New solvates of the drug naltrexone: protonation, conformation and inter­play of synthons

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dc.creatorBorges, Karolina de Oliveira Gonçalves
dc.creatorRibeiro, Leandro
dc.creatorOliveira, Cecilia Maria Alves de
dc.creatorCarvalho, Jesiel Freitas
dc.creatorMartins, Felipe Terra
dc.date.accessioned2023-09-05T10:16:40Z
dc.date.available2023-09-05T10:16:40Z
dc.date.issued2018
dc.description.abstractNaltrexone [systematic name: (4R,4aS,7aR,12bS)-3-cyclo­propyl­methyl-4a,9-di­hy­droxy-2,4,5,6,7a,13-hexa­hydro-1H-4,12-methano­benzofuro[3,2-e]iso­quino­lin-7-one] is an important morphine-related drug used for combating alcoholism and opioid dependence. Of the eight crystal forms of naltrexone known thus far, only one exists in the neutral form and it crystallizes as a monohydrate. We have isolated the naltrexone free base as two new solvate forms, i.e. the ethyl acetate 0.33-solvate, C20H23NO4·0.33C4H8O2, (I), and the diethyl ether hemisolvate, C20H23NO4·0.5C4H10O, (II). While just one solvent mol­ecule is present in the asymmetric unit of each solvate, there are three drug mol­ecules (Z′ = 3) in ethyl acetate solvate (I) and two (Z′ = 2) in diethyl ether solvate (II). In (I), one of the three crystallographically independent drug mol­ecules is present with its cyclo­propyl group disordered over two sets of positions, as is the whole diethyl ether solvent mol­ecule in (II). In all known forms, including the title forms, the naltrexone molecule exhibits the same conformation of the fused rings. The only conformational variability of naltrexone is in the cyclo­propyl­methyl group. Two conformations can be found around the bond connecting this group to the N-heterocycle, which is directly related to drug protonation. We have calculated, at the B3LYP/6-31G** level of theory, the minimum energy conformations of protonated and neutral naltrexone mol­ecules for a chosen torsion angle about this bond. The lowest energy conformers depend on the protonation state and are in agreement with those found in the solid state. Within the cyclopropylmethyl group, the bond joining the methylene C atom to the cyclopropyl fragment also evidences conformational variability. In the literature, there are two well defined conformations around this bond. A third cyclo­propyl conformation around this second bond is observed in the title solvates. Concerning the supra­molecular features of the previously reported crystal structures, only one classical hydrogen bond between naltrexone mol­ecules and one C(8) homosynthon is known, pointing to the robustness of this synthon and the difficulty in disrupting it. New R22(7) and C22(10) homo­synthons are found in both (I) and (II), suggesting that their occurrence derives from crystallization of the neutral drug from nonpolar solvents.pt_BR
dc.identifier.citationGONÇALVES, Karolina de Oliveira et al. New solvates of the drug naltrexone: protonation, conformation and interplay of synthons. Acta Crystallographica Section C: structural chemistry, Chester, v. 74, n. 3, p. 274-282, 2018. DOI: 10.1107/S2053229618001791. Disponível em: http://scripts.iucr.org/cgi-bin/paper?S2053229618001791. Acesso em: 28 ago. 2023.pt_BR
dc.identifier.doi10.1107/S2053229618001791
dc.identifier.issne- 2053-2296
dc.identifier.urihttp://scripts.iucr.org/cgi-bin/paper?S2053229618001791
dc.language.isoengpt_BR
dc.publisher.countryGra-bretanhapt_BR
dc.publisher.departmentInstituto de Química - IQ (RMG)pt_BR
dc.rightsAcesso Restritopt_BR
dc.subjectNaltrexonept_BR
dc.subjectSolvatept_BR
dc.subjectDrugpt_BR
dc.subjectProtonationpt_BR
dc.subjectConformationpt_BR
dc.subjectSynthonpt_BR
dc.subjectComputational chemistrypt_BR
dc.subjectMorphine-related drugpt_BR
dc.subjectCrystal structurept_BR
dc.subjectDensity functional theorypt_BR
dc.titleNew solvates of the drug naltrexone: protonation, conformation and inter­play of synthonspt_BR
dc.typeArtigopt_BR

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