Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Cynthia A. Challener

	On Oct. 7, 2014 at CPhI Worldwide in Paris, France, UBM Live announced the winners of the 11th annual CPhI Pharma Awards. Winners were recognized for their innovative solutions in formulation, process development, packaging, and partnering. The first three category winners were selected by a panel of judges representing industry and academia, while the latter, which was a new category this year, was determined by voting on the CPhI Pharma Awards website. The winners included MJR PharmJet in the Formulation category, ACIB (Austrian Research Center of Industrial Biotechnology) for Process Development, Locked4Kids for Packaging, and Catalent for Partnering.


	Technologies considered for the innovation in formulation category can be related to drug delivery, excipients, controlled release, stability, or bioavailability. The three finalists included Aptalis Pharmaceutical Technologies for its Diffucaps customized drug-release technology, Powder Systems Ltd. for its advanced microsphere formulation technology, and the winner MJR PharmJet for its counter-ion technology, which enables higher loading of hydrophobic drugs in nanoparticles for more effective delivery.

	Using its Microjet reactor technology, PharmJet generated a self-assembled, equimolar counter-ion complex of the antibiotic ciprofloxacin with sodium dodecyl sulfate (SDS) via formation of electrostatic interactions between the sulfonyl group of SDS and the tertiary amine of ciprofloxacin. The complex, which exhibited higher solubility in organics, was then dissolved with biodegradable poly(lactide-co-glycolide) and precipitated against water, again using its MicroJet reactor technology, to obtain nanoparticles with the desired particle size and much higher drug loading. The nanoparticles can be further formulated into a pulmonary treatment for cystic fibrosis infections due to its higher antibiotic load. The Microjet reactor technology can also be applied to a wide range of drug molecules to increase bioavailability and effectiveness, according to the company.


	Technologies evaluated in the process development category relate to synthesis techniques, crystallization methods, polymorphism control, catalysts, and the use of green chemistry. Finalists for the 2014 award included DSM Sinochem Pharmaceuticals with new statin compounds, Supply Chain Strategies International with new approaches to pharmaceutical manufacturing, and the winner ACIB for its Catalophor system for discovering new enzyme functionalities.

	Unlike typical bioinformatics techniques that generally seek similar amino acid sequences to identify homologous enzymes, the ACIB system identifies enzymes using specific three-dimensional templates of active site geometries and chemical functionalities associated with specific activities (catalophores). The system is comprised of a proprietary search engine and the Protein Data Bank, which contains more than 100,000 proteins. It can also search public databases for new enzyme structures. The search generates a list of possible candidates that contain the desired active site characteristics, avoiding the need to run large numbers of screening experiments. The most promising are then synthesized and tested. This approach is attractive because it creates the opportunity to identify enzymes that operated via previously unknown reaction pathways, thus enabling more environmentally friendly methods for the synthesis of both known and completely new compounds, including chiral molecules.


	New technologies considered in the packaging category must be related to primary packaging, devices and technology, patient compliance, dispensers, materials, or anticounterfeit systems. The finalists for the 2014 award included Haemopharm Healthcare for its Fillchoice room, a compounding pharmacy incorporated in a bag for use in a hospital room, Stiplastics for its granule and tablet dispenser for the distribution of various shapes and sizes of solid forms, and the winner Locked4Kids BV, for its child-resistant carton.

	Locked4Kids, an initiative of Ecobliss, is designed to protect small children from accidental poisoning. The carton contains a tray that holds blister strips. Hooks on the tray insert into openings diagonally positioned on two sides of the carton, resulting in automatic locking of the tray when it is fully loaded into the carton. The hooks, which are placed too far apart for children to reach but easy for adults to manage, must be simultaneously pushed to unlock the tray. The reclosable carton meets the requirements for child-resistant packaging in the United States and Europe and can be mass-produced in multiple sizes using existing manufacturing equipment.


	The new partnering category focuses on partnering methods, novel uses of technology, unexpected outcomes, and unique relationships. The finalists for the first award in 2014 included the licensing of Codexis’s CodeEvolver protein engineering platform technology to GlaxoSmithKline for the development of new enzymes, the new collaborative ID3 innovative business model for the development of customized pharmaceutical building blocks from Solvay Aroma Performance, and the winner, Catalent Pharma Solutions, for its collaboration with Redwood Bioscience on the development and application of SMARTag bioconjugation technology. Catalent brought to the partnership its expertise in biologic development, advanced GPEx expression system, and biomanufacturing capabilities, while Redwood Bioscience contributed its proprietary conjugation platform, advanced cytotoxin-linker chemistry, and ADC development expertise.

	Unlike conventional heterogeneous cysteine and lysine conjugation, the SMARTag site-specific system produces homogeneous antibody drug conjugates (ADCs). An antibody (mAb) containing an inserted formylglycine generating enzyme (FGE) recognition sequence is produced in a cell line that over-expresses FGE, which mediates formylglycine (an aldehyde) formation during sulfatase biosynthesis. The result is the production of an aldehyde-tagged mAb, which is purified using standard processes and then subjected to site-specific conjugation with a proprietary cytotoxin-linker system that reacts selectively with the aldehyde tag. The aldehyde tags can be placed at multiple positions in the antibody in order to maximize ADC performance without affecting its aggregation behavior or other properties, and the linkers are suitable for use with a variety of payloads. Compared to conventional ADCs, a SMARTag-generated ADC has a better toxicity profile, is well tolerated and provides statistically significant survival benefits, and has greater exposure and a longer circulating half-life, according to Catalent, which in early October 2014 acquired the remaining stake in Redwood Bioscience. The company believes that the new bioconjugation technology will lead to the development of bispecific ADCs and ADCs for indications beyond oncology.

Articles

On Oct. 7, 2014 at CPhI Worldwide in Paris, France, UBM Live announced the winners of the 11th annual CPhI Pharma Awards.

Novel Technologies Win CPhI Pharma Awards

Medicinal chemistry generally involves the preparation of a lead drug candidate on a milligram scale and uses non-optimized chemistry that will produce the target in the shortest time possible. Often hundreds to thousands of compounds must be synthesized for testing against the target. The chemistry to the specific target is therefore typically not optimized but is phase-appropriate for this stage of development. The process chemistry group then develops safe, robust, and efficient chemistry to enable the preparation of multi-kilogram quantities of the API. This approach is the case for complex heterocyclic APIs. Recent efforts at Genentech and Pfizer and by Phil S. Baran at The Scripps Research Institute have led to improved, practical methods for the synthesis of such complex heterocyclic compounds.


	In one case study from Genentech, the PI3k β-sparing inhibitor Taselisib (GDC-0032) was discovered as a potential treatment for breast cancer (1). The main structural feature of Taselisib is a seven-membered benzoxazepine core that is substituted with a functionalized pyrazole at one end and an 

-isopropyl-3-methyl-1,2,4-triazole heterocycle at the other end.

	The discovery route to prepare the benzoxazepine core of Taselisib required eight chemical steps from commercially available 3-bromophenol, according to Travis Remarchuk, a scientist in the small molecule process chemistry group at Genentech. He notes that while this chemistry was successful for producing the first five kilograms of the benzoxazepine core, it involved the use of hazardous reagents including carbon monoxide gas, 

-dimethylacetamide dimethyl acetal, and 1,2-dibromoethane and, therefore, was not amenable to the large-scale production of hundreds of kilograms. As a result, it was necessary to consider alternative and more practical routes for the preparation of the benzoxazepine core.

	In the second-generation process route, Remarchuk explains that a pre-assembled 

-isopropyl-3-methyl-1,2,4-triazole was prepared via a one-pot, two-step synthesis from isopropylhydrazine. This triazole was then converted to a chloroketone derivative, which was directly reacted in a convergent manner with an aryl amidine to generate the fluoroaryl imidazole ring system. The seven-membered benzoxazepine core compound was then installed via alkylation with ethylene carbonate. “Notably, this reagent is a much safer alternative to 1,2-dibromoethane,” says Remarchuk. Following alkylation of the imidazole, the hydroxyl group underwent S

2 substitution with the aryl fluoride of a second equivalent of the imidazole in the same reaction pot to afford the carboxylic acid precursor to the API. “Using this approach, which involved more efficient methods for assembling both the imidazole ring system and the 1,2,4-triazole component, more than 60 kg of the product was manufactured for the Phase I resupply of the API,” Remarchuk observes.

	A third-generation route was then developed that involved an efficient three-step, one-pot synthesis of the carboxylic acid precursor. In addition, in the final step of the API synthesis, the carboxylic acid group was converted to the primary amide using 1,1-carbonyldiimidazole (CDI) in place of the guanidinium coupling reagent HATU, which is not attractive for use in the last step of the synthesis due to release of several byproducts (tetramethylurea, hydroxybenzotriazole, and hexafluorophosphate anion) that require rigorous analytical testing to mitigate any safety risk for the patients, according to Remarchuk. The CDI coupling reagent is used in several other Genentech small molecule APIs in development.

Pyrazinyl-imidazo and pyrazinyl-pyrazolo pyridines from Pfizer


	Pfizer was interested in compounds containing 5/6 fused ring systems as candidates for oncology treatments. One of the lead compounds, a 3-pyrazinyl-imidazo[1,2-a]pyridine was initially prepared via a palladium-catalyzed reaction of 2,6-dichloropyrazine involving direct arylation at the 3 position of the imidazo ring. This reaction was not amenable to the synthesis of a library of compounds. In addition, few imidazo pyridines are commercially available, and they were synthesized using chloroacetaldehyde, which is a toxic reagent. Therefore, an alternative route to 3-pyrazinyl-imidazo[1,2-a]pyridines for both compound library synthesis and potentially larger-scale preparation was needed.

	Based on the known reaction of a dithiane with 2,6-dichloropyrazine involving nucleophilic tele-substitution, Michael R. Collins, a senior principal scientist at Pfizer, attempted the reaction of 2,3-dichloropyrazines with methyl vinyl ether (metallated), which proceeded as desired to afford the 2,6-disubstituted pyrazine products in good yields (50-60%) (2). A range of 3-pyrazinyl-imidazo[1,2-a]pyridines were then obtained in 31-76% yield by reacting the enol ether intermediates with N-bromosuccinimide in dioxane/water to generate the corresponding hemiacetals, followed by the addition of a 2-amino pyridine without isolation (2). In this reaction, the ring nitrogen of the pyridine displaces the bromide of the bromohydrin. “This reaction is very advantageous because it is done in one pot,” says Collins. The overall yields for both steps were also higher than those obtained for the palladium-catalyzed direct arylation route. “Not only does the reaction proceed fairly rapidly in decent yields, it is possible to prepare a wide variety of imadazo heterocycles, which is important for library synthesis,” Collins observes. He adds that substituents in the 6-position of 2-amino pyridine do not hinder the reaction with the enol ether.  The analogous compound was formed only in trace quantities using the Pd catalyzed procedure.

	Separately, Collins and his colleagues developed an efficient route to 3-pyrazinyl-pyrazolo[1,5-a]pyridines via the [3+2] cycloaddition of enol ethers and 4-substituted 1-aminopyridinim iodides that is, according to Collins, simple to perform, scalable, and proceeds at room temperature. In addition, the reaction proceeds in good yield with 1-aminopyridinium iodides bearing both electron withdrawing and electron donating substituents at the 4-position (3). In this case, to identify the optimum reaction conditions (base and solvent), a high-throughput reaction screen was performed. According to Collins, the best results were obtained using potassium tert-pentylate, sodium hydride, or potassium hexamethyldisilazide in tert-amyl alcohol with a pyrazinyl enol ether.

Sulfur reagents for the alkylation of heterocycles from Scripps and Pfizer


	The Baran group at The Scripps Research Institute, in conjunction with Collins and his colleagues at Pfizer, has also recently developed new reagents for the functionalization of heteroarene compounds. In one example, inexpensive, carboxylic acids are converted to sulfinate salts via an interrupted Barton decarboxylation reaction (4). The generated sulfinate salts are high value reagents and efficient radical precursors. The researchers readily prepared 10 different sulfinate reagents. One of the most interesting, according to Collins, is trifluoromethyl cyclopropyl sulfinate (TFCS-Na), which is effective for the C-H functionalization of various heterocycles. Most importantly, the reaction of the sulfinates is highly tolerant of a wide variety of functional groups, thus allowing for the introduction of substituents in the later stages of a synthesis, according to Collins.

	In a second example, Baran and the Pfizer researchers developed a practical method for the methylation of heteroarenes via C-H functionalization using zinc bis(phenylsulfonyl-methanesulfinate), or PSMS (5). This reagent was designed based on S-adenosylmethionine (SAM), a biologically relevant methylating reagent. In the reaction with PSMS, a (phenylsulfonyl)methylated intermediate is generated that is readily separated from the reaction mixture, and subsequent desulfonylation reveals the methylated (or deuteriomethylated) product. As with the previous sulfinate-based C-H activation reaction, this transformation proceeds under mild conditions in air at room temperature and tolerates numerous functional groups, allowing for functionalization of pharmaceutical intermediates in the later stages of complex synthetic routes, according to Collins.


	1. C.O. Ndubaku et al., J. Med. Chem., 56 (11) 4597-4610 (2013).
	2. M.R. Collins et al., Tet. Lett., 51 (27) 3528-3530 (2010).
	3. M.R. Collins et al., Tet. Lett., 53 (33), 4372-4375 (2012).
	4. P.S. Baran et al., Ang. Chem. Int. Ed., 53 (37) 9851-9855 (2014).
	5. P.S. Baran et al., J. Am. Chem. Soc., 136 (13) 4853-4856 (2014).


	Cynthia A. Challener is a contributing editor at 

New practical approaches to the synthesis of complex heterocycles are reviewed.

Practical Approaches to Large-Scale Heterocyclic Synthesis

CPhI Worldwide 2014, held in early October in Paris, France, presented an optimal opportunity for pharmaceutical manufacturers and their raw material suppliers and service providers to introduce new capabilities. According to UBM Live, host of the show, approximately 35,000 total attendees viewed the offerings of 2250 exhibitors that represented 140 countries. Companies both large and small highlighted a vast range of new products, technologies, services, and facilities designed to meet the needs of the pharmaceutical industry. A few of these new capabilities are described below.


  Rigaku Raman Technologies, a manufacturer of portable Raman analyzers, highlighted its new Progeny handheld device for rapid material identification, including both raw and in-process materials, finished products, and products already on the market (as an anti-fraud measure). What sets Progeny apart from other handheld Raman analyzers, according to marketing director Jennifer Lynch, is the fact that it is the first fully sealed 1064-nm-powered handheld Raman analyzer that enables the analysis of fluorescent compounds, colored materials, and materials stored in colored containers, which hasn’t been possible in the past. “When a company adopts Progeny for their material analysis needs, the quality control laboratory can focus on more value-added work, such as methods development, instead of being bogged down by routine analyses,” Lynch says. 


  SGS Life Science Services, a pharmaceutical analytical and bioanalytical contract solutions provider, has grown rapidly since the business line was established 10 years ago. In 2014 alone, the company is expanding capacity in three regions of the world. Most recently, SGS completed the construction of a new 8000-sq.-ft. GMP/GLP facility in Carson, California, its fifth in North America and the first on the west coast. The location was chosen so the company can provide local support to the significant pharmaceutical and biotechnological community in California, according to Jeff McDonald, COO of SGS North America.
  

SGS is also investing in a new facility in Villeneuve la Garenne, France, which will replace an existing laboratory in Clichy and will include state-of-the art equipment designed to increase the quality control service throughput and support an ever-expanding research and development pipeline of new biopharmaceutical drugs within the country. Services will include analytical chemistry, microbiological analysis, stability studies and method development, as well as amino acid analysis and mycoplasma testing. “We see this investment as an strategically important for meeting the needs of both the small molecule and quality control markets,” notes Paul Beyou, director of life science services, Clichy. SGS is also increasing analytical capabilities at its facility in Poitiers, France, and the company opened a new laboratory in Italy in 2013.


In China, SGS is expanding its Shanghai facility, adding to its cGMP chemistry and microbiology laboratories; constructing a new biotechnology laboratory for cytotoxicity testing, cell-based assays, and endotoxin and ELISA testing; and introducing packaging testing capabilities, including extractables and leachables. “The investment in the Shanghai facility, and the increased and enhanced service offerings that will result, are essential to our continued expansion in China,” states Andy Yi, general manager, SGS Life Science Services, Shanghai.
  

Finally, SGS has also launched a new, searchable web-based database of biopharmaceutical, biosafety, and bioanalysis methods that are available throughout its global network of GMP, good laboratory practice, and good clinical-compliant laboratories. Selection criteria include service type, sample type (e.g., biologic, vaccine, biomarker), and technique. 


  A notable trend in the contract manufacturing industry that was apparent at CPhI Worldwide 2014 is a growing emphasis on integrated services. In addition, several contract manufacturing organizations (CMOs) that are either a business unit of a larger pharmaceutical company and/or a manufacturer of generic APIs and sometimes formulated products see their positions as advantageous compared to CMOs that do not have such capabilities. Two companies in the former category include Pfizer CentreSource and CPS, the custom pharmaceutical services division of Dr. Reddy’s, while examples of the latter type include Hovione and Piramal Pharma Solutions.
  

Reorganization at Pfizer has Pfizer CentreSource (PCS) now reporting through Pfizer Global Supply, the external supply group that manages all the CMOs used by Pfizer. This alignment brings numerous synergies with respect to technology and market knowledge, according to Kenneth F. Ball, senior manager of marketing for PCS. The company is also adding capacity at its Ringaskiddy, Ireland facility, which is the product launch site for all of Pfizer, and thus has extensive experience working with R&D and third parties to introduce new processes and expertise in new product scale-up, process improvement, launch, and commercial manufacture, according to Jeffrey W. Frazier, vice-president of global marketing for fine chemicals at PCS. Additional investments in facilities located in important and stable emerging markets are also under consideration, such as Brazil, Morocco, and Indonesia.
  

For biologics manufacturing, PCS is emphasizing its extensive network of manufacturing facilities and their broad range of capabilities, including mammalian cell expression, microbial fermentation, vaccines, and antibody-drug conjugates (ADCs). The company is also highlighting its high potency production capabilities. It has both development and commercial-scale facilities for the manufacture of high-containment, solid-dosage drugs. “In addition to the depth and breadth of our manufacturing capabilities, because PCS is part of Pfizer, we also have access to the technology and knowhow of a large, successful pharmaceutical company, that we can apply as needed to rapidly design effective solutions for our customers,” says Cristin B. Grove, PCS’s director of contract manufacturing.
  

CPS has made responsiveness to the market a key focus of the company, introducing a new “Power of Now” customer-centric initiative. “We differentiate ourselves in the marketplace by being aware of our customer needs, and today there is great demand for more rapid responses. The ‘Power of Now” reflects that need for immediacy, as well as empowerment of both our customers and employees, partnership, and trust,” says Christian Jones, head of Asia Pacific sales and business development for CPS. The initiative focuses on accelerating project delivery through dedicated response networks with shortened decision-making chains and reduced lead times, according to Jones. To support the initiative, CPS has appointed a new head of R&D and a new North American sales manager and created a new business development position in Asia that Jones has filled. 
  

In addition to its increased responsiveness, Jones notes that CPS offers an integrated portfolio of services from discovery to formulation development through to commercialization and lifecycle extension that is backed by the extensive expertise in generic-drug manufacturing of its parent company. “The experience gained in the competitive generics industry is directly transferred to our CMO services at CPS in the form of efficient and robust process development that includes the use of green chemistry and continuous processing,” Jones notes. Other key technologies for CPS include chiral chemistry, highly potent drug substance and formulated product manufacturing at development and commercial scales, steroid manufacturing, and pegylation.
  

Hovione is a company that offers both customer-manufacturing services (e.g., intermediates, APIs, and finished products) and produces its own generic APIs and formulated products. CEO Guy Villax of Hovione does not see any conflict between the two operations, and in fact, believes that being in the generic-drug business has helped the company’s competitiveness as a CMO. “With generics, it is imperative to be as cost-effective as possible, and to do that requires advanced technologies and science. Those capabilities benefit our custom manufacturing efforts as well,” he says. 
  

Hovione also has the largest installed capacity for commercial GMP spray drying, according to Villax. In 2014, the company is celebrating 10 years of spray drying services. “Through these 10 years, we have accumulated a large amount of knowledge, expertise, and data on spray drying that now enable us to control the physical processes involved in spray drying and predict product behavior on a commercial scale,” comments Villax. 
  

In addition, to reflect the fact that it now has capabilities in both chemistry and biotechnology, Hovione changed its logo. The company will also be expanding its Hovione New Jersey manufacturing site, which has capabilities in cryogenic chemistry, hydrogenation, fluorination, and the production of highly potent APIs.
  Piramal Enterprise is another company that offers contract research and manufacturing services across all phases of the drug lifecycle and the value chain, and has expertise in specialized services such as ADCs and highly potent compounds with a focus on green chemistry. To support its end-to-end manufacturing capabilities including discovery, Phase I-III clinical and commercial production, and off-patent formulation, the company is continuing to invest in its facilities and new technologies that provide value to customers, such as continuous flow chemistry and bio- and chemocatalysis. More than $70 million worth of investments are at various stages of execution, according to Vijay Shah, COO at Piramal Enterprises and pharma business lead. Specifically, the company invested approximately $10 million in a world-class, GMP clinical manufacturing facility in Ahmedabad, India, approximately $15 million in its Morpeth, UK site to triple production capacity for hormonal products, and approximately $5 million at its Grangemouth site to expand commercial ADC capacity. Piramal is also expanding capacity for generic drug production and has plans for the addition of a pilot plant and scale-up facility as it prepares for a tripling of this business over the next five years on a top-line basis.
  

Piramal is also focused on becoming more customer-centric, and has established an internal customer advocacy team that represents the customer throughout all stages of a project. Its PULSE program, launched early in October 2014, is a values-based initiative designed to take the pulse of the customer and create a culture of ‘customer centricity’ across the organization. “It is critical that we maintain our focus on the customer at all times, both internally and externally,” says Shah. 
  

Patheon, a pharmaceutical services business owned by DPx Holdings, a holding company focused on the CDMO business, is not part of a larger pharmaceutical company, but has been expanding its capabilities through numerous acquisitions to create a true integrated offering. Recent activities have included a merger with DSM Fine Chemicals in March 2014 and most recently the acquisition of Gallus Biopharmaceuticals in August 2014. At CPhI Worldwide 2014, Patheon introduced OneSource, its new integrated development offering for Phase I through Phase II projects. “When assembled correctly and executed with great discipline, an integrated service offering such as OneSource will deliver innovative solutions with regard to critical timing, including contracting, liability coverage, and tax advantages in the design of the supply chain,” states DPx Fine Chemicals president Lukas Utiger. Patheon also has future plans to provide similar simplicity to Phase III through commercial-scale capabilities as well. “We feel strongly that it is important to bring fast and simple solutions to our customers that really address their needs,” Utiger observes.


  Excipients are crucial for effective drug formulation, and excipient manufacturers continue to make advances in technology designed to address the formulation challenges presented by new drug substances. 
  

Dow Pharma & Food Solutions, meanwhile, has expanded its AFFINISOL portfolio of excipients for the solubility enhancement of spray-dried dispersion (SDD) and hot-melt extrusion (HME) formulations. Dow began production of AFFINISOL hydroxypropyl methylcellulose acetate succinate (HPMCAS) products in October 2013 in a new facility located at the Cambrex Karlskoga site. The polymers are the result of a research collaboration between Dow Pharma & Food Solutions and Bend Research that are designed to maintain stable solid dispersions and inhibit API crystallization when formulated as spray-dried dispersions. The original products, however, require the use of plasticizers for processing over a wide temperature range. At CPhI Worldwide 2014, Dow also introduced versatile AFFINISOL HPMC HME with a low glass transition temperature requiring no plasticizers, thus allowing formulation of stable amorphous solid dispersions and controlled-release profiles via extrusion processes. The effectiveness of the new excipient has been demonstrated with the 

 (BCS) Class II API itraconazole and the BSC Class II API griseofulvin, according to Christophe Massip, global marketing director, Dow Pharma & Food Solutions.


Separately, as part of its Dow-Colorcon alliance (the Controlled Release Alliance), Dow announced at CPhI Worldwide 2014 that its next-generation METHOCEL DC2 hydroxypropyl methyl cellulose (HPMC) polymer, an excipient that facilitates roller compaction and direct compression of tablets as alternatives to wet granulation, will be commercially available on a global basis by the end of 2014. Installation of its new manufacturing line in Midland, MI is being finalized, according to Massip. “The designed morphology of METHOCEL DC2 notably improves the flow and processability of powder blends for compression into matrix tablets, which helps the drug product manufacturer produce higher quality tablets using streamlined manufacturing processes,” notes True Rogers, technologies leader for Dow Pharma & Food Solutions.
  

Lubrizol is another company that has, for many years, provided a wide range of polymer-based excipients for use in solid, semisolid, and liquid dosage forms. At CPhI Worldwide 2014, the company highlighted is new Pathway excipient-grade thermoplastic polyurethanes (TPUs) for controlled, sustained drug release in implantable drug delivery and combination products. "As pharmaceutical companies face the challenges of the patent cliff, the development of new routes of administration for existing drug products is an important strategy they can use to help maintain the success of their product franchises. Our new Pathway excipient portfolio is designed to help drug manufacturers achieve their goals of developing these novel, controlled-release drug products," observes Jean Claude Deneuville, global business director for Lubrizol’s LifeSciences business. 
  

The non-biodegradable excipients are ideal for drug delivery over an extended period of time and work with both hydrophobic and hydrophilic APIs. Drug loading can be achieved through blending, or for thermally stable APIs, melt-processing followed by injection molding or extruding. The API and TPU can also be dissolved in a suitable solvent and then cast into shapes such as rods, tubes, films, or a variety of matrix-type designs, according to Deb Langer, vice-president and general manager of Lubrizol Life Sciences. Implantable devices can provide sustained drug delivery for short and longer time periods with, for example, 30-day contraceptive and/or HIV vaginal rings and other subcutaneous implants that last up to 18 months. 
  

“TPUs have a long history of use in medical devices because they are robust and readily customizable. Polyether, polyester, or polycarbonate-based soft segments can be combined with aromatic or aliphatic hard segments to obtain a vast range of release properties while retaining durability chemical resistance, clarity, and abrasion resistance,” says Deneuville. He adds that TPU excipients are being investigated in formulations for hormone regulations and the treatment of mental health, in addition to HIV and pain. They can be used in controlled-release products, as drug reservoirs and matrices, in rate-controlling membranes and drug-eluting medical implants, and other applications. Possible routes of administration include subcutaneous, transdermal, oral, interorganal, intraperitoneal, and intravaginal, among others, according to Langer.


   Vertellus has long been recognized as an expert in pyridine chemistry, offering both standard catalog products and custom manufacturing important pharmaceutical building blocks. At CPhI Worldwide 2014, the company was looking to increase awareness of its full and much broader capability for meeting the needs of the pharmaceutical industry. “The Vertellus Specialty Materials (VSM) business unit comprises a broad basket of complex technologies, manufacturing biomaterials, CPC (cetylpyridinium chloride) biocides, pyridine derivatives, DEET (

-diethyl-meta-toluamide), sulfones, EMA (ethylene maleic anhydride) copolymers, alkenyl succinic anhydrides, reducing agents, and a host of natural and renewable chemistries based on castor and citrates, and we specialize in developing and producing fine chemicals and intermediates for sophisticated chemistry applications,” explains global sales director Mark Lewis. He adds that for the pharmaceutical industry in particular, the company has a broad range of products and synthesis technologies that provide pharmaceutical companies with a unique combination of intermediates and customer manufacturing capabilities.
  

Vertellus was established in 2006 when Rutherford and Reilly merged, and was then acquired by Wind Point Partners in 2007. President and CEO Rich Preziotti was previously vice-president and general manager of Honeywell’s $1.2 billion chemicals business and is focused on improving productivity, reducing costs, and enhancing customer relationships, according to Lewis.


BASF announced at CPhI Worldwide 2014 that Colorcon will be using its Kollicoat IR immediate-release coating polymer in Colorcon’s fully formulated ready-to-use coatings. Kollicoat IR is an ethylene glycol and vinyl alcohol graft copolymer that enables processing at low temperatures and high solids contents while delivering targeted coating results, according to Daniele Piergentili, vice president of global marketing for pharma ingredients at BASF. With the addition of Kollicoat IR to its portfolio, Colorcon will be able to expand its polyvinyl alcohol-based offerings, providing more choice to its customers, according to Cornelis van den Muyzenberg, vice-president of sales and business development at Colorcon.


  IDT Biologica, a manufacturer of human vaccines for infectious diseases, announced at CPhI Worldwide 2014 that it has completed and certified a new large-scale production facility in Dessau, Germany for the filling and lyophilization of biologics and vaccines. The facility includes a sterile liquid filling line for up to 24,0000 vials per hour and has been certified to biosafety levels 1 and 2 for live vaccines. Notably, in addition to capacity for live recombinant and non-recombinant vaccines, the plant includes capacity for the fill-finish of other biologics and small-molecule drugs, including cytotoxics, in separate units. “Completion of this project allows us to accommodate production of an ever more diverse range of biomedical technologies with the precision and efficiency that comes with a highly integrated and automated facility,” says Dr. Ralf Pfirmann, IDT Biologica CEO.

Selected new technologies, products, and facilities from CPhI Worldwide 2014 are reviewed.

CPhI 2014 Highlights

Advanced analytical methods are speeding up the targeted evaluation of potential viral contaminants.

The Challenge of Finding the Unknown

Methods must be suitable at each development phase, robust, and effective on multiple platforms.

Keys to Successful Method Transfer


  In one case study from Genentech, the PI3k β-sparing inhibitor Taselisib (GDC-0032) was discovered as a potential treatment for breast cancer (1). The main structural feature of Taselisib is a seven-membered benzoxazepine core that is substituted with a functionalized pyrazole at one end and an 

The discovery route to prepare the benzoxazepine core of Taselisib required eight chemical steps from commercially available 3-bromophenol, according to Travis Remarchuk, a scientist in the small molecule process chemistry group at Genentech. He notes that while this chemistry was successful for producing the first five kilograms of the benzoxazepine core, it involved the use of hazardous reagents including carbon monoxide gas, 

In the second-generation process route, Remarchuk explains that a pre-assembled 

A third-generation route was then developed that involved an efficient three-step, one-pot synthesis of the carboxylic acid precursor. In addition, in the final step of the API synthesis, the carboxylic acid group was converted to the primary amide using 1,1-carbonyldiimidazole (CDI) in place of the guanidinium coupling reagent HATU, which is not attractive for use in the last step of the synthesis due to release of several byproducts (tetramethylurea, hydroxybenzotriazole, and hexafluorophosphate anion) that require rigorous analytical testing to mitigate any safety risk for the patients, according to Remarchuk. The CDI coupling reagent is used in several other Genentech small molecule APIs in development.


Pfizer was interested in compounds containing 5/6 fused ring systems as candidates for oncology treatments. One of the lead compounds, a 3-pyrazinyl-imidazo[1,2-a]pyridine was initially prepared via a palladium-catalyzed reaction of 2,6-dichloropyrazine involving direct arylation at the 3 position of the imidazo ring. This reaction was not amenable to the synthesis of a library of compounds. In addition, few imidazo pyridines are commercially available, and they were synthesized using chloroacetaldehyde, which is a toxic reagent. Therefore, an alternative route to 3-pyrazinyl-imidazo[1,2-a]pyridines for both compound library synthesis and potentially larger-scale preparation was needed.

Based on the known reaction of a dithiane with 2,6-dichloropyrazine involving nucleophilic tele-substitution, Michael R. Collins, a senior principal scientist at Pfizer, attempted the reaction of 2,3-dichloropyrazines with methyl vinyl ether (metallated), which proceeded as desired to afford the 2,6-disubstituted pyrazine products in good yields (50-60%) (2). A range of 3-pyrazinyl-imidazo[1,2-a]pyridines were then obtained in 31-76% yield by reacting the enol ether intermediates with N-bromosuccinimide in dioxane/water to generate the corresponding hemiacetals, followed by the addition of a 2-amino pyridine without isolation (2). In this reaction, the ring nitrogen of the pyridine displaces the bromide of the bromohydrin. “This reaction is very advantageous because it is done in one pot,” says Collins. The overall yields for both steps were also higher than those obtained for the palladium-catalyzed direct arylation route. “Not only does the reaction proceed fairly rapidly in decent yields, it is possible to prepare a wide variety of imadazo heterocycles, which is important for library synthesis,” Collins observes. He adds that substituents in the 6-position of 2-amino pyridine do not hinder the reaction with the enol ether.  The analogous compound was formed only in trace quantities using the Pd catalyzed procedure.

Separately, Collins and his colleagues developed an efficient route to 3-pyrazinyl-pyrazolo[1,5-a]pyridines via the [3+2] cycloaddition of enol ethers and 4-substituted 1-aminopyridinim iodides that is, according to Collins, simple to perform, scalable, and proceeds at room temperature. In addition, the reaction proceeds in good yield with 1-aminopyridinium iodides bearing both electron withdrawing and electron donating substituents at the 4-position (3). In this case, to identify the optimum reaction conditions (base and solvent), a high-throughput reaction screen was performed. According to Collins, the best results were obtained using potassium tert-pentylate, sodium hydride, or potassium hexamethyldisilazide in tert-amyl alcohol with a pyrazinyl enol ether.


The Baran group at The Scripps Research Institute, in conjunction with Collins and his colleagues at Pfizer, has also recently developed new reagents for the functionalization of heteroarene compounds. In one example, inexpensive, carboxylic acids are converted to sulfinate salts via an interrupted Barton decarboxylation reaction (4). The generated sulfinate salts are high value reagents and efficient radical precursors. The researchers readily prepared 10 different sulfinate reagents. One of the most interesting, according to Collins, is trifluoromethyl cyclopropyl sulfinate (TFCS-Na), which is effective for the C-H functionalization of various heterocycles. Most importantly, the reaction of the sulfinates is highly tolerant of a wide variety of functional groups, thus allowing for the introduction of substituents in the later stages of a synthesis, according to Collins.

In a second example, Baran and the Pfizer researchers developed a practical method for the methylation of heteroarenes via C-H functionalization using zinc bis(phenylsulfonyl-methanesulfinate), or PSMS (5). This reagent was designed based on S-adenosylmethionine (SAM), a biologically relevant methylating reagent. In the reaction with PSMS, a (phenylsulfonyl)methylated intermediate is generated that is readily separated from the reaction mixture, and subsequent desulfonylation reveals the methylated (or deuteriomethylated) product. As with the previous sulfinate-based C-H activation reaction, this transformation proceeds under mild conditions in air at room temperature and tolerates numerous functional groups, allowing for functionalization of pharmaceutical intermediates in the later stages of complex synthetic routes, according to Collins.


  1.	C.O. Ndubaku et al., J. Med. Chem., 56 (11) 4597-4610 (2013).
  2.	M.R. Collins et al., Tet. Lett., 51 (27) 3528-3530 (2010).
  3.	M.R. Collins et al., Tet. Lett., 53 (33), 4372-4375 (2012).
  4.	P.S. Baran et al., Ang. Chem. Int. Ed., 53 (37) 9851-9855 (2014).
  5.	P.S. Baran et al., J. Am. Chem. Soc., 136 (13) 4853-4856 (2014). 


Cynthia A. Challener is a contributing editor at 