Assessment, Pretreatment and Treatment of Pharmaceutical Production Wastewaters in the Roche Group.

The manufacturing of pharmaceuticals also produces wastes, mainly wastewaters (WWs). These WWs must be responsibly managed. Sometimes, the organic contents of these WWs are not easily removable in standard WW treatment, hence technical options must be investigated to pretreat such WWs in order to remove or destroy the recalcitrant compounds, mostly the active pharmaceutical ingredients themselves. This contribution from a pharmaceuticals company describes WW assessment and management principles, the search for pretreatment options and several case studies on WW (pre)treatment at some pharma production sites of the Roche Group.

Performance of an anaerobic membrane bioreactor for pharmaceutical wastewater treatment.

Anaerobic treatment of wastewater and waste organic solvents originating from the pharmaceutical and chemical industries was tested in a pilot anaerobic membrane bioreactor, which was operated for 580days under different operational conditions. The goal was to test the long-term treatment efficiency and identify inhibitory factors. The highest COD removal of up to 97% was observed when the influent concentration was increased by the addition of methanol (up to 25gL-1 as COD). Varying and generally lower COD removal efficiency (around 78%) was observed when the anaerobic membrane bioreactor was operated with incoming pharmaceutical wastewater as sole carbon source. The addition of waste organic solvents (>2.5gL-1 as COD) to the influent led to low COD removal efficiency or even to the breakdown of anaerobic digestion. Changes in the anaerobic population (e.g., proliferation of the genus Methanosarcina) resulting from the composition of influent were observed.

Rational selection of alternative, environmentally compatible surfactants for biotechnological production of pharmaceuticals--a step toward green biotechnology.

The biotechnological production of pharmaceutical active substances needs ancillary substances. Surfactants are used at the end of the cell culture as a protection against potential viral or bacterial contamination and to lyse the producing cells for isolation and purification of the products. To find a replacement for a surfactant that had raised environmental concern, environmentally relevant data for potential alternatives were searched for in the literature. Significant data gaps were filled with additional tests: biodegradability, algal growth inhibition, acute daphnid immobilization and chronic daphnid reproduction toxicity, acute fish toxicity, and activated sludge respiration inhibition. The results were used to model removal in the wastewater treatment plants (WWTPs) serving 3 biotechnological production sites in the Roche Group. Predicted environmental concentrations (PECs) were calculated using realistic amounts of surfactants and site-specific wastewater fluxes, modeled removals for the WWTPs and dilution factors by the respective receiving waters. Predicted no-effect concentrations (PNECs) were derived for WWTPs and for both fresh and marine receiving waters as the treated wastewater of 1 production site is discharged into a coastal water. This resulted in a spreadsheet showing PECs, PNECs, and PEC ÷ PNEC risk characterization ratios for the WWTPs and receiving waters for all investigated surfactants and all 3 sites. This spreadsheet now serves as a selection support for the biotechnological developers. This risk-based prioritization of surfactants is a step toward green biotechnological production.

Environmental risk assessment for ancillary substances in biotechnological production of pharmaceuticals.

An increasing number of pharmaceutical active substances are produced through biotechnological processes. For sustained and safe growth of the host organisms as well as optimal expression, purification, and formulation of the product, biotechnological manufacturing processes need optimal and robust environmental conditions, which are attained through the use of buffers, chelators, and antibiotics, beside nutrients. These ancillary substances are drained with the wastewater to a wastewater treatment plant (WWTP) and are released after treatment with the effluent to receiving waters. The potential risks of such substances to WWTPs and surface waters were investigated. Three common buffers (morpholinoethane sulfonic acid [MES], morpholinopropanesulfonic acid [MOPS], 1,4-piperazine (diethanesulfonic acid) [PIPES]), one chelator (ethylenediaminetetraacetic acid [EDTA]), and one antibiotic (gentamycin) were searched in the literature for environmental data or tested for biodegradability and inhibition of activated sludge as well as acute toxicity to algae, daphnids, and fish. Amounts of the ancillary substances used in the European biotechnological production plants of F. Hoffmann-La Roche Ltd in Basle (Switzerland) and Penzberg (Germany), and actual wastewater fluxes through the respective WWTP, as well as realistic dilution factors for the local receiving water, were documented. Based on this information, site-specific predicted environmental concentrations (PECs) for the WWTPs and surface waters in Basle and Penzberg were extrapolated. These PECs were compared with predicted no effect concentrations (PNECs) for the WWTP and surface waters, derived from sludge inhibition and ecotoxicity results, respectively. For all five ancillary substances investigated, all PEC/PNEC risk characterization ratios are <1, indicating no significant risk to the WWTPs or the receiving waters at both sites.

Cinchona-modified platinum catalysts: from ligand acceleration to technical processes.

This Account records work carried out in our laboratories during the last 2 decades in the field of enantioselective heterogeneous hydrogenation. Of particular interest was Orito's catalytic system, platinum catalysts modified with cinchona alkaloids for the hydrogenation of activated ketones. Described are the development of the optimal platinum catalyst and modifier and the expansion of the scope of the catalyst. Kinetic studies aimed at understanding the mode of action of the catalyst revealed that the cinchona modifier not only renders the catalyst enantioselective but strongly accelerates the hydrogenation. This was the first case of ligand acceleration with a heterogeneous catalytic system. Finally, a number of industrial processes are summarized with the enantioselective hydrogenation of various alpha-keto esters as a key step.

Enantioselective hydrogenation of alkenes with iridium-PHOX catalysts: a kinetic study of anion effects.

In the asymmetric hydrogenation of unfunctionalized olefins with cationic iridium-PHOX catalysts, the reaction kinetics and, as a consequence, catalyst activity and productivity depend heavily on the counterion. A strong decrease in the reaction rate is observed in the series [Al[OC(CF3)3]4]- >BArF- >[B(C6F5)4]- >PF6- >>BF4- >CF3SO3-. With the first two anions, high rates, turnover frequencies (TOF >5000 h(-1) at 4 degrees C), and turnover numbers (TONs) of 2000-5000 are routinely achieved. The hexafluorophosphate salt reacts with lower rates, although they are still respectable; however, this salt suffers from deactivation during the reaction and extreme water-sensitivity, especially at low catalyst loading. Triflate and tetrafluoroborate almost completely inhibit the catalyst. In contrast to the hexafluorophosphate salt, catalysts with [Al[OC(CF3)3]4]-, BArF-, and [B(C6F5)4]- as counterions do not lose activity during the reaction and remain active, even after all the substrate has been consumed. In addition they are much less sensitive to moisture and, in general, rigorous exclusion of water and oxygen is not necessary. A first-order rate dependence on the hydrogen pressure was determined for the BArF- and the PF6- salts. At low catalyst loading, the rate dependence on catalyst concentration was also first order. The rate dependence on the alkene concentration was strikingly different for the two salts. While the reaction rate observed for the BArF- salt slightly decreased with increasing alkene concentration (rate order -0.2), a rate order of approximately 1 was determined for the corresponding hexafluorophosphate at low alkene concentrations.

Synthesis, characterization, and catalytic activity of N-heterocyclic carbene (NHC) palladacycle complexes.

Palladacycle dimers possessing bridging halides can be easily cleaved by using N-heterocyclic carbenes (NHCs) to generate novel monomeric complexes. The structure of one of these was determined by single-crystal diffraction study and consists of a square-planar coordination around the palladium center where the NHC ligand is trans to the amine of the palladacycle. The complex was found to be equally active in aryl amination and alpha-arylation of ketones even at very low catalyst loading (0.02 mol %). Primary and secondary alkyl/arylamines are equally active partners in coupling reactions. [reaction: see text]

No stirring necessary: parallel carbonylation of aryl halides with CO and various alcohols under pressure.

The parallel carbonylation of aryl halides with 6-25 bar of CO in 1-mL vials in a standard autoclave was investigated. 4-Bromoacetophenone and 2-chloropyridine were used as model substrates with 102 different O-nucleophiles (primary and secondary alcohols, phenols). No inertization during the loading was necessary. Fifty esters (43 new, yield up to 60%) were isolated and characterized. Ether, ester, ketone, and sometimes even olefin functions were usually tolerated. The new method is suitable for screening and small scale products synthesis.