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Polymorphic characterization and compatibility study of clozapine: implications on its stability and some biopharmaceutics properties

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Abstract

Clozapine is an antipsychotic drug used for refractory schizophrenia and severe psychiatric disorders associated with several side effects. Studies on standardization of raw material and bulk products are necessary to ensure reproducibility batch to batch during all stages of the industrial pharmaceutical process. The aim of this study was to conduct studies of polymorphic characterization and compatibility study of clozapine. Different solvatomorphic forms of clozapine were obtained by recrystallization technique. Polymorphic characterization was performed using optical microscopy, SEM, intrinsic dissolution, and thermal analysis. Compatibility studies of clozapine:excipients were performed by TG and DSC techniques. The polymorphic characterization obtained by analytical and thermal techniques showed the formation of a solvatomorphic form of clozapine (clozapine monohydrate) when recrystallized in aqueous solvents and in alkaline medium. The polymorphic form (clozapine anhydrate) showed higher intrinsic dissolution rate compared to solvatomorphic form (clozapine monohydrate). All industrial batches of clozapine presented in anhydrate form. The DSC/TG data demonstrated similar melting peaks for 2 polymorphic forms, but desolvation peaks characteristic of monohydrate form was observed in clozapine monohydrate. Studies of binary mixtures showed no incompatibilities between clozapine and excipients, except for clozapine:lactose which can reduce the stability of bulk and tablets of clozapine. Tablets of clozapine presented the same thermal analysis profile of clozapine:lactose but did not contribute in decreasing shelf life of clozapine tablets before 24 months of storage. Dissolution studies of the tablets did not show variability between batches of clozapine during 24 months but presented decreasing on stability for 36 months of storage.

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Acknowledgements

The authors thank to the CAPES and CNPq for its financial support with Grant Number 478390/2010-06 of the funding of research no 14/2010—Universal/MS/CNPq. The authors thank to FINEP for its financial support (CT-INFRA) in acquisition of some equipments and laboratorial facilities. The authors also want to thank to the Pharmaceutical Industrial Laboratory of Alagoas (LIFAL) in the persons of Vânia do Nascimento Rocha, manager of the department of quality assurance, Solange S. Moura and Denise M. de Melo França pharmacists and Maria Cícera C. Santos for the technical support in the selection of the raw materials and Intrinsic Dissolution and dissolution profile and Ana Rúbia Ribeiro for the support in the SEM analysis at the Institute of Physics from Federal University of Alagoas.

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Authors and Affiliations

  1. Laboratório Industrial Farmacêutico do Estado de Alagoas, Polo Multissetorial Dr. Luiz Cavalcanti, s/n Tabuleiro dos Martins, Maceió, AL, 57082-000, Brazil

    Simone Buarque Tavares Dias

  2. Laboratory of Quality Control of Drugs and Medicines, Postgradute Program in Pharmaceutical Sciences, School of Nursing and Pharmacy, Federal University of Alagoas, Campus A. C. Simões, University City, Maceió, AL, 57072-970, Brazil

    Ticiano Gomes Nascimento, Rusiene Monteiro Almeida & Irinaldo Diniz Basílio Júnior

  3. Unified Laboratories of Pharmaceutical Development and Assays, Department of Pharmaceutical Sciences, Federal University of Paraíba, Campus I, University City, João Pessoa, PB, 58059-970, Brazil

    Ana Flávia Oliveira Santos & Rui Oliveira Macêdo

  4. Postgraduate Program in Biological and Health Sciences, Institute of Biological and Health Sciences, Federal University of Alagoas, Campus A. C. Simões, University City, Maceió, AL, 57072-970, Brazil

    Iana Mayane M. Nicácio Viana & João Xavier de Araújo-Júnior

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  1. Simone Buarque Tavares Dias
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  2. Ticiano Gomes Nascimento
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Correspondence to Ticiano Gomes Nascimento.

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Dias, S.B.T., Nascimento, T.G., Santos, A.F.O. et al. Polymorphic characterization and compatibility study of clozapine: implications on its stability and some biopharmaceutics properties. J Therm Anal Calorim 120, 795–805 (2015). https://doi.org/10.1007/s10973-014-4142-3

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