Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

Catalysis plays a crucial role in the synthesis of pharmaceutical intermediates and APIs. Catalysts can enable more efficient chemical transformations, improve reaction conditions, better product yields, and produce greater enantioselectivity. Some key recent developments involve palladium-catalyzed hydrogenation, visible-light photocatalysis, chemocatalytic approaches for making heterocyclic compounds, and advances in biocatalysis.  

Palladium-catalyzed hydrogenation reactions are important in industrial chemistry and fine-chemicals manufacture, but precious metal catalysts, such as palladium, are costly. Researchers at Tufts University's School of Arts and Sciences and School of Engineering in Medford, Massachusetts, recently reported on the arrangement of individual atoms in a metal alloy and their ability to catalyze hydrogenation reactions.  

Hydrogenation requires the presence of a catalyst, usually a metal or an alloy of both precious and common metals, which allows the hydrogen atoms to bind with other molecules. It is difficult to produce alloys that are selective hydrogenation catalysts and are able to attach the hydrogen atoms to specific sites of another molecule. Tufts chemists and chemical engineers reported that when single atoms of palladium were added to copper, which is much cheaper and readily available, the resulting "single atom alloy" became active and selective for hydrogenation reactions, according to a Mar. 9, 2012, Tufts University press release.   

NICHOLAS EVELEIGH/STOCKBYTE/GETTY IMAGES			

The Tufts scientists scattered single atoms of palladium less than half a nanometer wide onto a copper support. For this research, the Tufts team heated small amounts of palladium to almost 1000 °C. At that temperature, individual atoms embedded themselves on the copper surface. A scanning tunneling microscope enabled the team to see how these single atoms dispersed in the copper and how molecular hydrogen could then dissociate at individual, isolated palladium sites and spill over onto the copper surface layer, according to the Tufts release. 

Specifically, the researchers used desorption measurements in combination with high-resolution scanning tunneling microscopy to show that the individual, isolated palladium atoms in a copper surface substantially lowered the energy barrier to both hydrogen uptake on and subsequent desorption from the copper metal surface. The hydrogen dissociation at the palladium atom sites and weak binding to copper allowed for very selective hydrogenation of styrene and acetylene as compared with pure copper or palladium metal alone (1). 

A team of University of Arkansas (US) researchers reported on using visible-light photocatalysis with a ruthenium catalyst to produce a building block in pharmaceutical synthesis. Specifically, the researchers reported on a visible-light-mediated intermolecular [3+2] cycloaddition of mono- and bicyclic cyclopropylamines with olefins catalyzed by [Ru(bpz)

O to produce aminocyclopentane derivatives in good yields. Saturated 5,5- and 6,5-fused heterocycles were obtained in synthetically useful yields and diastereoselectivity (2). 

Heterocyclic compounds are important in pharmaceutical applications, and researchers at the California Institute of Technology (Caltech) recently reported on an advance in the synthesis of such compounds. They reported on their work in the enantioselective construction of quaternary 

-heterocycles by palladium-catalyzed decarboxylative allylic alkylation of lactams (3).  

"We think it's going to be a highly enabling reaction, not only for preparing complex natural products, but also for making pharmaceutical substances that include components that were previously very challenging to make," said Brian Stoltz, professor of chemistry at Caltech, in a Jan. 13, 2012, university press release. "This has suddenly made them quite easy to make, and it should allow medicinal chemists to access levels of complexity they couldn't previously access. 

Specifically, the researchers reported on the highly enantioselective palladium-catalyzed decarboxylative allylic alkylation of lactams to form 3,3-disubstituted pyrrolidinones, piperidinones, caprolactams and structurally related lactams. The researchers assert that the synthesis provides a new approach for the asymmetric synthesis of such structures, an important development given the prevalence of quaternary 

-heterocycles in biologically active alkaloids and pharmaceutical agents. The researchers reported that the catalysis provided enantiopure quaternary lactams that intercept synthetic intermediates previously used in the synthesis of the 

 alkaloids, quebrachamine and rhazinilam, but that were previously produced by chiral auxiliary approaches or as racemic mixtures (3). 

Codexis, a biocatalysis company, reported last month on its work with Merck & Co. for developing an enzyme-based production method for a key intermediate in the production of boceprevir, the API in Merck's Victrelis, a drug to treat hepatitis C. The companies reported on a chemoenzymatic process for manufacturing the boceprevir bicyclic proline intermediate based on amine oxidase-catalyzed desymmetrization. The key structural feature in boceprevir is the bicyclic proline moiety, which during development stages, was produced by a classical resolution. As the drug candidate advanced, Codexis and Schering–Plough (now Merck) jointly developed a chemoenzymatic asymmetric synthesis where the net reaction was an oxidative Strecker reaction. The key part of the reaction sequence is an enzymatic oxidative desymmetrization of a prochiral amine substrate (4).  

According to Codexis, the new method increased chemical intermediate yield 150% over the previous process. It also reduced raw material use by 60%, water use by 61%, and overall process waste by 63%. Codexis used its proprietary CodeEvolver directed evolution technology to develop the custom enzyme for use in the commercial-scale manufacturing of the boceprevir intermediate. 

Codexis had earlier partnered with Merck & Co. for another biocatalytic route. In 2010, Merck and Codexis reported on the biocatalytic asymmetric synthesis of chiral amines from ketones in the manufacture of sitagliptin, the API in Merck's antidiabetes drug Januvia. The biocatalytic process replaced a rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of sitagliptin. The researchers started from an (

)-selective transaminase that showed slight activity on a smaller truncated methyl ketone analogue of the sitagliptin ketone. After creating this transaminase, which had marginal activity for the synthesis of the chiral amine, they further engineered the enzyme through directed evolution to optimize its use for large-scale manufacturing (5–8). 

)-selective transaminase was a homologue of an enzyme from 

)-specific transamination of methyl ketones and small cyclic ketones. For the sitagliptin synthesis, the researchers generated a structural homology model of this transaminase and found that the enzyme would not bind to the prositagliptin ketone because of steric interference and potentially undesired interactions. The evolved transaminase was a successful biocatalyst that synthesized the chiral amines that previously were accessible only through resolution (5–8). 

Codexis and Merck were recognized in 2010 with an Environmental Protection Agency's Presidential Green Chemistry Challenge Award, an annual recognition of advances in green chemistry. Codexis also submitted for consideration in 2010 and 2011 a biocatalytic route for making simvastatin, the active ingredient in Merck & Co.'s anticholesterol drug Zocor, which is now off patent (5, 8, 9). 

For the simvastatin route, Codexis licensed technology from Yi Tang, professor in the Department of Chemical and Biomolecular Engineering at the University of California at Los Angeles. The previous synthetic routes to simvastatin involved converting lovastatin into simvastatin by adding a methyl group that required protecting and then deprotecting other functionalities in the lovastatin molecule in a multistep synthesis. In the first route, lovastatin was hydrolyzed to the triol, monacolin J, followed by protection with selective silylation, esterification with dimethyl butyryl chloride, and deprotection. The second route involved protecting the carboxylic acid and alcohol functionalities, methylating the C2' carbon with methyl iodide, and deprotecting the product. These routes were inefficient because they produced less than 70% overall yield and were mass-intensive due to protection and deprotection (5, 8). 

The route developed by Tang and his group circumvented protection and deprotection and resulted in greater atom economy, reduced waste, and overall less hazardous reaction conditions. First, they cloned LovD, a natural acyltransferase produced by 

 that is involved in synthesizing lovastatin and that can accept nonnatural acyl donors. Recognizing that LovD might be a type of simvastatin synthase and a starting point for creating a new biocatalytic process, they evolved the enzyme toward commercial utility (5, 8–10). Codexis licensed Tang's technology, engineered the enzyme further, and optimized the process for pilot-scale simvastatin manufacture.  

Codexis is an example of a firm specializing in biocatalysis. Another is evocatal GmbH, which was founded in 2006 as a spin-off of the Institute for Molecular Enzyme Technology at the University of Düsseldorf in the Research Center Jülich. Last November, evocatal issued a carbon–carbon coupling kit using thiamine pyrophosphate-dependent (TPP) enzymes to produce enantiopure 2-hydroxy-ketones, an important intermediate class for pharmaceutical syntheses. The kit includes seven different TPP-enzymes with the relevant cofactor.  

 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, 

8 EPA, "The Presidential Green Chemistry Challenge Awards Program: Summary of 2010 Award Entries and Recipients" (Washington, DC, 2010). 

9. EPA, "The Presidential Green Chemistry Challenge Awards Program: Summary of 2011 Award Entries and Recipients" (Washington, DC, 2011). 

Articles

Advances in palladium-catalyzed hydrogenation, visible-light photocatalysis, and chemocatalyisis for heterocycles are some recent developments.

Seeking Chemocatalytic and Biocatalytic Solutions

, in New York, which brought together leaders from business, government, and nongovernmental organizations (NGOs) to discuss ways to improve the economic, political, and social rights of women globally. The summit, organized by 

 generated a meaningful dialogue on the innovative and diversified approaches for educational progress, business development, and individual economic advancement. These projects brought to mind the collaboration by the pharmaceutical industry, NGOs, and the public sector in improving women's and children's health in the developing world and the role that we can collectively and individually play.  

A large part of those efforts center on the United Nations' Millennium Development Goals, a set of eight antipoverty goals, which include specific targets to reduce maternal and child mortality. In support of these efforts, UNICEF and the United Nations Population Fund launched in March the Commission on Life-Saving Commodities for Women and Children to identify ways for improving the delivery of essential health supplies, including strengthening local production capacities, promoting new technologies, bolstering regulatory frameworks, and enhancing financing mechanisms at the global and local levels. The commission followed the launch by UN Secretary-General Ban Ki-moon in 2010 of the Global Strategy for Women's and Children's Health supported by 

, a global effort to improve the health of women and children.  

Pharmaceutical companies also are participating. In September 2011, Merck & Co. launched 

, a 10-year, $500-million initiative with global health partners to advance solutions and raise public- and private-sector engagement for reducing maternal mortality. Last October, the Sanofi Espoir Foundation lent its support for 

, an initiative by AMREF, an African public health NGO, which seeks to reduce maternal mortality in Africa by 25% by training 30,000 midwives by 2015. In September 2010, Johnson & Johnson launched a five-year effort aimed at helping 120 million women and children in developing countries on an annual basis through programs focused on maternal and children's health, including mobile health, R&D programs, and safe-birth programs.  

The value of such efforts cannot be underestimated as US Secretary of State Hillary Clinton, who spoke at the 

, emphasized. "Nations that invest in women's employment, health, and education are just more likely to have better outcomes. Their children will be healthier and better educated....So this is not just the right thing to do for us, to hold up these women, to support them, to encourage their involvement; this is a strategic imperative." The takeaway from Clinton and other notable women at the summit, such as Nobel Peace Prize Laureate Leymah Gbowee, International Monetary Fund chief Christine Lagarde, Facebook COO Sheryl Sandberg, Chair of the White House Council on Women and Girls Valerie Jarrett, and former US Secretary of State Madeleine K. Albright, was clear. "Every one of us needs to be part of the solution," she said."  

Industry, the public sector, and individuals can play an important role in creating solutions.

Tackling Global Health Concerns

	In attending the exhibitions and conference sessions at Interphex 2012 this week in New York, we gain a pulse on the current and future state of pharmaceutical manufacturing. So, a fundamental question arises: what is modern pharmaceutical manufacturing?

	It is clear that the industry is moving toward a new model in pharmaceutical manufacturing, a science- and risk-based approach under a product life-cycle concept as many of the conference sessions reflected. Driven by quality-by-design principles, companies are seeking ways to enhance their process understanding and build better control strategies based on that understanding in their manufacturing processes. Strategies for risk assessment and risk mitigation have been an important theme among the conference sessions as well as the tools, such as process analytical technology (PAT), which can be used to better that understanding. Related to these efforts is a focus on FDA’s  recent process validation guidance, also a subject of several conference sessions. The guidance aligns process validation activities with a product life-cycle concept and with existing FDA guidance and ICH  guidelines, such as Q8 (R2) P

 as a means to encourage the use of modern pharmaceutical development concepts, quality risk management, and quality systems at all stages of the manufacturing process life cycle.

	As much as regulatory considerations and the overall goal of product quality shape manufacturing processes, there also are market considerations. As pharmaceutical companies continue to align their manufacturing networks with product demand, decisions on how to best manage capital and operating costs emerge. In certain areas, such as biopharmaceutical production, a prevalent theme among the conference sessions and in the product innovation of exhibitors is the adoption of single-use components and technology to afford greater manufacturing flexibility as a means to reduce capital expenses as well as operating costs, such as by facilitating turnaround times between product campaigns and reducing set-up times. Modular manufacturing is the further iteration of this paradigm, and although still a niche area, several exhibitors emphasized these approaches in bioprocessing and fill–finish operations.

	So as much as the new products and product enhancements are the stars of Interphex, they reflect the underlying themes for the new paradigm for pharmaceutical manufacturing: one based on deeper process knowledge and understanding using a science and risk-based approach to manufacturing that can meet the always foremost goal of  product quality.

In attending the exhibitions and conference sessions at Interphex 2012 this week in New York, we gain a pulse on the current and future state of pharmaceutical manufacturing.

From Interphex 2012: Modern Pharmaceutical Manufacturing

Catalysis plays a crucial role in the synthesis of pharmaceutical intermediates and APIs. Catalysts can enable more efficient chemical transformations, improve reaction conditions, better product yields and produce greater enantioselectivity. Some key recent developments involve palladiumcatalysed hydrogenation, visiblelight photocatalysis, chemocatalytic approaches for making heterocyclic compounds and advances in biocatalysis.  

Palladium-catalysed hydrogenation reactions are important in industrial chemistry and fine-chemicals manufacture, but precious metal catalysts, such as palladium, are costly. Researchers at the Tufts University's School of Arts and Sciences and School of Engineering in Medford, Massachusetts (US) recently reported on the arrangement of individual atoms in a metal alloy and their ability to catalyse hydrogenation reactions.  

Hydrogenation requires the presence of a catalyst, usually a metal or an alloy of both precious and common metals, which allows the hydrogen atoms to bind with other molecules. It is difficult to produce alloys that are selective hydrogenation catalysts and able to attach the hydrogen atoms to specific sites of another molecule. Tufts chemists and chemical engineers reported that when single atoms of palladium were added to copper, which is much cheaper and readily available, the resulting "single atom alloy" became active and selective for hydrogenation reactions, according to a Tufts University press release.  

The Tufts scientists scattered single atoms of palladium less than half a nanometer wide onto a copper support. For this research, the Tufts team heated small amounts of palladium to almost 1000 °C. At that temperature, individual atoms embedded themselves on the copper surface. A scanning tunneling microscope enabled the team to see how these single atoms dispersed in the copper and how molecular hydrogen could then dissociate at individual, isolated palladium sites and spill over onto the copper surface layer. 

Specifically, the researchers used desorption measurements in combination with high-resolution scanning tunneling microscopy to show that the individual, isolated palladium atoms in a copper surface substantially lowered the energy barrier to both hydrogen uptake on and subsequent desorption from the copper metal surface. The hydrogen dissociation at the palladium atom sites and weak binding to copper allowed for very selective hydrogenation of styrene and acetylene, as compared with pure copper or palladium metal alone (1). 

A team of University of Arkansas (US) researchers reported on using visible-light photocatalysis with a ruthenium catalyst to produce a building block for in pharmaceutical synthesis. Specifically, the researchers reported on a visible-light-mediated intermolecular [3+2] cycloaddition of mono- and bicyclic cyclopropylamines with olefins catalysed by [Ru(bpz)

 O to produce aminocyclopentane derivatives in good yields. Saturated 5,5- and 6,5fused heterocycles were obtained in synthetically useful yields and diastereoselectivity (2). 

Heterocyclic compounds are important in pharmaceutical applications, and researchers at the California Institute of Technology (Caltech) (US) recently reported on an advance in the synthesis of such compounds. They reported on their work in the enantioselective construction of quaternary N-heterocycles by palladium-catalysed decarboxylative allylic alkylation of lactams (3).  

"We think it's going to be a highly enabling reaction, not only for preparing complex natural products, but also for making pharmaceutical substances that include components that were previously very challenging to make," said Brian Stoltz, professor of chemistry at Caltech, in a university press release. "This has suddenly made them quite easy to make, and it should allow medicinal chemists to access levels of complexity they couldn't previously access. 

Specifically, the researchers reported on the highly enantioselective palladiumcatalysed decarboxylative allylic alkylation of lactams to form 3,3-disubstituted pyrrolidinones, piperidinones, caprolactams and structurally related lactams. The researchers assert that the synthesis provides a new approach for the asymmetric synthesis of such structures, an important development given the prevalence of quaternary N-heterocycles in biologically active alkaloids and pharmaceutical agents. The researchers reported that the catalysis provided enantiopure quaternary lactams that intercept synthetic intermediates previously used in the synthesis of the Aspidosperma alkaloids, quebrachamine and rhazinilam, but that were previously produced by chiral auxiliary approaches or as racemic mixtures (3). 

Codexis, a biocatalysis company, reported last month on its work with Merck & Co. for developing an enzyme-based production method for a key intermediate in the production of boceprevir, the API in Merck's Victrelis, a drug to treat hepatitis C. The companies reported on a chemoenzymatic process for manufacturing the boceprevir bicyclic proline intermediate based on amine oxidasecatalysed desymmetrisation. The key structural feature in boceprevir is the bicyclic proline moiety, which during development stages, was produced by a classical resolution. As the drug candidate advanced, Codexis and Schering–Plough (now Merck) jointly developed a chemoenzymatic asymmetric synthesis where the net reaction was an oxidative Strecker reaction. The key part of the reaction sequence is an enzymatic oxidative desymmetrisation of a prochiral amine substrate (4).  

According to Codexis, the new method increased chemical intermediate yield 150% over the previous process. It also reduced raw material use by 60%, water use by 61% and overall process waste by 63%. Codexis used its proprietary CodeEvolver directed evolution technology to develop the custom enzyme for use in the commercialscale manufacturing of the boceprevir intermediate. 

Codexis had earlier partnered with Merck & Co. for another biocatalytic route. In 2010, Merck and Codexis reported on the biocatalytic asymmetric synthesis of chiral amines from ketones in the manufacture of sitagliptin, the API in Merck's antidiabetes drug Januvia. The biocatalytic process replaced a rhodium-catalysed asymmetric enamine hydrogenation for the largescale manufacture of sitagliptin. The researchers started from an (R)-selective transaminase that showed slight activity on a smaller truncated methyl ketone analogue of the sitagliptin ketone. After creating this transaminase, which had marginal activity for the synthesis of the chiral amine, they further engineered the enzyme through directed evolution to optimise its use for large-scale manufacturing (5–8). 

The initial (R)-selective transaminase was a homologue of an enzyme from Arthrobacter sp., which was previously used for (R)-specific transamination of methyl ketones and small cyclic ketones. For the sitagliptin synthesis, the researchers generated a structural homology model of this transaminase and found that the enzyme would not bind to the prositagliptin ketone because of steric interference and potentially undesired interactions. The evolved transaminase was a successful biocatalyst that synthesised the chiral amines that previously were accessible only through resolution (5–8). 

For the simvastatin route, Codexis licensed technology from Yi Tang, professor in the Department of Chemical and Biomolecular Engineering at the University of California at Los Angeles (US). The previous synthetic routes to simvastatin involved converting lovastatin into simvastatin by adding a methyl group that required protecting and then deprotecting other functionalities in the lovastatin molecule in a multistep synthesis. In the first route, lovastatin was hydrolysed to the triol, monacolin J, followed by protection with selective silylation, esterification with dimethyl butyryl chloride and deprotection. The second route involved protecting the carboxylic acid and alcohol functionalities, methylating the C2´ carbon with methyl iodide, and deprotecting the product. These routes were inefficient because they produced less than 70% overall yield and were mass-intensive due to protection and deprotection (5, 8). 

The route developed by Tang and his group circumvented protection and deprotection and resulted in greater atom economy, reduced waste and overall less hazardous reaction conditions. First, they cloned LovD, a natural acyltransferase produced by 

 that is involved in synthesizing lovastatin and that can accept nonnatural acyl donors. Recognising that LovD might be a type of simvastatin synthase and a starting point for creating a new biocatalytic process, they evolved the enzyme toward commercial utility (5, 8–10). Codexis licensed Tang's technology, engineered the enzyme further and optimised the process for pilot-scale simvastatin manufacture.  

Codexis is an example of a firm specialising in biocatalysis. Another is evocatal GmbH, which was founded in 2006 as a spin-off of the Institute for Molecular Enzyme Technology at the University of Düsseldorf (Germany) in the Research Center Jülich. Last November, evocatal issued a carbon–carbon coupling kit using thiamine pyrophosphate-dependent (TPP) enzymes to produce enantiopure 2-hydroxy-ketones, an important intermediate class for pharmaceutical syntheses. The kit includes seven different TPP-enzymes with the relevant cofactor. 

Formulation development forum: targeted polymeric nanoparticles

Researchers recently reported positive clinical results for a targeted therapeutic nanoparticle as an anticancer therapy. The targeted nanotechnology-based, drugdelivery method is considered an important breakthrough in targeting and better controlling dosing of a chemotherapeutic agent.  

The targeted polymeric nanoparticle (TNP) contained the chemotherapeutic docetaxel and was developed from a combinatorial library of more than 100 TNP formulations varying with respect to particle size, targeting ligand density, surface hydrophilicity, drug loading and drug-release properties (1). The targeted nanoparticle, BIND-014 is a nanomedicine that combines a targeting ligand and a therapeutic nanoparticle containing docetaxel encapsulated in biocompatible and biodegradable polymers. BIND-014 is targeted to the prostatespecific membrane antigen (PSMA), a cellsurface antigen abundantly expressed on the surface of cancer cells and on new blood vessels that feed a wide array of solid tumours. In preclinical cancer models, BIND014 was shown to deliver tenfold more docetaxel to tumours than an equivalent dose of conventional docetaxel. The increased accumulation of docetaxel at the site of disease translated to marked improvements in antitumour activity and tolerability, according to an April press release from the Prostate Cancer Foundation.   

BIND-014 entered trials in January 2011. Phase I clinical trial was performed by researchers at the biopharmaceutical company BIND Biosciences, a company cofounded by Robert Langer, the David H. Koch Institute Professor in the Department of Chemical Engineering at the Massachusetts Institute of Technology (MIT) and Omid Farokhzad, director of the Laboratory of Nanomedicine and Biomaterials at Brigham and Women's Hospital, associate professor of anesthesia at Harvard Medical School. 

"The initial clinical results of tumour regression even at low doses of the drug validates our preclinical findings that actively targeted nanoparticles preferentially accumulate in tumours," said Langer, in a MIT press release. "Previous attempts to develop targeted nanoparticles have not successfully translated into human clinical studies because of the inherent difficulty of designing and scaling up a particle capable of targeting tumours, evading the immune system, and releasing drugs in a controlled way." 

The BIND-014 nanoparticles have three components: one that carries the drug, one that targets PSMA and one that helps evade macrophages and other immune-system cells. "This study demonstrates for the first time that it is possible to generate medicines with both targeted and programmable properties that can concentrate the therapeutic effect directly at the site of disease, potentially revolutionising how complex diseases such as cancer are treated," said Farokhzad in the MIT release. One of the challenges in developing effective drug-delivery nanoparticles is designing them so they can evade the body's normal immune response and reach their intended targets. "You need exactly the right combination of these properties because if they don't have the right concentration of targeting molecules, they won't get to the cells you want, and if they don't have the right stealth properties, they'll get taken up by macrophages," added Langer. 

The Phase I clinical trial involved 17 patients with advanced or metastatic tumours who had already gone through traditional chemotherapy. To determine safe dosages, patients were given escalating doses of the nanoparticles. In the 48 hours after treatment, the researchers found that docetaxel concentration in the patients' blood was 100 times higher with the nanoparticles as compared to docetaxel administered in its conventional form. Higher blood concentration of BIND-014 facilitated tumour targeting resulting in tumour shrinkage in patients, in some cases with doses of BIND-014 that correspond to as low as 20% of the amount of docetaxel normally given. The nanoparticles were also effective in cancers in which docetaxel usually has little activity,. The researchers also found that in animals treated with the nanoparticles, the concentration of docetaxel in the tumours was up to tenfold higher than in animals treated with conventional docetaxel injection for the first 24 hours, and that nanoparticle treatment resulted in enhanced tumour reduction. 

The Phase I clinical trial is still ongoing. BIND Biosciences is now planning Phase II trials, which will further investigate the treatment's effectiveness in a larger number of patients. 

8. EPA, "The Presidential Green Chemistry Challenge Awards Program: Summary of 2010 Award Entries and Recipients" (Washington, DC, 2010). 

Advances in palladium-catalysed hydrogenation, visible-light photocatalysis and improved chemocatalytic approaches for making heterocyclic compounds are some recent industry developments.

Seeking New Chemocatalytic and Biocatalytic Solutions

In a move designed to increase its international presence, Watson Pharmaceuticals has agreed to acquire Actavis for EUR 4.25 billion ($5.6 billion). With the acquisition, Watson will become the third largest global generic-drug company with 2012 anticipated 

 revenues of approximately $8 billion. Once the transaction is completed, approximately 40% of Watson’s generic-drug revenues will come from markets outside of the United States.

Actavis has a commercial presence in more than 40 countries, markets more than 1000 products globally, has approximately 300 projects in its development pipeline, and manufactured more than 22 billion pharmaceutical doses in 2011, according to an Apr. 25, 2012, Watson press release. The company has more than 10,000 employees worldwide and had 2011 revenues of approximately $2.5 billion.

The combined company will hold a top-three position in 11 markets and a top-five position in 15 markets, according to Watson. Actavis’s position in Central and Eastern Europe and Russia complements Watson's position in established markets, including the United Kingdom, France, and Australia. The acquisition will expand Watson's position in modified-release, solid oral dosage, and transdermal products into semisolids, liquids, and injectables. Combined, Watson will have more than 17,000 employees globally, and at acquisition close will have approximately 20 manufacturing facilities.

Under the terms of the agreement, Watson will acquire Actavis for an upfront payment of EUR 4.25 billion ($5.62 billion). Actavis stakeholders could also receive additional consideration, contingent upon Actavis achieving negotiated levels of certain 2012 performance targets. The contingent payment, if fully earned, would result in the delivery of up to 5.5 million shares of Watson common stock in 2013. This contingent payment was valued during the negotiations at EUR 250 million ($331 million), based on a per share price of $60, using a euro-to-US dollar exchange rate of 1.32. Watson expects to achieve annual synergies of $300 million within three years following transaction close, predominantly consisting of selling, general, and administrative expenses, R&D, and corporate cost synergies. The acquisition is subject to customary conditions, including review by the US Federal Trade Commission. Pending approvals, Watson anticipates closing the transaction in the fourth quarter of 2012.

In a move designed to increase its international presence, Watson Pharmaceuticals has agreed to acquire Actavis for EUR 4.25 billion ($5.6 billion).

Watson Pharmaceuticals to Acquire Actavis for $5.6 Billion

	The Obama Administration released last week the National Bioeconomy Blueprint. The report outlines steps that federal agencies will take to drive the bioeconomy-economic activity powered by research and innovation in the biosciences-and details  ongoing efforts across the federal government to realize this goal. Given the importance of biotechnology to the pharmaceutical industry, does the plan do enough?

	The report recognizes the importance of biotechnology not only in healthcare but in other sectors. “The bioeconomy emerged as an Administration priority because of its tremendous potential for growth and job creation as well as the many other societal benefits it offers,” says the 

.”A more robust bioeconomy can enable Americans to live longer and healthier lives, develop new sources of bioenergy, address key environmental challenges, transform manufacturing processes, and increase the productivity and scope of the agricultural sector while generating new industries and occupational opportunities.”

	The Bioeconomy Blueprint outlines five strategic imperatives: support R&D investments; facilitate the transition of bioinventions from research laboratories to market, including an increased focus on translational and regulatory sciences; reduce barriers to increase the speed of regulatory processes; update training programs and align academic institution incentives with student training for national workforce needs; and identify and support opportunities for the development of public–private partnerships and precompetitive collaborations.

	Key industry organizations, such as The Biotechnology Industry Organization have issued its 

 for the blueprint. But one item seems to missing in the area of biopharmaceuticals and healthcare. Although the report recognizes the importance of biomanufacturing in areas such as clean fuels and renewable energy, it fails to recognize and provide to provide incentives to retain and develop biomanufacturing for biopharmaceuticals.

	Innovation as a means of economic growth is a laudable goal, but federal policy should also help to stimulate and retain biomanufacturing activity in existing sectors, such as biopharmaceuticals and pharmaceuticals. The erosion of the US domestic pharmaceutical manufacturing base in the single largest national market in the world, namely the US, has been a cause for concern for some time and should be part of any viable plan for biomedical innovation. In looking at any plan, it is important that fundamentals, such as retention of a domestic manufacturing based, be considered.

The Obama Administration released last week the National Bioeconomy Blueprint. The report outlines steps that federal agencies will take to drive the bioeconomy.