skip to main content
Idioma:
Primo Search
Clear Search Box
Search in: Busca Geral
Busca Avançada
Busca por Índices
Tipo de recurso Mostra resultados com: Mostra resultados com: Índice

Structure and energetics of intermolecular association in two lurasidone co-amorphous drug systems

Silva, Joana F.C. ; Rosado, Mário T.S. ; Eusébio, M. Ermelinda S.

Journal of molecular structure, 2021-10, Vol.1242, p.130709, Article 130709 [Periódico revisado por pares]

Elsevier B.V

Texto completo disponível

Citações Citado por
  • Título:
    Structure and energetics of intermolecular association in two lurasidone co-amorphous drug systems
  • Autor: Silva, Joana F.C. ; Rosado, Mário T.S. ; Eusébio, M. Ermelinda S.
  • Assuntos: Co-amorphous drug systems ; conformational search ; DFT ; dimers ; NBO
  • É parte de: Journal of molecular structure, 2021-10, Vol.1242, p.130709, Article 130709
  • Descrição: •Computational study of aggregation in two lurasidone co-amorphous systems.•Conformational landscape of lurasidone explored by random search and DFT.•Study of heterodimer vs homodimer structures derived from experimental data.•NBO and NCI analysis reveal details of molecular interaction.•Stronger H-bonding with cysteine than saccharin is evidenced. [Display omitted] The use of amorphous phases has been proposed as one of the alternatives for drug formulations of low solubility active pharmaceutical ingredients (API). To overcome stability problems of these metastable phases, co-amorphous mixtures of API with safe small molecule co-formers are being investigated. Therefore, it is of great importance to study the factors that control the supramolecular association of drug substance with the co-formers, despite lack of long-range order in these systems creating some experimental and computational challenges. This work aims to apply various computational chemistry methods to the study of co-amorphous drug systems, namely the local structural and intermolecular interactions responsible for the intimate drug–co-former association that prevents relaxation to the crystalline state. The subjects of this study are two co-amorphous systems, recently proposed and studied experimentally, that include the drug lurasidone with two different co-formers, saccharin and cysteine. First, the conformational landscape of lurasidone is explored by random search molecular mechanics to provide a varied set of initial conformations. Then, these conformations and those extracted from the available X-ray diffraction crystal structures of the three component substances are subject to geometry optimization by a DFT method (B3LYP/def2-SVP), including corrections for dispersion. The same optimization procedure is applied to homodimers extracted from the crystal structures, and to heterodimers built using the evidence for the manner of aggregation provided by the published experimental studies. The intermolecular association is further explored with Natural Bond Orbital (NBO) and Non-Covalent Interaction (NCI) analyses of the dimers, to better understand the electronic structure of the supramolecular drug–co-former entities and compare how they interact. It is concluded that faster, more approximate, methods were useful to deal with large and conformationally flexible drug molecules that are typical amorphous phase formers, and that the more rigorous quantum mechanical methods are necessary to rationalize and evaluate the molecular interactions in co-amorphous systems. The NBO analysis indicated that lurasidone has stronger hydrogen bonding with cysteine than with saccharin.
  • Editor: Elsevier B.V
  • Idioma: Inglês
Voltar para lista de resultados
Ir para página anteriorAnterior Resultado  4 AvançarIr para próxima página

  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

Buscando em bases de dados remotas. Favor aguardar.