a faster and simpler approach for dissolution/liberation testing can be used.

Contipro a s 561 02 Dolní Dobrouč Czech Republic

Department of Analytical Chemistry Faculty of Pharmacy in Hradec Králové Charles University 500 05 Hradec Králové Czech Republic

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European Pharmacopoeia Commission . European Pharmacopoeia (Ph. Eur.) 10th ed. European Pharmacopoeia Commission; Strasbourg, France: 2020. Article 2.9.3 Dissolution of solid formulations.

Liu X.Z., Liu S.S., Wu J.F., Fang Z.L. 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;392:273–281. doi: 10.1016/S0003-2670(99)00235-4. DOI

Fang Z.L., Fang Q., Liu X.Z., Chen H.W., Liu C.L. Continuous monitoring in drug dissolution testing using flow injection systems. Trends Anal. Chem. 1999;18:261–271. doi: 10.1007/s002160051347. DOI

Solich P., Sklenářová H., Huclová J., Šatínský D., Schaefer U. Fully automated drug liberation apparatus for semisolid preparations based on sequential injection analysis. Anal. Chim. Acta. 2003;499:9–16. doi: 10.1016/j.aca.2003.09.002. DOI

Klimundová J., Mervartová K., Sklenářová H., Solich P., Polášek M. Automated sequential injection fluorimetric set-up for multiple release testing of topical formulation. Anal. Chim. Acta. 2006;573–574:366–370. doi: 10.1016/j.aca.2006.04.012. PubMed DOI

Klimundová J., Šatínský D., Sklenářová H., Solich P. Automation of simultaneous release tests of two substances by sequential injection chromatography coupled with Franz cell. Talanta. 2006;69:730–735. doi: 10.1016/j.talanta.2005.11.011. PubMed DOI

Tzanavaras P.D., Verdoukas A., Balloma T. Optimization and validation of a dissolution test for famotidine tablets using flow injection analysis. J. Pharm. Biomed. Anal. 2006;41:437–441. doi: 10.1016/j.jpba.2005.12.011. PubMed DOI

Pimenta A.M., Montenegro M.C.B.S.M., Araujo A.N., Martínez Calatayud J. Application of sequential injection analysis to pharmaceutical analysis. J. Pharm. Biomed. Anal. 2006;40:16–34. doi: 10.1016/j.jpba.2005.10.006. PubMed DOI

Motz S.A., Klimundova J., Schaefer U.F., Balbach S., Eichinger T., Solich P., Lehr C.M. Automated measurement of permeation and dissolution of propranolol HCl tablets using sequential injection analysis. Anal. Chim. Acta. 2007;581:174–180. doi: 10.1016/j.aca.2006.07.080. PubMed DOI

Alves A.C., Ramos I., Nunes C., Magalhaes L.M., Sklenářová H., Segundo M., Lima J.L.F.C., Reis S. On-line automated evaluation of lipid nanoparticles transdermal permeation using Franz diffusion cell and low-pressure chromatography. Talanta. 2016;146:369–374. doi: 10.1016/j.talanta.2015.08.070. PubMed DOI

[(accessed on 3 September 2021)]. Available online: https://www.sotax.com/dissolution_testing/solutions/automated_dissolution_testing.

[(accessed on 3 September 2021)]. Available online: https://permegear.com/franz-cells/

Zelená L., Marques S.S., Segundo M.A., Miró M., Pávek P., Sklenářová H., Solich P. Fully automatic flow-based device for monitoring of drug permeation across a cell monolayer. Anal. Bioanal. Chem. 2016;408:971–981. doi: 10.1007/s00216-015-9194-0. PubMed DOI

Ducrotté-Tassel A., Kirilov P., Salvi J.P., Tran V.H., Dore V., Marignac G., Pignon C.P., Perrot S., Boulieu R. Ex-vivo permeation of enrofloxacin through shed skin of Python molurus bivittatus, as evaluated with a Franz cell. J. Drug Deliv. Sci. Technol. 2016;36:89–94. doi: 10.1016/j.jddst.2016.06.017. DOI

Vanti G., Grifoni L., Bergonzi M.C., Antiga E., Mentefusco F., Caproni M., Bilia A.R. Development and optimisation of biopharmaceutical properties of a new microemulgel of cannabidiol for locally-acting dermatological delivery. Int. J. Pharm. 2021;607:121036. doi: 10.1016/j.ijpharm.2021.121036. PubMed DOI

Szabados M., Gácsi A., Gulyás Y., Kónya Z., Kukovecz Á., Csányi E., Pálinkó I., Sipos P. Conventional or mechanochemically-aided intercalation of diclofenac and naproxen anions into the interlamellar space of CaFe-layered double hydroxides and their application as dermal drug delivery systems. Appl. Clay Sci. 2021;212:106233. doi: 10.1016/j.clay.2021.106233. DOI

Katakam L.N.R., Katari N.K. Development of in-vitro release testing method for permethrin cream formulation using Franz Vertical Diffusion Cell apparatus by HPLC. Talanta Open. 2021;4:100056. doi: 10.1016/j.talo.2021.100056. DOI

Dezani A.B., Pereira T.M., Caffaro A.M., Reis J.M., dos Reis Serra C.H. Determination of lamivudine and zidovudine permeability using a different ex vivo method in Franz cells. J. Pharmacol. Toxicol. Methods. 2013;67:194–202. doi: 10.1016/j.vascn.2013.01.005. PubMed DOI

Hoang V.C., Shafaat A., Jankovskaja S., Gomes V.G., Ruzgas T. Franz cells for facile biosensor evaluation: A case of HRP/SWCNT-based hydrogen peroxide detection via amperometric and wireless modes. Biosens. Bioelectron. 2021;191:113420. doi: 10.1016/j.bios.2021.113420. PubMed DOI

[(accessed on 12 March 2020)]. Available online: https://www.drugbank.ca/structures/DB00257/image.svg.

[(accessed on 12 March 2020)]. Available online: https://www.drugs.com/ppa/clotrimazole-topical.html.

Kast C.E., Valenta C., Leopold M., Bernkop-Schnurch A. Design and in vitro evaluation of a novel bioadhesive vaginal drug delivery system for clotrimazole. J. Control. Release. 2002;81:347–354. doi: 10.1016/S0168-3659(02)00077-9. PubMed DOI

Alam M.A., Al-Janoobi F.I., Alzahrani K.A., Al-Agamy M.H., Abdelgalil A.A., Al-Mohizea A.M. In-vitro efficacies of topical microemulsions of clotrimazole and ketoconazole; and in-vivo performance of clotrimazole microemulsion. J. Drug Deliv. Sci. Technol. 2017;39:408e416. doi: 10.1016/j.jddst.2017.04.025. DOI

Santos S.S., Lorenzoni A., Pegoraro N.S., Denardi L.B., Alves S.H., Schaffazick S.R., Cruz L. Formulation and in vitro evaluation of coconut oil-core cationic nanocapsules intended for vaginal delivery of clotrimazole. Colloids Surf. B. 2014;116:270–276. doi: 10.1016/j.colsurfb.2014.01.011. PubMed DOI

Nematpour N., Moradipour P., Zangeneh M.M., Arkan E., Abdoli E., Behbood L. The application of nanomaterial science in the formulation a novel antibiotic: Assessment of the antifungal properties of mucoadhesive clotrimazole loaded nanofiber versus vaginal films. Mater. Sci. Eng. C. 2020;110:110635. doi: 10.1016/j.msec.2020.110635. PubMed DOI

Blokhina S., Sharapova A., Ol’khovich M., Perlovich G. Experimental solubility of clotrimazole and some thermodynamic aspects of dissolution in different solvents. Thermochim. Acta. 2019;682:178431. doi: 10.1016/j.tca.2019.178431. DOI

Pedersen M., Bjerregaard S., Jacobsen J., Mehlsen Sørensen A. A genuine clotrimazole γ-cyclodextrin inclusion complex-isolation, antimycotic activity, toxicity and an unusual dissolution rate. Int. J. Pharm. 1998;176:121–131. doi: 10.1016/S0378-5173(98)00310-X. DOI

Jung Y.C., Yu-Kyoung O., Hak S.K., Eun J.K., Dong D.J., Ki T.N., Chong-Kook K. Prolonged antifungal effects of clotrimazole-containing mucoadhesive thermosensitive gels on vaginitis. J. Control. Release. 2002;82:39–50. doi: 10.1016/S0168-3659(02)00086-X. PubMed DOI

ICH Expert Working Group . ICH Harmonised Tripartite Guideline. ICH Expert Working Group; Geneva, Switzerland: 2005. Validation of analytical procedures: Text and methodology Q2(R1)

Paradkar M., Thakkar V., Soni T., Gandhi T., Gohel M. Formulation and evaluation of clotrimazole transdermal spray. Drug Dev. Ind. Pharm. 2015;41:1718–1725. doi: 10.3109/03639045.2014.1002408. PubMed DOI

Wagner H., Zghoul N., Lehr C.-M., Schäfer U.F. Human skin and skin equivalents to study dermal penetration and permeation. In: Lehr C.-M., editor. Cell Culture Models of Biological Barriers. Taylor & Francis; London, UK: 2002.