Biomedical subjects

Karl F Blom

Publications and source records attributed to Karl F Blom.

3 recordsLinked to original sources

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↗

PubMedDate not supplied

Two-pump at-column-dilution configuration for preparative liquid chromatography-mass spectrometry.

Preparative liquid chromatography-mass spectrometry (LC-MS) is widely used in parallel synthesis schemes to expedite purification. Recently, an alternative sample loading scheme, at column dilution, has been shown to dramatically increase the mass loading capacity of LC-MS purification methods. The prototype system utilized separate sample loading and binary gradient pumps. We report here a configuration for effecting at-column dilution using only the two pumps that provide the binary gradient flow. The advantages of a two-pump configuration are reduced cost, reduced space requirements, simplified control, and reduced service and maintenance issues. The two-pump at-column-dilution configuration is demonstrated for large- and small-scale LC-MS purifications. Purification on scales appropriate for high-throughput parallel synthesis can be achieved with small-scale chromatography using at-column dilution; purification of 20 mg of material is demonstrated using a 4.6 mm x 150 mm column and a flow rate of 3 mL/m. Reducing the scale of chromatography required for LC-MS purification has significant benefits, including the following. It requires less expensive columns, consumes less solvent, generates smaller-volume fractions (shorter dry-down time and the ability to collect into small-volume collector formats, such as 96-well plates), and has the potential for faster separations.

Journal Article↗

PubMedDate not supplied

Preparative LC-MS purification: improved compound-specific method optimization.

One of the remaining challenges in providing effective preparative LC-MS purification is balancing throughput and compound purity. We describe here an approach to optimizing preparative LC-MS methods that provides significantly better chromatographic resolution and, hence, better compound purity than generic preparative LC methods consuming the same amount of time. This approach is easier to implement, is more rugged, and permits significantly greater flexibility than previously reported approaches. The instrument configurations and protocols presented here are specifically tailored for open access support, but the basic approach is equally suitable and effective in high-throughput situations.

Journal Article↗