Green Chemistry in Pharmaceutical Applications - Pharmaceutical Technology

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Green Chemistry in Pharmaceutical Applications
A recent review highlights contributions in process research and development and manufacturing using the principles of green chemistry.


PTSM: Pharmaceutical Technology Sourcing and Management
Volume 5, Issue 9
Untitled Document

An important tool for advancing green chemistry in pharmaceutical applications is sharing information on its use. Members of the American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable (ACS GCISPR) recently provided a review of research from this field (1). The ACS GCIPR, which consists of several major pharmaceutical companies and suppliers, encourages the innovation and integration of green chemistry and green engineering in the pharmaceutical industry. The group reviewed 14 areas in assessing contributions in the applications of green chemistry in the pharmaceutical industry.

Measuring the pharmaceutical industry

Given the complexity of the molecules that are used as active pharmaceutical ingredients (APIs) and the resulting complexity in the synthesis and purification needed to produce a given API, the pharmaceutical industry as a whole ranks low compared with other chemical sectors in its green practices. A widely used and established green metric is the E factor, developed by Roger Sheldon, professor emeritus at the Delft University of Technology in The Netherlands, which evaluates the "greenness” of a manufacturing route by its process efficiency. The E factor is simply the mass ratio of waste to desired product. A higher E factor means more waste and a more negative environmental impact. The pharmaceutical industry as a whole has a high E factor compared with other industrial chemical manufacturing segments. The E factor for bulk chemicals ranges from 1–5, and for fine chemicals, 5-50, but for the pharmaceuticals, the E factor ranges from 25-100 (2).

To improve the environmental profile of chemical processes, a widely used roadmap for green chemistry is encompassed in the 12 Principles of Green Chemistry (3, 4). These principles identify strategies for meeting goals of sustainability. These approaches include: waste reduction in chemical synthesis; using raw materials and feedstocks from renewable sources; employing catalysts, not stoichiometric reagents, to minimize waste and increase process efficiency; avoiding chemical derivatives by not using blocking or protecting groups or temporary modifications if possible; maximizing atom economy; replacing or reducing solvents; increasing energy efficiency of chemical reactions by running them at ambient temperature and pressure when possible; using in-process or real-time monitoring to reduce or eliminate byproduct formation; and other process safety and environmental considerations.

Highlighting contributions

In its review, the ACS GCIPR reviewed work in the following areas: solvent reduction or replacement; amide formation; oxidations; asymmetric hydrogenations; carbon-hydrogen activation; fluorination; biocatalysis; alcohol activation for nucleophilic displacement; Friedel-Crafts chemistry; chemistry in water; continuous processing and process intensifcation; and supercritical fluid chromatography separations (1). Some highlights of their review are provided below.

Pfizer (New York) recently published its solvent-selection guide that the company uses in its medicinal-chemistry efforts. The solvents are evaluated using nine factors in several areas, which include worker-safety, process-safety, environmental, and regulatory assessments (1, 5). GlaxoSmithKline (GSK London) developed a tool to assist in the selection of the greenest solvent that is compatible with the reagents and reaction conditions used (1). GSK’s Eco-Design Toolkit provides bench-level chemists and engineers green-chemistry information and tools for process research and development and manufacturing (6). The toolkit has five modules: a green chemistry and technology guide; a materials guide to solvents and bases with related environmental, health, and safety data; a fast life-cycle assessment for synthetic chemistry that streamlines evaluations of the environmental life cycle and measures green metrics, including mass efficiency; a green packaging guide; and a guide that identifies legislation phasing out hazardous substances (6).

An important development relating to amide formation was reported from the process development group of AstraZeneca (London) regarding the utility of imidazole hydrochloride to speed up reactions by evaluating its applications for several aniline derivatives and heteroarenes (1, 7). N,N ′-carbonyldiimidazole (CDI) is a commonly used reagent for coupling carboxylic acids with aliphatic or aromatic amines to form amides. Woodman et al., however, point out that slow reaction rates between aromatic amines and the CDI intermediates have limited the scope of the reaction in the pharmaceutical and fine-chemicals industries. The group’s work showed that the rate of CDI-mediated amidation to be significantly enhanced upon introduction of imidazole hydrochloride as a proton source for acid catalysis (1, 7).

Asymmetric hydrogenation is an important reaction in pharmaceutical synthesis as many bioactive molecules are chiral compounds and strategies to produce a single enantiomer in high optical purity are valued. The ACS GCIPR review article reported that more than 150 articles relating to asymmetric hydrogenation were published in 2008, with the majority of articles relating to the modification of the catalyst and ligands (1). An important development that may lead to improving reaction conditions for asymmetric hydrogenation was the use of an iron-catalyst system for asymmetric hydrogenation at 50 °C and asymmetric transfer hydrogenation at room temperature that offered transfer hydrogenation activity similar to that of ruthenium-based catalysts (1, 8).

In the area of biocatalysis, researchers at Merck & Co. (Whitehouse Station, NJ) reported the pilot-scale asymmetric synthesis of 4,4-dimethoxytetrahydro-2H-pyran-3-ol with a ketone reductase and in situ cofactor recycling using glucose dehydrogenase in high yield and enantiomeric excess (1,9).

References

1. I. Andrews et al., “Green Chemistry Articles of Interest to the Pharmaceutical Industry,” Org. Process Res. Dev. 13 (3), pp 397–408 (2009).

2. R. Sheldon, I. Arends, and U. Hanefield, Green Chemistry and Catalysis (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007), p 3.

3. EPA, “An Introduction to the Concept of Green Chemistry” (Washington, DC), available at epa.gov/gcc/pubs/principles.html, accessed Aug. 17, 2009.

4. P. Anastas and J. Warner, Green Chemistry: Theory and Practice (Oxford University Press, New York, 1998).

5. Kim Alfonsi et al., “Green Chemistry Tools to Influence a Medicinal Chemistry and Research Chemistry Based Organization,” Green Chem. 10 (1) , 31–36 (2008).

6. P. Van Arnum, “Going Green in Pharmaceuticals,” Pharm. Technol. 33 (2), 44–46 (2009).

7. E. Woodman et al., “ N,N ′-Carbonyldiimidazole-Mediated Amide Coupling: Significant Rate Enhancement Achieved by Acid Catalysis with Imidazole HCl,” Org. Process Res. Dev. 13 (1), 106–113 (2009).

8. C. Sui-Seng, “Highly Efficient Catalyst Systems Using Iron Complexes with a Tetradentate PNNP Ligand for the Asymmetric Hydrogenation of Polar Bonds,” Agnew. Chem. Int. Ed. 47 (5), 940–943 (2008).

9. B. Kosjek et al., “Preparative Asymmetric Synthesis of 4,4-Dimethoxytetrahydro-2H-pyran-3-ol with a Ketone Reductase and In Situ Cofactor Recycling using Glucose Dehydrogenase,” Org. Process Res. Dev. 12 (4), p 584–588 (2009).

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