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The solubility of artemisnin in 12 different organic solvents, methanol, ethanol, butanol, acetone, ethyl acetate, isopropyl acetate, acetonitrile, hexane, heptane, 2-butanone (MEK), methyl tert-butyl ether (MTBE), and toluene, as well as in three binary solvent mixtures of ethyl acetate + ethanol, ethyl acetate + acetone, and ethanol + acetone, within the temperature range of (284.10 and 323.15) K, is obtained. The solubility data were fitted to the Two-Liquid-Non-Random (NRTL) activity coefficient equation to obtain the model binary interaction parameters, which were used to predict the solubility of artemisinin in ethyl acetate and acetone or ethanol binary solvent mixtures. The predicted values compared favorably with the experimental data.

The asymmetric enzymatic ketone reduction of 4,4-dimethoxytetrahydro-2H-pyran-3-one provided the (R)-r-hydroxyketal, an important chiral precursor for a pharmaceutical intermediate, with high enantioselectivity (>99% ee). An economical process including in situ NADPH-cofactor regeneration using glucose dehydrogenase has been developed to produce the desired material in high yield (96-98%). The two-enzyme process was employed at pilotplant scale to produce 80 kg of (R)-4,4-dimethoxytetrahydro-2Hpyran-3-ol. Critical factors for scale-up were found to be pH control and agitation speed.

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Clearance of aggregates during protein purification is increasingly paramount as protein aggregates represent one of the major impurities in biopharmaceutical products. Aggregates, especially dimer species, represent a significant challenge for purification processing since aggregate separation coupled with high purity protein recovery can be difficult to accomplish. Biochemical characterization of the aggregate species from the hydrophobic interaction and cation exchange chromatography elution peaks revealed two different charged populations, i.e. heterogeneous charged aggregates, which led to further challenges for chromatographic removal. This paper compares multimodal versus conventional cation exchange or hydrophobic chromatography methodologies to remove heterogeneous aggregates. A full, mixed level factorial design of experiment strategy together with high throughput experimentation was employed to rapidly evaluate chromatographic parameters such as pH, conductivity, and loading. A variety of operating conditions were identified for the multimodal chromatography step, which lead to effective removal of two different charged populations of aggregate species. This multimodal chromatography step was incorporated into a monoclonal antibody purification process and successfully implemented at commercial manufacturing scale.

A material-conserving analytical solubility measurement technique, with in-line reversed HPLC separation protocol, was employed to measure the mole fraction solubility of lovastatin in methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate, acetone, and 2-butanone between (285 and 313) K. We examine three methods for the estimation of the ideal solubility of lovastatin by using different approximations for the difference between the heat capacity of the solid and the liquid at the melting point ΔC P = C P L − C P S. The solubility data were combined with calculated ideal solubility data to determine the activity coefficients of lovastatin which are then fitted to a van’t Hoff form equation to obtain estimated values of the partial molar enthalpy of mixing, Δmix H ∞, and partial molar entropy of mixing, Δmix S ∞, respectively. Thermodynamic consistency was confirmed when ΔC P = C P L − C P S was used in the ideal solubility calculation.

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Lipopeptides such as pneumocandin B(0) are often produced by fermentation processes. Many compounds with similar structures (structural analogues), and hence similar physiochemical properties, are coproduced in the fermentation. We employed high performance liquid chromatography using silica gel as the stationary phase and a ternary ethyl acetate/MeOH/water mobile phase to separate pneumocandin B(0) from these structural analogues. Despite extensive efforts to optimize this system, two key structural analogues, pneumocandin E(0) and pneumocandin B(5), continued to be poorly resolved from the main product peak (pneumocandin B(0)). As a result, feed load was restricted and productivity was limited. In situ modification of the silica gel stationary phase with l-proline or other amino acids significantly enhances the resolution of the two key structural analogues from the compound of interest, enabling a two-fold increase in productivity. Results of a systematic study showed that the amine group in l-proline and other amino acids plays a key role in the modification of the surface of the silica gel to mediate the selectivity enhancement.