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Obtaining, characterization and evaluation of novel crystalline solid forms of drugs used treatment of tuberculosis

Grant number: 15/25694-0
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): March 01, 2016
Effective date (End): November 30, 2017
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Principal Investigator:Javier Alcides Ellena
Grantee:Luan Farinelli Diniz
Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil

Abstract

This present research project is dedicated to desing and obtaining new multicomponent crystalline forms of antituberculosis drugs, followed by characterization of the physical and chemical properties in the solid state and subsequent evaluation of pharmacokinetic properties such as solubility and dissolution. New multicomponent crystalline forms have different chemical, conformational and supramolecular aspects and, in some cases, improved pharmacokinetic properties. Therefore, this work aims to design and obtaining new multicomponent forms of antituberculosis drugs: isoniazid, pyrazinamide, ethambutol, ethionamide, cycloserine, linezolid and p-aminosalicylic acid using the principles of crystal engineering. The drugs mentioned above will be subject to statistical analysis to establish the preferential supramolecular synthons for recognizing the specific coformadores to these drugs. With these data, obtaining protocols of new solid forms with improved pharmacokinetic properties will be designed and implemented. Once obtained, they will be characterized and their properties in the solid state will be evaluated by single crystal X-ray diffraction (SCXRD) and X-ray powder diffraction (XRPD) , by thermogravimetry (TG) and differential scanning calorimetry (DSC), infrared (IR) and Raman spectroscopy and thermal optical microscopy (Hot-Stage). Finally, the new crystalline forms are evaluated and compared with reference drug in relation to solubility and dissolution profile.

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Scientific publications (15)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DE MELO, CRISTIANE C.; CARVALHO, JR., PAULO DE SOUSA; DINIZ, LUAN F.; D'VRIES, RICHARD F.; AYALA, ALEJANDRO P.; ELLENA, JAVIER. Supramolecular synthesis and thermochemical investigations of pharmaceutical inorganic isoniazid salts. CrystEngComm, v. 18, n. 34, p. 6378-6388, . (12/05616-7, 15/25694-0)
DA SILVA, CECILIA C. P.; DE MELO, CRISTIANE C.; SOUZA, MATHEUS S.; DINIZ, LUAN F.; CARNEIRO, RENATO L.; ELLENA, JAVIER. 5-Fluorocytosine/5-Fluorouracil Drug-Drug Cocrystal: a New Development Route Based on Mechanochemical Synthesis. JOURNAL OF PHARMACEUTICAL INNOVATION, v. 14, n. 1, p. 50-56, . (15/25694-0)
DINIZ, LUAN F.; CARVALHO, JR., PAULO S.; DE MELO, CRISTIANE C.; ELLENA, JAVIER. Reducing the Hygroscopicity of the Anti-Tuberculosis Drug (S,S)-Ethambutol Using Multicomponent Crystal Forms. Crystal Growth & Design, v. 17, n. 5, p. 2622-2630, . (12/05616-7, 15/25694-0)
DINIZ, LUAN F.; SOUZA, MATHEUS S.; CARVALHO, JR., PAULO S.; DA SILVA, CECILIA C. P.; D'VRIES, RICHARD F.; ELLENA, JAVIER. Novel Isoniazid cocrystals with aromatic carboxylic acids: Crystal engineering, spectroscopy and thermochemical investigations. Journal of Molecular Structure, v. 1153, p. 58-68, . (12/05616-7, 15/25694-0)
DINIZ, LUAN F.; CARVALHO, JR., PAULO S.; DE MELO, CRISTIANE C.; ELLENA, JAVIER. Development of a salt drug with improved solubility: Ethionamide nitrate. Journal of Molecular Structure, v. 1137, p. 119-125, . (15/25694-0, 12/05616-7)
SOUZA, MATHEUS S.; DINIZ, LUAN F.; ALVAREZ, NATALIA; DA SILVA, CECILIA C. P.; ELLENA, JAVIER. Supramolecular synthesis and characterization of crystalline solids obtained from the reaction of 5-fluorocytosine with nitro compounds. NEW JOURNAL OF CHEMISTRY, v. 43, n. 40, p. 15924-15934, . (15/25694-0)
SOUZA, MATHEUS S.; DINIZ, LUAN F.; VOGT, LAUTARO; CARVALHO JR, PAULO S.; D'VRIES, RICHARD F.; ELLENA, JAVIER. Mechanochemical Synthesis of a Multicomponent Solid Form: The Case of 5-Fluorocytosine Isoniazid Codrug. Crystal Growth & Design, v. 18, n. 9, p. 5202-5209, . (15/25694-0)
CARVALHO JR, PAULO S.; GUIMARAES, GETTON G. F.; DINIZ, LUAN F.; ELLENA, JAVIER; RIBEIRO, CAUE. Highly water soluble agrichemicals by using engineered organic salts for reducing adverse environmental impacts. GREEN CHEMISTRY, v. 21, n. 23, p. 6419-6429, . (16/09198-6, 16/10636-8, 15/25694-0)
SOUZA, MATHEUS S.; DINIZ, LUAN F.; VOGT, LAUTARO; CARVALHO JR, PAULO S.; D'VRIES, RICHARD F.; ELLENA, JAVIER. Avoiding irreversible 5-fluorocytosine hydration via supramolecular synthesis of pharmaceutical cocrystals. NEW JOURNAL OF CHEMISTRY, v. 42, n. 18, p. 14994-15005, . (15/25694-0)
GUTIERREZ, EDUARDO L.; SOUZA, MATHEUS S.; DINIZ, LUAN F.; ELLENA, JAVIER. Synthesis, characterization and solubility of a new anthelmintic salt: Mebendazole nitrate. Journal of Molecular Structure, v. 1161, p. 113-121, . (15/25694-0, 13/03487-8)
SOUZA, MATHEUS S.; DA SILVA, CECILIA C. P.; ALMEIDA, LEONARDO R.; DINIZ, LUAN F.; ANDRADE, MARCELO B.; ELLENA, JAVIER. Protonation of inorganic 5-Fluorocytosine salts. Journal of Molecular Structure, v. 1161, p. 412-423, . (13/03487-8, 16/09152-6, 15/25694-0)
CARVALHO, JR., PAULO S.; DINIZ, LUAN F.; TENORIO, JUAN C.; SOUZA, MATHEUS S.; FRANCO, CHRIS H. J.; RIAL, RAFAEL C.; WARSZAWSKI DE OLIVEIRA, KARLA REGINA; NAZARIO, CARLOS E. D.; ELLENA, JAVIER. Pharmaceutical paroxetine-based organic salts of carboxylic acids with optimized properties: the identification and characterization of potential novel API solid forms. CrystEngComm, v. 21, n. 24, p. 3668-3678, . (16/08823-4, 12/05616-7, 15/25694-0)
DAYO OWOYEMI, BOLAJI C.; DA SILVA, CECILIA C. P.; DINIZ, LUAN F.; SOUZA, MATHEUS S.; ELLENA, JAVIER; CARNEIRO, RENATO L.. Fluconazolium oxalate: synthesis and structural characterization of a highly soluble crystalline form. CrystEngComm, v. 21, n. 7, p. 1114-1121, . (15/25694-0, 10/16520-5)
OWOYEMI, BOLAJI C. DAYO; DA SILVA, CECILIA C. P.; SOUZA, MATHEUS S.; DINIZ, LUAN F.; ELLENA, JAVIER; CARNEIRO, RENATO L.. Fluconazole: Synthesis and Structural Characterization of Four New Pharmaceutical Cocrystal Forms. Crystal Growth & Design, v. 19, n. 2, p. 648-657, . (15/25694-0, 10/16520-5)
DINIZ, LUAN F.; SOUZA, MATHEUS S.; CARVALHO, JR., PAULO S.; CORREA, CHARLANE C.; ELLENA, JAVIER. Modulating the water solubility and thermal stability of the anti-tuberculosis drug Isoniazid via multicomponent crystal formation. Journal of Molecular Structure, v. 1171, p. 223-232, . (15/25694-0, 12/05616-7)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
DINIZ, Luan Farinelli. Design, production and characterization of new solid forms of tuberculostatic drugs. 2017. Master's Dissertation - Universidade de São Paulo (USP). Instituto de Física de São Carlos (IFSC/BT) São Carlos.

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Filed patent(s) as a result of this research project

COCRISTAL FARMACÊUTICO E SEU USO BR1020170245640 - Universidade de São Paulo (USP) . Javier Alcides Ellena / LUAN FARINELLI DINIZ / MATHEUS DA SILVA SOUZA - November 2017, 16

COCRISTAIS FARMACÊUTICOS E SEUS USOS BR1020170245764 - Universidade de São Paulo (USP) . Javier Alcides Ellena / LUAN FARINELLI DINIZ / MATHEUS DA SILVA SOUZA - November 2017, 16