Multiplexed small molecule impurity monitoring in antibody-based therapeutics by mixed-mode chromatography paired with charged aerosol detection.

With advanced genetic engineering technologies and better understanding of disease biology, antibody-based therapeutics are emerging as promising new generation biopharmaceuticals. These novel antibody formats are carefully designed to possess desired features such as enhanced selectivity. However, their high level of structural complexity with multiple components often leads to long development and complex multi-step manufacturing processes, through which a variety of potential small molecule impurities can be introduced. In this work, an in-process assay was developed in which mixed-mode chromatography coupled with charged aerosol detection was utilized for multiplexed detection of nine reagents commonly used in development and manufacturing of antibody-based therapeutics: isopropyl ß-d-1-thiogalactopyranoside, methionine sulfoximine, ampicillin, guanidine, dehydroascorbic acid, glutathione, tris(2-carboxyethyl)phosphine, N-acetyl cysteine, and arginine. This method utilized a mixed-mode column with ion-exchange properties operated in the hydrophilic interaction chromatography mode. Various parameters were systematically optimized and under optimal conditions, the method demonstrated excellent specificity, sensitivity, linearity, precision, accuracy, and was successfully applied to determine residual impurities in multiple samples from antibody-derived molecules.

Impact of polymer type, ASD loading and polymer-drug ratio on ASD tablet disintegration and drug release.

Amorphous solid dispersion (ASD) has become an attractive strategy to enhance solubility and bioavailability of poorly water-soluble drugs. To facilitate oral administration, ASDs are commonly incorporated into tablets. Disintegration and drug release from ASD tablets are thus critical for achieving the inherent solubility advantage of amorphous drugs. In this work, the impact of polymer type, ASD loading in tablet and polymer-drug ratio in ASD on disintegration and drug release of ASD tablets was systematically studied. Two hydrophilic polymers PVPVA and HPMC and one relatively hydrophobic polymer HPMCAS were evaluated. Dissolution testing was performed, and disintegration time was recorded during dissolution testing. As ASD loading increased, tablet disintegration time increased for all three polymer-based ASD tablets, and this effect was more pronounced for hydrophilic polymer-based ASD tablets. As polymer-drug ratio increased, tablet disintegration time increased for hydrophilic polymer-based ASD tablets, however, it remained short and largely unchanged for HPMCAS-based ASD tablets. Consequently, at high ASD loadings or high polymer-drug ratios, HPMCAS-based ASD tablets showed faster drug release than PVPVA- or HPMC-based ASD tablets. These results were attributed to the differences between polymer hydrophilicities and viscosities of polymer aqueous solutions. This work is valuable for understanding the disintegration and drug release of ASD tablets and provides insight to ASD composition selection from downstream tablet formulation perspective.