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AAPS PharmSciTech

, Volume 19, Issue 7, pp 3019–3028 | Cite as

Polymorphic and Quantum Chemistry Characterization of Candesartan Cilexetil: Importance for the Correct Drug Classification According to Biopharmaceutics Classification System

  • Débora Priscila de Campos
  • Neila Márcia Silva-Barcellos
  • Renata Rodrigues Lima
  • Ranylson Marcello Leal Savedra
  • Melissa Fabíola Siqueira
  • Maria Irene Yoshida
  • Wagner da Nova Mussel
  • Jacqueline de Souza
Research Article
  • 94 Downloads

Abstract

The recommended method for the biopharmaceutical evaluation of drug solubility is the shake flask; however, there are discrepancies reported about the solubility of certain compounds measured with this method, one of them is candesartan cilexetil. The present work aimed to elucidate the solubility of candesartan cilexetil by associating others assays such as stability determination, polymorphic characterization and in silico calculations of intrinsic solubility, ionized species, and electronic structures using quantum chemistry descriptors (frontier molecular orbitals and Fukui functions). For the complete biopharmaceutical classification, we also reviewed the permeability data available. The polymorphic form used was previously identified as the form I of candesartan cilexetil. The solubility was evaluated in biorelevant media in the pH range of 1.2–6.8 at 37.0°C according to the stability previously assessed. The solubility of candesartan cilexetil is pH dependent and the dose/solubility ratios obtained demonstrated the low solubility of the prodrug. The in silico calculations supported the found results and evidenced the main groups involved in the solvation, benzimidazole, and tetrazol-biphenyl. The human absolute bioavailability reported demonstrates that candesartan cilexetil has low permeability and when associated with the low solubility allows to classify it as class 4 of the Biopharmaceutics Classification System.

KEY WORDS

candesartan cilexetil equilibrium solubility polymorphism Quantum Chemistry Biopharmaceutics Classification System 

Notes

Funding Information

This work was supported by the Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) under grant APQ-02247-14; Rede Mineira de Ensaios Toxicológicos e Farmacológicos da FAPEMIG (Rede TOXIFAR) under grant CBB—RED-00008-14; Brazilian Health Surveillance Agency (Anvisa); Federal University of Ouro Preto (PROPP/UFOP); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); Ministério da Educação (MEC/FNDE); and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Supplementary material

12249_2018_1129_MOESM1_ESM.doc (644 kb)
ESM 1 (DOC 643 kb)

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Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Débora Priscila de Campos
    • 1
    • 2
  • Neila Márcia Silva-Barcellos
    • 1
  • Renata Rodrigues Lima
    • 1
  • Ranylson Marcello Leal Savedra
    • 3
  • Melissa Fabíola Siqueira
    • 3
  • Maria Irene Yoshida
    • 4
  • Wagner da Nova Mussel
    • 4
  • Jacqueline de Souza
    • 1
  1. 1.Department of Pharmacy and Pharmaceutical SciencesFederal University of Ouro PretoOuro PretoBrazil
  2. 2.Morro do Cruzeiro University CampusOuro PretoBrazil
  3. 3.Department of PhysicsFederal University of Ouro PretoOuro PretoBrazil
  4. 4.Department of ChemistryFederal University of Minas GeraisBelo HorizonteBrazil

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