Results of a pharmaceutical roundtable organised to highlight the areas of chemistry that the pharmaceutical industry needs to become more environmentally friendly have been published in the latest issue of Green Chemistry.
The roundtable was organised by the American Chemical Society (ACS) Green Chemistry Institute (GCI) and included spokespeople from the following pharmaceutical companies: GlaxoSmithKline (GSK), Pfizer, Merck, Eli Lilly, Schering-Plough and AstraZeneca.
The roundtable's mission was to identify and monitor new research that could enable more efficient process development and production as well as trying to influence the technical agendas of worldwide funding agencies by defining specific processes the pharmaceutical industry believes could be more environmentally friendly.
The ideas were grouped into three areas: reactions that pharmaceutical companies use but would prefer better and greener reagents; reactions that companies would like to use if they were available; and ideas concerned with minimising solvent use.
The roundtable identified thirteen reactions currently used in pharmaceutical manufacturing that the industry would like to see cleaner and more active reagents for.
The most crucial of these reactions was identified as amide forming reactions which often suffer from poor atom economy (low efficiency based on all atoms involved).
65 per cent of recent drug candidates from three of the attending companies were prepared using an amide formation step.
The use of enzyme catalysts eliminates some of the issues with poor atom economy as well as removing the need for non-aqueous solvents.
Despite significant progress using enzyme based catalysts, their lack of broad-substrate applicability severely limits their commercial use.
The activation of alcohols towards nucleophilic substitution is frequently used in the preparation of active pharmaceutical ingredients and the roundtable highlighted this area as an area needing attention.
Recent advances in the area were noted to include catalytic activation using indium(III) chloride, iridium catalysts and 4-toluensulfonic acids.
The roundtable also highlighted the reduction of amides to amines as an area requiring safer and greener reagents as essentially all medicines contain at least one basic nitrogen atom.
The reduction of an amide to an amine is commonly conducted using potentially flammable hydride reagents such as LiAlH
4and B
2H
6(which is also used as a rocket propellant).
These reagents require stringent safety designs to be built into reactors and form inorganic by-products that are often difficult to remove with long filtration times and product loss being typical of such processes.
Of the more aspirational reactions, C-H activation of aromatics that would allow cross-coupling reactions while avoiding the need to prepare halogenated aromatics was deemed the most desirable.
The synthesis of chiral amines from ammonia, the asymmetric hydrogenation of unsubstituted olefins and greener methods of fluorination were also deemed important.
Replacements for dipolar aprotic solvent such as N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMAc) were high on the wishlist, This is because these solvents have been found to have adverse effects on the human reproductive system and are also difficult to separate and dispose of.
The article also highlighted that organic solvents account for over 75 per cent of the waste associated with the manufacture of active pharmaceutical ingredients (APIs) with the volumes used for cleaning 2-3 times that used in the process.
To this end, pharmaceutical manufacturers would like to see a way to eliminate solvent usage in the cleaning step as this would significantly reduce the environmental footprint of most pharmaceutical processes.
