title: A thermodynamic based approach on the investigation of a diflunisal pharmaceutical co-crystal with improved intrinsic dissolution rate.
abstract: A thermodynamic based approach is used to investigate diflunisal+nicotinamide binary and solution mixtures. A 2:1 co-crystal could be prepared by liquid assisted ball mill grinding and by solution crystallization from ethanol. The diflunisal+nicotinamide+ethanol ternary phase diagram points out conditions for co-crystal scaling-up. From the diflunisal+nicotinamide binary phase diagram, besides identification of the co-crystal stoichiometry, two additional useful binary compositions, eutectic mixtures, were characterized. From a solution enthalpy based approach, the enthalpic stabilization of the co-crystal relative to the pure solid components is quantified. Intrinsic dissolution rate, IDR, in test conditions consistent with USP requirements, including those referred in the diflunisal tablet monograph, were carried out, indicating that the co-crystal improves diflunisal IDR by about 20%. The systematic study of diflunisal+nicotinamide mixtures presented in this work is of particular interest due to the relevance of diflunisal, both as a non-steroidal anti-inflammatory drug and also due to the potentiality of orally administrated diflunisal in familial amyloid polyneuropathy.
authors.affiliation: Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal.
authors.forename: António O L
authors.initials: AO
authors.lastname: Evora
authors.affiliation: Faculty of Pharmacy, University of Coimbra, Portugal.
authors.forename: Ricardo A E
authors.initials: RA
authors.lastname: Castro
authors.affiliation: Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal.
authors.forename: Teresa M R
authors.initials: TM
authors.lastname: Maria
authors.affiliation: Department of Physics, University of Coimbra, Portugal.
authors.forename: M Ramos
authors.initials: MR
authors.lastname: Silva
authors.affiliation: Process & Energy Department, Delft University of Technology, Leeghwaterstraat 39, 2628 CB Delft, The Netherlands. Electronic address: J.H.terHorst@tudelft.nl.
authors.forename: J H
authors.initials: JH
authors.lastname: Ter Horst
authors.affiliation: Faculty of Pharmacy, University of Coimbra, Portugal. Electronic address: jcano@ci.uc.pt.
authors.forename: João
authors.initials: J
authors.lastname: Canotilho
authors.affiliation: Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal. Electronic address: quierme@ci.uc.pt.
authors.forename: M Ermelinda S
authors.initials: ME
authors.lastname: Eusébio
mesh_terms: D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D004061:Diflunisal / Q000737:chemistry*; D000431:Ethanol / Q000737:chemistry; D009536:Niacinamide / Q000737:chemistry*; D033362:Powder Diffraction; D012995:Solubility; D013055:Spectrophotometry, Infrared; D013816:Thermodynamics; D014961:X-Ray Diffraction
chemical_list: D009536:Niacinamide; D000431:Ethanol; D004061:Diflunisal
keywords: Binary phase diagram; Co-crystal; Diflunisal; Diflunisal (PubChem CID: 3059); Ethanol (PubChem CID: 702); Intrinsic dissolution rate; Nicotinamide; Nicotinamide (PubChem CID: 936); Ternary phase diagram