Mechanochemical Synthesis and Physicochemical Characterization of Isoniazid and Pyrazinamide Co-crystals With Glutaric Acid.

The present work reports two novel pharmaceutical co-crystals; 2:1 isoniazid-glutaric acid (INHGA) and 2:1 pyrazinamide-glutaric acid (PGA). Isoniazid and pyrazinamide are key first-line drugs used for the treatment of tuberculosis. The co-crystals were produced via solid-state and solvent assisted grinding methods. Thermal characteristics of the samples were obtained using the differential scanning calorimetry, hot stage microscopy, and thermogravimetric analyses. The morphology of the powder samples by scanning electron microscopy, structural analysis by Fourier transform infrared spectroscopy and powder X-rays diffraction ensured co-crystal formation. Thermal analyses confirmed the co-crystals with new melting transitions ranging between their respective starting materials. Unique morphologies of the co-crystal particles were clear in SEM micrographs. The formation of intermolecular interactions with the co-crystal former was confirmed by the FT-IR spectral band shifting and was supported by distinct PXRD patterns of co-crystals thereby authenticating the successful co-crystal formation. In vitro solubility evaluation of the synthesized co-crystals by HPLC suggested a remarkable increase in solubility of both INH and PZA in their respective co-crystals.

Short communication. Challenges relating to comparison of flavonoid glycosides dissolution profiles from Sutherlandia frutescens products.

Unlike the case of conventional drug formulations, dissolution tests have hitherto not been required for herbal medicinal products commercially available in South Africa. This study investigated dissolution of the South African Sutherlandia frutescens using selected flavonoid glycosides as marker compounds. Dissolution of markers was assessed in three dissolution media at pH 1.2, 4.5 and 6.8, and samples were analysed using a validated HPLC method. The dissolution profile of each marker varied for the different materials investigated. All three media utilised showed differences in flavonoid glycoside dissolution between the S. frutescens products evaluated, with f2 values < 50 for comparison of flavonoid dissolution from any two of the materials. Dissolution of S. frutescens materials could thus be characterised using the markers in all the media tested. This tool may be employed in the future for comparison of orally administered S. frutescens products, provided between- batch variability is evaluated and found less than between-sample variability.

Thermal, X-ray Structural, and Dissolution Characteristics of Solid Forms Derived from the Anticancer Agents 2-Methoxyestradiol and 2-Methoxyestradiol-3,17-O,O-Bis-Sulfamate.

The aim of the study was to generate alternative solid forms of 2-methoxyestradiol (2ME) and its sulfamoylated derivative 2-methoxyestradiol-3,17-O,O-bis-sulfamate (2MES), both of which are potent anticancer agents with no significant history of solid-state investigation. Screening for polymorphs and solvates by a variety of procedures yielded four distinct species: a crystalline form of 2ME, an amorphous form of 2ME, a chloroform solvate 2ME·(CHCl3 )2 , and the hemihydrate of the bis-sulfamate, 2MES·(H2 O)0.5 . Hydrogen-bonded assembly of 2ME molecules into layers in both crystalline 2ME and its chloroform solvate was established using single-crystal X-ray diffraction. This technique also revealed disorder of the sulfamate group at position 17 in both molecules comprising the asymmetric unit in the crystal of 2MES·(H2 O)0.5 . The thermal stabilities of the crystalline phases were recorded using hot-stage microscopy, thermogravimetry, and differential scanning calorimetry, and the results were reconciled with the crystal structures. Aqueous dissolution rates measured at 37°C generally decreased in the order 2MES·(H2 O)0.5 > 2ME(amorphous) > 2ME(crystalline).

Inclusion complexes of 2-methoxyestradiol with dimethylated and permethylated ß-cyclodextrins: models for cyclodextrin-steroid interaction.

The interaction between the potent anticancer agent 2-methoxyestradiol (2ME) and a series of cyclodextrins (CDs) was investigated in the solid state using thermal analysis and X-ray diffraction, while the possibility of enhancing its poor aqueous solubility with CDs was probed by means of equilibrium solubility and dissolution rate measurements. Single crystal X-ray diffraction studies of the inclusion complexes between 2ME and the derivatised cyclodextrins heptakis(2,6-di-O-methyl)-ß-CD (DIMEB) and heptakis(2,3,6-tri-O-methyl)-ß-CD (TRIMEB) revealed for the first time the nature of the encapsulation of a bioactive steroid by representative CD host molecules. Inclusion complexation invariably involves insertion of the D-ring of 2ME from the secondary side of each CD molecule, with the 17-OH group generally hydrogen bonding to a host glycosidic oxygen atom within the CD cavity, while the A-ring and part of the B-ring of 2ME protrude from the secondary side. In the case of the TRIMEB·2ME complex, there is evidence that complexation proceeds with mutual conformational adaptation of host and guest molecules. The aqueous solubility of 2ME was significantly enhanced by CDs, with DIMEB, TRIMEB, randomly methylated ß-CD and hydroxypropyl-ß-CD being the most effective hosts. The 2:1 host-guest ß-CD inclusion complex, prepared by two methods, yielded very rapid dissolution in water at 37 °C relative to untreated 2ME, attaining complete dissolution within 15 minutes (co-precipitated complex) and 45 minutes (complex from kneading).