Supramolecular chemistry of antiretroviral nucleoside reverse transcriptase inhibitor drugs

Author(s)

Felipe Terra Martins

• Document type: Doctoral Thesis
• Press: São Carlos.
• Institution: Universidade de São Paulo (USP). Instituto de Física de São Carlos (IFSC/BT)
• Defense date: 2010-10-07

Examining board members

Javier Alcides Ellena; Nelson Gonçalves Fernandes; Rosangela Itri; Carlito Lariucci; Bernardo Lages Rodrigues

• Advisor: Javier Alcides Ellena; Antônio Carlos Doriguetto

Abstract

Solid state properties are directly related to drug performance. Among all physical and chemical properties dependent on the crystal phase of a drug, stability and solubility are the main ones that alter its bioavailability. In this way, molecular crystal engineering is a strategy to improve solid state properties of drugs related to their efficacies. In this work, nine new crystal forms of antiretroviral nucleoside reverse transcriptase inhibitor drugs, namely, lamivudine, zalcitabina and didanosine, were prepared and their crystal structures were elucidated by single crystal X-ray diffraction. Some of the prepared crystal modifications were also characterized by scanning electron microscopy, powder X-ray diffraction, infrared and Raman vibrational spectroscopy, differential scanning calorimetry and thermogravimetry. The water solubilities and purities of the lamivudine crystal modifications prepared as monophasic samples were determined by ultraviolet absorbance spectrophotometry and high performance liquid chromatography, respectively. The solubility of lamivudine in the prepared crystal modifications can be either increased or decreased when compared to the solubility of the drug crystal phase incorporated into pharmaceutical formulations. The solubilities were also correlated to calorimetric and structural features, which allowed the establishment of relationships between crystal lattice energy/structure and solid state property. In addition, two crystal modifications of lamivudine, in which drug molecules are paired through their cytosine fragments, being these pairs helically stacked, mimicking a polymeric structure of deoxyribonucleic acid, have revealed that nucleosides possess the structural information necessary to assemble double stranded helices of nucleic acids. (AU)

• FAPESP's process: 07/07185-5 - Screening, characterization and evaluation for novel crystal forms from antiretroviral and antineoplastic drugs
• Grantee: Felipe Terra Martins
• Support Opportunities: Scholarships in Brazil - Doctorate