title: Preformulation studies of novel 5'-O-carbonates of lamivudine with biological activity: solubility and stability assays.
abstract: As a part of preformulation studies, the aim of this work was to examine the solubility and stability of a series of 5'-O-carbonates of lamivudine with proven antihuman immunodeficiency virus activity. Solubility studies were carried out using pure solvents (water, ethanol and polyethylene glycol 400 [PEG 400]), as well as cosolvents in binary mixture systems (water-ethanol and water-PEG 400). These ionizable compounds showed that their aqueous solubility is decreasing as the carbon length of the substituent moiety increases, but being enhanced as the pH was reduced from 7.4 to 1.2. Thus, 3TC-Metha an active compound of the series, with an intrinsic solubility at 25 °C of 17 mg/mL, was about 70 times more soluble than 3TC-Octa (0.24 mg/mL), and at pHs of 1.2, 5.8 and 7.4 had intrinsic solubilities of 36.48, 19.20 and 15.40 mg/mL, respectively. In addition, the solubility was enhanced significantly by using ethanol and PEG 400 as cosolvents. A stability study was conducted in buffer solutions at pH 1.2, 5.8, 7.4 and 13.0 and in human plasma at 37 °C. Stability-indicating high-performance liquid chromatography procedure was found to be selective, sensitive and accurate for these compounds and good recovery, linearity and precision were also observed.
authors.affiliation: Departamento de Farmacia, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria , Córdoba , Argentina.
authors.forename: María S
authors.initials: MS
authors.lastname: Gualdesi
authors.forename: Soledad
authors.initials: S
authors.lastname: Ravetti
authors.forename: Mónica A
authors.initials: MA
authors.lastname: Raviolo
authors.forename: Margarita C
authors.initials: MC
authors.lastname: Briñón
mesh_terms: D002021:Buffers; D002254:Carbonates / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004355:Drug Stability; D000431:Ethanol / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019259:Lamivudine / Q000737:chemistry*; D010949:Plasma / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D012995:Solubility; D012996:Solutions / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D002021:Buffers; D002254:Carbonates; D012996:Solutions; D012997:Solvents; D014867:Water; D019259:Lamivudine; D000431:Ethanol; D011092:Polyethylene Glycols
keywords: Aqueous stability; cosolvency; human plasma stability; pH-solubility profiles; prodrugs; solubility