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Fluconazole–excipient compatibility studies as the first step in the development of a formulation candidate for biowaiver

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Abstract

The biowaiver of bioequivalence studies on class I drugs of the biopharmaceutics classification system (BCS) is aimed mainly at reducing the costs and the exposure of health volunteers to a new pharmaceutical formulation. Fluconazole is an important antifungal agent but in the literature it is not clear whether it belongs to BCS class I or III. Compatibility studies are considered to be the first step in product development and on considering a biowaiver candidate these gain even greater importance since the final product will not be submitted to in vivo tests. The aim of this study was to qualitatively determine the composition of a commercially available fluconazole formulation in the form of capsules with regard to the presence of critical excipients and to carry out compatibility studies by differential scanning calorimetry (DSC). One formulation did not contain sodium lauryl sulfate and contained mannitol, in contrast to the reference formulation, which could hinder the acceptance of the biowaiver. The interaction of fluconazole with microcrystalline cellulose and calcium hydrogen phosphate dihydrate was observed; however, no indication of incompatibility was found in the DSC analysis of the commercial pharmaceutical formulations. These interactions were also studied by Fourier transform infrared spectroscopy, where small changes in the bands were observed, and by X-ray Powder diffraction and scanning electron microscopy that did not evidence any modification in the solid state characteristics.

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References

  1. Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutical drug classification: the correlation of in vitro drug product dissolution in the in vivo bioavailability. Pharm Res. 1995;12:413–20.

    Article  CAS  Google Scholar 

  2. Bergström CAS, Andersson SBE, Fagerberg JH, Ragnarsson G, Lindahl A. Is the full potential of the biopharmaceutics classification system reached? Eur J Pharm Sci. 2014;57:224–31.

    Article  Google Scholar 

  3. Takagi T, Ramachandran C, Bermejo M, Yamashita S, Yu LX, Amidon GL. A provisional biopharmaceutical classification of the top 200 oral drug products in the United States, Great Britain, Spain, and Japan. Mol Pharm. 2006;3:631–43.

    Article  CAS  Google Scholar 

  4. Cook JA, Davit BM, Polli JE. Impact of biopharmaceutics classification system-based biowaivers. Mol Pharm. 2010;7:1539–44.

    Article  CAS  Google Scholar 

  5. BRAZIL, Agência Nacional de Vigilância Sanitária (ANVISA). Resolução - RDC Nº 37, de 3 de agosto de 2011. Dispõe sobre o Guia para isenção e substituição de estudos de biodisponibilidade relativa/bioequivalência e dá outras providências, Brasília, Brazil, 2011. http://www.brasilsus.com.br/legislacoes/anvisa/109151-37.html. Accessed 10 Mar 2014.

  6. BRAZIL, Agência Nacional de Vigilância Sanitária (ANVISA). Instrução normativa - IN nº 2, de 14 de março de 2013. Determina a publicação da “Lista de fármacos candidatos à bioisenção baseada no sistema de classificação biofarmacêutica (SCB)” e dá outras providências, Brasília, Brazil, 2013. http://bvsms.saude.gov.br/bvs/saudelegis/anvisa/2013/int0002_14_03_2013.html. Accessed 10 Mar 2014.

  7. World Health Organization. Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms, vol. 937 of WHO Technical Report Series, 2006. http://apps.who.int/prequal/info_general/documents/TRS937/WHO_TRS_937_annex8_eng.pdf. Accessed 10 Mar 2014.

  8. International Pharmaceutical Federation. Biowaiver Monographs. https://www.fip.org/bcs_monographs. Accessed 10 Mar 2014.

  9. The (USP) Convention. UNITED STATES PHARMACOPEIA. 34 ed. Rockville, MD: USP Convention; 2011.

  10. Food and Drug Administration. Diflucan: (Fluconazole Tablets), (Fluconazole Injection—for intravenous infusion only), (Fluconazole for Oral Suspension) package insert. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019949s057,019950s061,020090s040lbl.pdf. Accessed 10 Mar 2014.

  11. Brunton LL, Chabner BA, Knollmann BC. Goodman & Gilman’s: the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill; 2011.

    Google Scholar 

  12. Castagnola E, Jacqz-Aigrain E, Kaguelidou F, Maragliano R, Stronati M, Rizzollo S, Farina D, Manzoni P. Fluconazole use and safety in the nursery. Early Hum Dev. 2012;88S2:S11–5.

    Article  Google Scholar 

  13. Spampinato C, Leonardi D. Candida infections, causes, targets, and resistance mechanisms: traditional and alternative antifungal agents. Biomed Res Int. 2013;2013:13.

    Google Scholar 

  14. Ramirez E, Laos O, Guerra P, Duque B, Mosquera B, Borobia AM, Lei SH, Carcas AJ, Frias J. Acceptability and characteristics of 124 human bioequivalence studies with active substances classified according to the Biopharmaceutic Classification System. Br J Clin Pharmacol. 2010;70:694–702.

    Article  CAS  Google Scholar 

  15. 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 Sci. 2004;58:265–78.

    Google Scholar 

  16. Chakraborty P, Dey S, Parcha V, Bhattacharya SS, Ghosh A. Design expert supported mathematical optimization and predictability study of buccoadhesive pharmaceutical wafers of loratadine. Biomed Res Int. 2013;2013:12.

    Google Scholar 

  17. McDaid FM, Barker SA, Fitzpatrick S, Petts CR, Craig DQM. Further investigations into the use of high sensitivity differential scanning calorimetry as a means of predicting drug–excipient interactions. Int J Pharm. 2003;252:235–40.

    Article  CAS  Google Scholar 

  18. Chadha R, Bhandari S. Drug–excipient compatibility screening—role of thermoanalytical and spectroscopic techniques. J Pharm Biomed Anal. 2014;87:82–97.

    Article  CAS  Google Scholar 

  19. Bernardi LS, Oliveira PR, Murakami FS, Silva MAS, Borgmann SHM, Cardoso SG. Characterization of venlafaxine hydrochloride and compatibility studies with pharmaceutical excipients. J Therm Anal Calorim. 2009;97:729–33.

    Article  CAS  Google Scholar 

  20. Roumeli E, Tsiapranta A, Pavlidou E, Vourlias G, Kachrimanis K, Bikiaris D, Chrissafis K. Compatibility study between trandolapril and natural excipients used in solid dosage forms. J Therm Anal Calorim. 2013;111:2109–15.

    Article  CAS  Google Scholar 

  21. 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, 2000. http://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/abbreviatednewdrugapplicationandagenerics/ucm154838.pdf. Accessed 20 Mar 2014.

  22. European Medicines Agency. Guideline on the investigation of bioequivalence, 2010.http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf. Accessed 20 Mar 2014.

  23. Barends D, Shah V, Dressman J. Biowaiver monographs: what have we learned? In: Dressman J, editor. Biowaiver Monographs 2004–2012 compiled and reviewed on the occasion of the FIP Centennial, The Netherlands, 2012. p. 8–33. https://fip.org/files/fip/publications/FIP_centennialbook_biowaiver_webversion.pdf. Accessed 20 Febr 2014.

  24. Chadha R, Arora P, Bhandari S, Garg M, Jain DVS. Thermoanalytical and spectroscopic studies on different crystal forms of nevirapine. J Therm Anal Calorim. 2013;111:2133–42.

    Article  CAS  Google Scholar 

  25. Badalkumar RP, Rajesh KJ, Rakesh KJ, Rajendra VS. Formulation development and evaluation of cefpodoxime proxetil dispersible tablets. Int J Drug Dev Res. 2012;4:124–31.

    Google Scholar 

  26. Santos A, Basílio I, Souza F, Medeiros A, Pinto M, Santana D, Macêdo R. Application of thermal analysis in study of binary mixtures with metformin. J Therm Anal Calorim. 2008;93:361–4.

    Article  CAS  Google Scholar 

  27. Júlio TA, Zâmara IF, Garcia JS, Trevisan MG. Compatibility of sildenafil citrate and pharmaceutical excipients by thermal analysis and LC–UV. J Therm Anal Calorim. 2013;111:2037–44.

    Article  Google Scholar 

  28. Rezende RLO, Santoro MIRM, Matos JR. Stability and compatibility study of Enalapril maleate using thermoanalytical techniques. J Therm Anal Calorim. 2008;93:881–6.

    Article  CAS  Google Scholar 

  29. Rowe RC, Sheskey PJ, Quinn ME. Handbook of pharmaceutical excipients. 6th ed. London: PhP Pharmaceutical Press; 2009.

    Google Scholar 

  30. Desai SR, Shaikh MM, Dharwadkar SR. Preformulation compatibility studies of etamsylate and fluconazole drugs with lactose by DSC. J Therm Anal Calorim. 2003;71:651–8.

    Article  CAS  Google Scholar 

  31. Oliveira PR, Stulzer HK, Bernardi LS, Borgmann SHM, Cardoso SG, Silva MAS. Sibutramine hydrochloride monohydrate: thermal behavior, decomposition kinetics and compatibility studies. J Therm Anal Calorim. 2010;100:277–82.

    Article  CAS  Google Scholar 

  32. Oliveira PR, Bernardi LS, Murakami FS, Mendes C, Silva MAS. Thermal characterization and compatibility studies of norfloxacin for development of extended release tablets. J Therm Anal Calorim. 2009;97:741–5.

    Article  CAS  Google Scholar 

  33. Thumma S, Repka MA. Compatibility studies of promethazine hydrochloride with tablet excipients by means of thermal and non-thermal methods. Pharmazie. 2009;64:183–9.

    CAS  Google Scholar 

  34. Monajjemzadeh F, Hassanzadeh D, Valizadeh H, Siahi-Shadbad MR, Mojarrad JS, Robertson TA, Roberts MS. Compatibility studies of acyclovir and lactose in physical mixtures and commercial tablets. Eur J Pharm Biopharm. 2009;73:404–13.

    Article  CAS  Google Scholar 

  35. Silva JPS, Lobo JMS. Compatibility studies between nebicapone, a novel COMT inhibitor, and excipients using stepwise isothermal high sensitivity DSC method. J Therm Anal Calorim. 2010;102:317–21.

    Article  Google Scholar 

  36. Aigner Z, Heinrich R, Sipos E, Farkas G, Ciurba A, Berkesi O, Szabó-Révész P. Compatibility studies of aceclofenac with retard tablet excipients by means of thermal and FT-IR spectroscopic methods. J Therm Anal Calorim. 2011;104:265–71.

    Article  CAS  Google Scholar 

  37. Tita D, Jurca T, Fulias A, Tita EMB. Compatibility study of the acetylsalicylic acid with different solid dosage forms excipients. J Therm Anal Calorim. 2013;112:407–19.

    Article  CAS  Google Scholar 

  38. Schildcrout SA, Risley DS, Kleemann RL. Drug–excipient interactions of seproxetine maleate hemihydrate: isothermal stress methods. Drug Dev Ind Pharm. 1993;19:1113–30.

    Article  CAS  Google Scholar 

  39. Signoretti EC, Dell’utri A, Salvo AD, Donini L. Compatibility study between clenbuterol and tablet excipients using differential scanning calorimetry. Drug Dev Ind Pharm. 1986;12:603–20.

    Article  CAS  Google Scholar 

  40. Veronez IP, Daniel JSP, Garcia JS, Trevisan MG. Characterization and compatibility study of desloratadine. J Therm Anal Calorim. 2014;115:2407–14.

    Article  CAS  Google Scholar 

  41. Daniel JSP, Veronez IP, Rodrigues LL, Trevisan MG, Garcia JS. Risperidone—solid-state characterization and pharmaceutical compatibility using thermal and non-thermal techniques. Thermochim Acta. 2013;568:148–55.

    Article  CAS  Google Scholar 

  42. Tita B, Fulias A, Bandur G, Marian E, Tita D. Compatibility study between ketoprofen and pharmaceutical excipients used in solid dosage forms. J Pharm Biomed Anal. 2011;56:221–7.

    Article  CAS  Google Scholar 

  43. Marini A, Berbenni V, Pegoretti M, Bruni G, Cofrancesco P, Sinistri C, Villa M. Drug excipient compatibility studies by physico chemical techniques. The case of atenolol. J Therm Anal Calorim. 2003;73:547–61.

    Article  CAS  Google Scholar 

  44. Bruni G, Berbenni V, Milanese C, Girella A, Marini A. Drug–excipient compatibility studies in binary and ternary mixtures by physico-chemical techniques. J Therm Anal Calorim. 2010;102:193–201.

    Article  CAS  Google Scholar 

  45. Chaves LL, Rolim LA, Gonçalves MLCM, Vieira ACC, Alves LDS, Soares MFR, Soares-Sobrinho JL, Lima MCA, Rolim-Neto PJ. Study of stability and drug–excipient compatibility of diethylcarbamazine citrate. J Therm Anal Calorim. 2013;111:2179–86.

    Article  CAS  Google Scholar 

  46. Bertol CD, Cruz AP, Stulzer HK, Murakami FS, Silva MAS. Thermal decomposition kinetics and compatibility studies of primaquine under isothermal and non-isothermal conditions. J Therm Anal Calorim. 2010;102:187–92.

    Article  CAS  Google Scholar 

  47. Lima NGPB, Lima IPB, Barros DMC, Oliveira TS, Raffin FN, Moura TFAL, Medeiros ACD, Gomes APB, Aragão CFS. Compatibility studies of trioxsalen with excipients by DSC, DTA, and FTIR. J Therm Anal Calorim. 2014;115:2311–8.

    Article  CAS  Google Scholar 

  48. Freire FD, Aragão CFS, Moura FAL, Raffin FN. Compatibility study between chlorpropamide and excipients in their physical mixtures. J Therm Anal Calorim. 2009;97:355–7.

    Article  CAS  Google Scholar 

  49. Collier JW, Shah RB, Gupta A, Sayeed V, Habib MJ, Khan MA. Influence of formulation and processing factors on stability of levothyroxine sodium pentahydrate. AAPS PharmSciTech. 2010;11:18–25.

    Article  Google Scholar 

  50. Adkin DA, Davis SS, Sparrow RA, Huckle PD, Wilding IR. The effect of mannitol on the oral bioavailability of cimetidine. J Pharm Sci. 1995;84:1405–9.

    Article  CAS  Google Scholar 

  51. Agatonovic-Kustrin S, Markovic N, Ginic-Markovic M, Mangan M, Glass BD. Compatibility studies between mannitol and omeprazole sodium isomers. J Pharm Biomed Anal. 2008;48:356–60.

    Article  CAS  Google Scholar 

  52. Fathy M, Hassan MA, Mohamed FA. Differential scanning calorimetry to investigate the compatibility of ciprofloxacin hydrochloride with excipients. Pharmazie. 2002;57:825–8.

    CAS  Google Scholar 

  53. Misra M, Misra AK, Panpalia GM. Interaction study between pefloxacin mesilate and some diluents using DSC supported with isothermal method. J Therm Anal Calorim. 2007;89:803–8.

    Article  CAS  Google Scholar 

  54. Dash AK, Elmquist WF. Fluconazole. In: Wozniak TJ, Brittain HG, Al-Badr AA, Kumar K, Dash AK, Mazzo DJ, Florey K, Shervington L, lndrayanto G, Ip DP, editors. Analytical profiles of drug substances and excipients. San Diego: Academic Press; 2001. p. 67–113.

    Google Scholar 

  55. Cyr TD, Dawson BA, Neville GA, Shurvell HF. Spectral characterization of fluconazole. J Pharm Biomed Anal. 1996;14:247–55.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank the Coordination for the Improvement of Higher Education Personnel (CAPES) and the National Council for Scientific and Technological Development (CNPQ) for the financial support.

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Authors and Affiliations

  1. Post Graduation Program in Pharmaceutical Sciences, Universidade Estadual do Centro Oeste/UNICENTRO, Guarapuava, PR, 85040-080, Brazil

    Lilian Klein Teleginski, Aline Biggi Maciel, Larissa Sakis Bernardi & Paulo Renato de Oliveira

  2. Quality Control Laboratory, Post Graduation Program in Pharmacy, Health Science Centre, Federal University of Santa Catarina, J/K 207, Florianópolis, SC, 88040-900, Brazil

    Cassiana Mendes & Marcos Antônio Segatto Silva

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  1. Lilian Klein Teleginski
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  2. Aline Biggi Maciel
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Teleginski, L.K., Maciel, A.B., Mendes, C. et al. Fluconazole–excipient compatibility studies as the first step in the development of a formulation candidate for biowaiver. J Therm Anal Calorim 120, 771–781 (2015). https://doi.org/10.1007/s10973-014-4316-z

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