C. Stewart Slater

LCA approach to the analysis of solvent waste issues in the pharmaceutical industry

Life cycle assessment offers a unique opportunity to analyze emission reductions across all manufacturing sectors. However, few efforts have been made to apply this method to the pharmaceutical industry. Typically, between 80 and 90% of the total mass used in the production of an active pharmaceutical ingredient (API) may be attributed to solvent use. Manufacture of virgin solvent and solvent waste management contribute significantly more life cycle emissions than comparable processes for commodity chemicals, with the majority of this waste consisting of CO2 and other green house gas emissions. Three case studies from Pfizer, Bristol-Myers Squibb, and Novartis are examined. In these cases, solvent recovery and reduction techniques are integrated into API syntheses. It is shown that the actual extent of the environmental footprint reduction can only be realized with a full life cycle analysis.

A method to characterize the greenness of solvents used in pharmaceutical manufacture

This paper describes the development of a method to calculate the overall “greenness” of a pharmaceutical process that uses multiple solvents. This calculation is made by taking into account various environmental parameters and determining an overall greenness index. Through this method a scientist or engineer can effectively determine alternative, “greener” solvents or processes based on the use of a solvent database and greenness score. The objective is to develop a means to improve the process of drug development through solvent replacement/reduction. A solvent selection table, using a common spreadsheet software routine, was developed for the purpose of allowing a user to compare the greenness between two different process routes. This table includes over 60 solvents and associated chemicals common in the pharmaceutical and chemical industries. The comparison was made possible by the creation of a user-defined, weighted-solvent, greenness index that is an overall weighted factor taking into consideration solvent type, quantity used, and environmental impact. A given process or solvent receives an index ranking based on a variety of environmental and health parameters. The index values, along with the mass of solvents used in the given process, are used to compute the index, which allows for a quick and easy quantitative environmental comparison between two potential process routes.

Pervaporation as a green drying process for tetrahydrofuran recovery in pharmaceutical synthesis

The use of pervaporation technology as a green drying process for the recovery and reuse of the solvent, tetrahyrdofuran, in a pharmaceutical synthesis has been evaluated. A case study has been performed on a step in the synthesis of a new oncology drug. Pervaporation has been integrated with a constant-volume distillation process to produce a hybrid system that allows for the recovery and reuse of tetrahydrofuran. An economic and environmental analysis shows that this is an effective technology for this application.

Separation of Diacteone Alcohol‐Water Mixtures by Membrane Pervaporation

Abstract A study was conducted to evaluate membrane pervaporation for the separation of diacetone alcohol‐water mixtures using commercially available membranes for organic enrichment and dehydration. Empirical correlations for the effect of the process parameters of feed concentration, feed temperature, permeate‐side pressure, and scale‐up were developed. The solvent‐water mixture was successfully separated with a poly(vinyl alcohol) based Sulzer PERVAP 2210 dehydration membrane. Various dehydration membranes were evaluated and a comparison of the flux and separation factor was made. The membrane performance in separating acetone‐water mixtures was also studied. An overall model to predict the membrane area needed for a scale‐up was developed based on the results.

Pervaporation study for the dehydration of tetrahydrofuran-water mixtures by polymeric and ceramic membranes

Pervaporation technology can effectively separate a tetrahydrofuran (THF) solvent-water waste stream at an azeotropic concentration. The performance of a Sulzer® 2210 polyvinyl alcohol (PVA) membrane and a Pervatech BV® silica membrane were studied, as the operating variables feed temperature and permeate pressure, were varied. The silica membrane was found to exhibit a flux of almost double that of the PVA membrane, but both membranes had comparable separation ability in purifying the solvent-water mixture. At benchmark feed conditions of 96 wt% THF and 4 wt% water, 50°C and 10 torr permeate pressure, the silica membrane flux was 0.276 kg/m2hr and selectivity was 365. For both membranes, flux was found to increase at an exponential rate as the feed temperature increased from 20 to 60°C. The flux through the silica membrane increases at a 6% faster rate than the PVA membrane. Flux decreased as permeate pressure was increased from 5 to 25 torr for both membranes. The amount of water in the permeate decreased exponentially as the permeate pressure was increased, but increased linearly with increasing temperature. Optimum conditions for flux and selectivity are at low permeate pressure and high feed temperature. When a small amount of salt is added to the feed solution, an increase in flux is observed. Overall models for flux and permeate concentration were created from the experimental data. The models were used to predict scale-up performance in separating an azeotropic feed waste to produce dehydrated THF solvent for reuse and a permeate stream with a dilute THF concentration.

Green design alternatives for isopropanol recovery in the celecoxib process

Various approaches to solvent recovery have been studied for the manufacturing process of celecoxib, the active ingredient in Celebrex®. A design case study has been performed by Rowan University with Pfizer through a green engineering partnership program. The manufacturing operation at one of their plants was evaluated and several green engineering alternatives for the purification and recovery of isopropanol (IPA) from waste streams proposed. This separation is complex due to the multiple waste streams generated, with varying compositions of IPA, ethanol, methanol, water, and dissolved solids. Overall goals were waste minimization and IPA recovery and purification. A conceptual study of distillation, extraction, reactive distillation, adsorption, and membrane-based processes was performed. Through use of computer simulation and literature/design methodologies, traditional methods were shown to be unable to obtain high IPA purities with the available equipment. Several green design approaches were evaluated using distillation combined with either molecular sieve adsorption or membrane pervaporation. These process schemes appear to have the most promise to effectively recover and purify IPA. The case study describes equipment and processing issues, and estimates environmental impacts from a life cycle analysis.

Environmental analysis of the life cycle emissions of 2-methyl tetrahydrofuran solvent manufactured from renewable resources.

ABSTRACT An environmental analysis has been conducted to determine the cradle to gate life cycle emissions to manufacture the green solvent, 2-methyl tetrahydrofuran. The solvent is considered a greener chemical since it can be manufactured from renewable resources with a lower life cycle footprint. Analyses have been performed using different methods to show greenness in both its production and industrial use. This solvent can potentially be substituted for other ether and chlorinated solvents commonly used in organometallic and biphasic reactions steps in pharmaceutical and fine chemical syntheses. The 2-methyl tetrahydrofuran made from renewable agricultural by-products is marketed by Penn A Kem under the name ecoMeTHF™. The starting material, 2-furfuraldehyde (furfural), is produced from corn cob waste by converting the available pentosans by acid hydrolysis. An evaluation of each step in the process was necessary to determine the overall life cycle and specific CO2 emissions for each raw material/intermediate produced. Allocation of credits for CO2 from the incineration of solvents made from renewable feedstocks significantly reduced the overall carbon footprint. Using this approach, the overall life cycle emissions for production of 1 kg of ecoMeTHF™ were determined to be 0.191 kg, including 0.150 kg of CO2. Life cycle emissions generated from raw material manufacture represents the majority of the overall environmental impact. Our evaluation shows that using 2-methyl tetrahydrofuran in an industrial scenario results in a 97% reduction in emissions, when compared to typically used solvents such as tetrahydrofuran, made through a conventional chemical route.

Life cycle analysis of solvent reduction in pharmaceutical synthesis using continuous adsorption for palladium removal.

The life cycle emissions associated with the reduction of wastes from an adsorption process to remove palladium complexes in drug manufacture have been evaluated. The study assessed a green improvement to a process step in an active pharmaceutical ingredient synthesis where palladium catalyst is removed from a reaction mixture. The greener process uses a continuous adsorption system, composed of a more efficient adsorbent, consuming less organic solvent and rinse water, which results in less waste disposal. The newer process is also more energy and cost efficient from an operational perspective. There is a 94% reduction in the carbon footprint of the new process when compared to the current operation.

Green Engineering: Integration of Green Chemistry, Pollution Prevention, and Risk-Based Considerations

Literature sources on green chemistry and green engineering are numerous. The objective of this chapter is to familiarize readers with some of the green engineering and chemistry concepts, approaches, and tools. In order to do this, the chapter is organized into five sections as follows.

Microfiltration of Streptomyces rimosus: Cell Harvesting Process Studies

ABSTRACT Process studies were carried out to investigate the feasibility of using tangential crossflow microfiltration to harvest antibiotic-producing cells such as Streptomyces rimosus from a whole fermentation broth. The microorganism was grown in a repeated batch fermentation up to the point of secondary mycelium formation in order to simulate broth age and mycelial morphology present in the terramycin production process. Cell separation was carried out in a Millipore Pellicon system equipped with a Durapore 0.45 μm membrane cassette and operated in a batch concentration mode. Permeate fluxes for untreated fermentation broth were measured and compared with those for broth that was pretreated by acidification—a typical process step used to improve antibiotic recovery. Acidification from pH 7 to 4 prior to filtration changed the cell morphology and significantly reduced the inlet feed pressure required to pump the broth. In addition, pretreatment enabled higher crossflow rates and higher steady-state flu...