John Anthony Grosso

Mechanism and Kinetics of Metal Ion-Mediated Degradation of Fosinopril Sodium

Fosinopril sodium (I), a new angiotensin converting enzyme inhibitor, is a diester prodrug of the active moiety II. We report here a novel transformation of fosinopril into β-ketoamide, III, and a phosphonic acid, IV, mediated through metal ion participation. The interaction of fosinopril with magnesium ions was studied in a solution model system in which methanol was used as the solvent and magnesium acetate as the source of metal ions. Kinetic analysis indicated the degradation to be a bimolecular process, with the rate being first order in both metal ion and fosinopril concentration. The degradation products II, III, and IV effectively retarded the magnesium ion mediated reaction of fosinopril. Based on the results of 31P-NMR, 1H-NMR, Mn(II)-EPR spectroscopy experiments and mass spectrometry, a mechanism is postulated for this transformation. A key reactive intermediate has been characterized that supports the proposed mechanism. The results can account for the observed degradation profile of the fosinopril sodium in a prototype tablet formulation.

A mild and efficient synthesis of 4-aryl-quinolin-2(1H)-ones via a tandem amidation/Knoevenagel condensation of 2-amino-benzophenones with esters or lactones

Abstract Using LiHMDS as the base, a tandem amidation/Knoevenagel condensation of 2-aminobenzophenones with α-methylene esters or lactones gives 4-aryl-quinolin-2(1H)-ones in 65–96% yield. This method is mild, highly efficient, and amenable to scaleup.

Low level drug product API form analysis - Avalide tablet NIR quantitative method development and robustness challenges.

Avalide(@), a medication used for the treatment of hypertension, is a combination of Irbesartan, and Hydrochlorothiazide. Irbesartan, one of the active pharmaceutical ingredients (API) in Avalide products, exists in two neat crystalline forms: Form A and Form B. Irbesartan Form A is the API form used in a wet granulation for the preparation of Avalide tablets. The presence of the less soluble Irbesartan Form B in Avalide tablets may result in the slower dissolution. In this paper, we have presented our work on the method development, verification and challenges of quantitatively detecting, via NIR and ssNMR, very small amounts of Irbesartan Form B in Avalide tablets. As part of the NIR method development and qualification, limit of detection, linearity and accuracy were examined. In addition, a limited study of the robustness of the method was conducted and a bias in the level of Form B was correlated to the ambient humidity. ssNMR, a primary method for the determination of polymorphic composition, was successfully used as an orthogonal technique to verify the accuracy of the NIR method and added to the confidence in the NIR method. The speed and efficiency of the NIR method make it a suitable and convenient tool for routine analysis of Avalide tablets for Form B in a QC environment.

Selective removal of a benzyl protecting group in the presence of an aryl chloride under gaseous and transfer hydrogenolysis conditions

Abstract Selective removal of a benzyl protecting group in the presence of an aryl chloride using Pd/C under gaseous and transfer hydrogenolysis conditions is described. The addition of chloride salts to the debenzylation reaction provides excellent selectivity.

A new perspective on the mechanical evaluation of granular material

The mechanical strength of granules is an important parameter to be determined prior to any further downstream formulation processing. It is important to have a good gauge on the granule integrity to forecast any foreseeable powder issues associated with the material processability such as segregation, content uniformity, and material flow-ability. In this study, a systematic methodology has been developed to quantify the integrity of these granules subjected to a low frequency acoustic field to arrive at the Granule Integrity (GI) index. This methodology has been compared to existing well-established bulk characterization techniques reported in the literature such as Heckel analysis, Kawakita analysis, and Young’s modulus for four different processed samples. Heckel analysis is more amenable to examine the material deformability while Kawakita analysis is better suited to understand the mechanics of granular material. Individual granule strength measurements to determine Young’s modulus often show large variations across the bulk sample. The GI index in conjunction with the Kawakita analysis provides us with more mechanistic insight and understanding into the formation of these granules from a processing perspective. This paper shows the benefits of using the GI index as a practical and direct methodology to characterize the GI of bulk samples in an industrial setting.