Biomedical subjects

Gregory A Nemeth

Publications and source records attributed to Gregory A Nemeth.

3 recordsLinked to original sources

PubMed2002

Solid-state carbon NMR characterization of the polymorphs of roxifiban.

Roxifiban, an experimental antithrombotic prodrug, exists as crystalline forms I and II. A quantitative solid-state nuclear magnetic resonance (NMR) method was developed to characterize the two polymorphs of roxifiban. The differences in the NMR spectra of the polymorphs were utilized in analyses of physical blends of the pure crystalline forms to establish a calibration curve. A detection limit of 9% form II in form I was determined from analysis of a 10% form II blend. Solid-state NMR was a valuable technique to quantify the polymorphic purity of roxifiban where other techniques such as differential scanning calorimetry (DSC) could not be used for this purpose.

Amidines↗

PubMed2002

The isolation and identification of a toxic impurity in XP315 drug substance.

In early safety assessment studies with the experimental anti-neoplastic drug XP315, a toxic reaction was observed in dogs immediately after intravenous (iv) infusion. The reaction was characterized by severe erythema around the ears, eyes, face and body; ocular hyperemia; head shaking; swelling around the eyes, face, paws, head, neck and legs; scratching; and reddened gums, which lasted several hours after dosing. By fractionating the drug substance using preparative HPLC and then infusing the residues into dogs by iv, this reaction was traced to an impurity in the drug substance. Following the preparative isolation of the toxic impurity, characterization was performed using a combination of NMR and mass spectral methods. The proposed impurity was found to be structurally related and nearly twice the molecular weight of XP315, resulting from a dimerization by ring fusion of two 3-aminonaphthalene fragments during the synthetic process. This paper details the steps taken to isolate the toxic impurity and characterize its structure using off-line methods.

Animals↗

PubMed2002

Polymorphism of roxifiban.

Roxifiban was found to exist in two polymorphic forms. The polymorphs were detected by X-ray powder diffraction and solid-state carbon nuclear magnetic resonance. A slight difference between the two polymorphs was also detected by isothermal microcalorimetry. However, no differences were observed by differential scanning calorimetry, infrared, or Raman spectroscopy. Solubility studies as a function of temperature in a discriminating solvent system permitted characterization of the thermodynamics of the polymorphs. The enthalpy of solution at 25 degrees C was 8.1 kcal/mol and 8.9 kcal/mol for Form I and Form II, respectively, and the thermodynamic transition point was 132 degrees C. The data confirm that the polymorphs are enantiotropic. Form II is the thermodynamically stable crystal form over the practical range of drug substance storage and handling and dosage form processing and storage. However, Form I has been kinetically stable after storage for more than 36 months at 25 degrees C/60% relative humidity with no conversion to Form II occurring.

Amidines↗