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

Cynthia A. Challener

Continuous processing for the production of key building blocks and intermediates for small-molecule APIs is no longer viewed as a technology of the future. Most pharmaceutical companies with in-house manufacturing use flow chemistry to some extent, and smaller companies that outsource production expect their contract-manufacturing partners to have continuous-flow systems available. Advances in microreactor technology for commercial-scale production and implementation of continuous downstream processes will ultimately enable the complete continuous synthesis of complex organic molecules required for small-molecule API manufacturing. Widespread adoption, however, will occur slowly as the industry shifts from the infrastructure in place today to smaller, modular, and flexible facilities.


“Continuous flow synthesis is a great alternative to traditional batch synthesis/production when it comes to demanding chemistries such as hazardous reactions or potentially challenging conditions like high pressure and temperature,” observes Dominique Roberge, head of continuous flow/microreactor technology business development at Lonza Custom Manufacturing. In addition, continuous flow processing provides many technical advantages over traditional batch methods, including speed of development, process reliability and product quality, maximization of process safety when employing hazardous chemistries, and minimization of investment during product development, according to Peter Poechlauer, principle scientist at DSM Fine Chemicals. For Jörg Schrickel, new business development manager for CABB, the more consistent quality that is achieved with continuous manufacturing, particularly for sensitive products, is of significance.

 “There are, in fact, some products that cannot be produced in large batch processes due to the thermodynamic nature of the reactions involved. Under continuous flow conditions, however, because only small quantities of reagents and products are present at any given time, these issues can be avoided,” Schrickel adds.

Another advantage is the improved environmental footprint of continuous processes. Poechlauer points to reduced raw material consumption and waste generation as two key benefits. CABB increases the sustainability of its continuous processes for the production of acid chlorides and derivatives by recycling off-gases (referred to by the company as its “verbund and recycling system”). “As a result, our building blocks have very low process mass intensity (PMI) and environmental factors (E-factors),” says Schrickel.


Despite the obvious technical advantages of continuous flow processing, companies are adopting the technology steadily, but slowly, and in a strictly opportunistic way, applying elements of continuous processing technologies when they pay off immediately,” states Poechlauer (1). “The technology is not developed to a certain degree of maturity and then waits to be applied, but is developed for and in close connection with a certain production process,” he adds.

Flow chemistry is often considered as an option when exploring new chemical routes, increasing yield, lowering the cost of goods, and generating IP, according to Roberge. “One of the main drivers for the implementation of flow chemistry is, however, to perform a reaction that cannot be done with traditional batch production, such as those involving azide intermediates or oxidation using oxygen,” he notes. Currently, the drivers for adoption are academia and institutes and providers of continuous flow equipment who are looking for innovation and often work together with the pharmaceutical industry to solve specific problems, according to Schrickel.

The main issue is the large existing batch manufacturing infrastructure. “If a company gets trapped in the question ‘use existing or build new?’, it will use the existing equipment in the present business environment,” states Poechlauer. Continuous equipment like microreactors are added when needed, and the existing vessels modified to serve other purposes, such as hold-up tanks used to define the batch for regulatory purposes. “We expect most pharmaceutical syntheses will continue to be a mix of continuous and batch manufacturing operations, which also enables manufacturers to build in inventory buffer zones,” observes Poechlauer.

In one recent example, researchers at GlaxoSmithKline found that for the large-scale manufacture of potassium bromomethyltrifluoroborate, a key raw material for a Suzuki−Miyaura coupling reaction (2), a hybrid approach involving the use of both continuous and batch processing where most appropriate was successful in achieving the project goals, according to Toby Broom, a chemist with GlaxoSmithKline R&D.


“The pharmaceutical industry is very much interested in continuous processes, and a lot of activity is underway within most pharmaceutical companies related to the development of continuous processes. However, we do see continuous processes being more relevant for the next generation of APIs,” says Schrickel. Lonza believes that at least the top 20 pharmaceutical companies have flow systems within their assets at this point in time, with some of the larger players calling continuous processing a disruptive or breakthrough technology, according to Roberge. At the same time, small to mid-size pharma and biotech companies often evaluate flow technology through outsourcing. “As a result, contract manufacturers that have flow processes in place are better positioned to engage in partnerships and collaboration discussions with these early start-ups,” Roberge comments. 

As the internal advocate groups within pharmaceutical companies push for the development of continuous processes, continuous processing will be applied in a growing number of processes, but in an evolutionary way, rather than a revolutionary one, as people come to accept the technology as mainstream rather than “experts only” territory, according to Poechlauer. In addition, he notes that with large pharmaceutical houses focusing on new leads rather than on process development, custom manufacturing organizations continue to play an important role in this field. 

Support from the authorities for continuous processing has also been crucial in furthering its acceptance by small-molecule API manufacturers. “The industry and FDA are in constant dialogue on continuous processing,” Poechlauer says.

Advances in continuous commercial production


One of the biggest issues for continuous flow chemistry has been scaling up to commercial production levels, because most early equipment for flow chemistry was designed for the laboratory. According to Poechlauer, however, chemical manufacturers and pharmaceutical companies have been working with microreactor manufacturers to address this issue, and pilot- and small commercial-scale equipment is now available, often by “numbering up” and running several microreactors in parallel. “One advantage of this approach is that modular designs that can be fitted to the specific needs of different reactions are possible,” he says. 

This advantage was taken into consideration when DSM installed its commercial-scale microreactor suite. “We are very interested in microreactor technology and continuous processing because, in some cases, it makes it easy to scale up reactions that can’t easily be done otherwise due to the nature of the raw materials or the kinetics of the reaction,” says Poechlauer. 

Lonza has designed a new type of production facility concept called the “Factory of Tomorrow” in which FlowPlate microreactors of various sizes are incorporated into the company’s development and manufacturing plants. “Flow processes lead to high intensification that radically reduces the size of a reactor and its footprint,” Roberge states. The range of FlowPlate equipment allows for production of a few grams of product in the lab setting and up to 5-ton campaigns for later-stage projects. “In such an environment, flexibility and versatility is needed to combine novel process conditions at high temperature and pressure, which can be difficult to achieve in a classical plant setting. Continuous manufacturing can significantly improve process efficiency with a reduced footprint, therefore reducing overall material consumption,” he observes.

In addition to addressing scale-up issues, advances have also been achieved in expanding flow chemistry beyond liquid systems, which are the traditional and most simple systems for continuous processing, according to Schrickel. “Much progress has been made with respect to the development of technology for the continuous processing of liquid/solid and multi-phase systems,” he explains. Lonza, for example, is developing microreactor plates with its partner Ehrfeld Mikrotechnik BTS, a Bayer Technology Services company, that will enable multi-phase reactions. Schrickel believes these advances will be important for the further application of continuous processes in API production. 

Poechlauer does add that there are uncertainties about scale-up, and managing intellectual property issues must be done carefully, given that in many cases new process chemistry is involved. 


More recently the focus has been on integrating continuous downstream processes with continuous flow synthesis. “Most downstream processes can be easily adapted to run continuously; extractions, phase separations, and distillations are actually more effective when done continuously,” says Poechlauer. On the other hand, he notes that solids handling processes, such as filtration and crystallization, present some difficulties. There are solutions being introduced to the market, however, such as belt filters and spray-drying, and Poechlauer expects others will follow.

Lonza, in fact, is currently extending the application of continuous flow technology to address continuous work-up unit operations such as distillation, according to Roberge. “The objective is the continuous operation of a complete mini-plant within the manufacturing unit ‘Factory of Tomorrow,’ which will allow its use for larger-scale manufacture,” explains Roberge.  


Research and development of continuous processes will continue and grow, first on specific, isolated topics, because there might not always be a solution that will enable a complete continuous process or at least a process without bottlenecks. To switch to continuous processes, companies will have to gain all of the possible benefits that the technology offers, and sustainability will be one of the key aspects, asserts Schrickel.

Poechlauer also believes that continuous processes will ultimately lead to simplified distributed manufacturing (on-site, on-demand) in modular container plants as well as enable application of “personalized medicines.” He also notes that the use of disposable devices in the manufacture of highly potent compounds will be beneficial to the further development of continuous processes for these challenging compounds.

“Our partners in the pharmaceutical industry are in a transition stage and are moving toward integrated solutions. Laboratory chemists consider the environmental consequences of raw materials and processes when developing synthetic routes. Drug manufacturers are also forming closer collaborations with suppliers to explore new technologies and concepts, such as continuous processing and the use of microreactors. Such relationships will help demonstrate the benefits of this approach and ultimately lead to adoption of process intensification when it is the most effective solution,” Poechlauer concludes.

At the same time, continuous processes will require new equipment and perhaps dedicated production lines for each API, according to Schrickel. “Pharmaceutical companies may insource the entire manufacturing of their APIs or force their outsourcing partners to install dedicated continuous plants. In either case, the adoption of continuous processes may result in a radical change in the pharmaceutical and outsourcing industry,” he asserts.

 17 (12), 1472-1478 (2013). 
2.	T. Broom et al., Org. Process Res. Dev. Article ASAP, DOI: 10.1021/op400090a Publication Date (Web): June 10, 2013.


Cynthia A. Challener is a contributing editor to 

Articles

The pharma industry is moving toward commercial-scale continuous processes for small-molecule API manufacturing.

The Mainstreaming of Continuous Flow API Synthesis

Unlike in the chemical and food industries, and even in small-molecule pharmaceutical manufacturing, which have well-established methods for automated online sampling, the biopharmaceutical sector remains in need of a reliable system that transfers bioprocess samples directly from bioreactors to analytical devices while maintaining process sterility. Such a system is necessary if biopharmaceutical companies are to effectively take advantage of process analytical technology (PAT) and gain a more fundamental understanding of what is happening within bioreactors.  While on-line Raman and dielectric spectroscopy provide some insight, there remains a need for integration of this data with off-line measurements, such as cell density, viability, metabolite levels, and titers. 

To overcome this issue, Bend Research (part of Capsugel Dosage Form Solutions), in collaboration with major biopharmaceutical companies, including Pfizer, Eli Lilly, and Boehringer Ingelheim, has developed the Modular Automated Sampling Technology (MAST) platform. MAST consists of a sterile sampling system, a sample scheduler and navigator for automated sampling and delivery of samples to various analytical instruments, and a data-management system for collecting and analyzing the results, and if desired, providing feedback to the bioreactor for direct adjustment of reaction conditions.  


The heart of the MAST platform is the new sterile sampling unit referred to as the Sample Pilot, which consists of a sampling module and an associated programable logic controller (PLC). There are two Sample Pilot modules, the SP100, which collects 50-mL samples for monitoring of pilot- and commercial-scale manufacturing operations, and the SP200, which takes incremental 5-mL samples for analysis of development-scale reactions and reactions that run in smaller laboratory-scale bioreactors and pilot-scale, single-use bioreactors. Each sample assembly consists of proprietary valves and a pump and is designed to draw samples from the bioreactor and push them out to user-defined destinations, according to Clint Pepper, a director at Bend Research. “Because we use positive displacement, rather than pulling the samples out with a vacuum, it is possible to deliver even viscous culture samples with high cell densities to analytical instruments more than 50 feet away.”  

Importantly, both systems can be sterilized in place (SIP), autoclave-sterilized, or gamma-sterilized depending on the model selected. “The entire system can be cleaned and sanitized between each sampling, and there is flexibility for users to adapt various cleaning procedures depending on their specific needs,” notes Lisa Graham, senior vice-president of Bend Research.   


To maximize the potential of sterile biopharmaceutical sampling, the MAST platform design includes software systems for managing sample scheduling, delivery of the samples, processing of the analytical results, and adjustment of bioreactor parameters if desired. The MAST Sample Scheduler and Navigator modules will work together to facilitate sample collection from bioreactors and transfer to analytical testing systems. 

The MAST Data Management system will maintain information on sampling activities and analysis results and has the ability to automatically adjust the feed rate of the bioreactor to meet desired growth rates according to the current condition of the cells. “With this data management system, it is possible to significantly reduce the time needed to process large sets of analytical results. Information on the state of cells and the process is obtained more rapidly, ” Pepper asserts. 

On-line measurement combined with at-line analysis  


Early studies at Pfizer have shown that automated at-line measurements obtained using the MAST system are similar to those obtained when using manual samples. The MAST platform has been incorporated with on-line analytical technologies to deliver overall cell-level “observability” and “guidance,” according to Graham. In one case, dielectric spectroscopy measurements were corrected to more accurately estimate total and viable cell density. Off-line measurements of Caspase-3 activation were related to on-line measurements of the variation in the capacitance due to the reduction in cell viability following staurosporine addition. This information was used to determine cell health in the bioreactor in real time. In another example, the amount of off-line data that was collected (Raman spectroscopy) was greatly increased due to the ability to more frequently collect samples automatically and without the need for an operator. The data were used to build robust process-monitoring models and develop a Raman system for laboratory use, according to Graham. “In this case,” she observes, “the Sample Pilot serves as enabling technology for the implementation of PAT.” 


The steam-sterilized SP100 module has been successfully demonstrated in five different bioreactors in three different facilities. “During recent development runs on pilot-scale bioreactors, the MAST platform and SP100 successfully delivered more than 480 samples without contamination, including more than 200 cumulative days of successful operation at the 30-L to 500-L scales in both cell culture and microbial applications,” reports Pepper. “The sanitant-sterilized SP200 module has been deployed in five different facilities ranging in scale from bench reactors to large-scale, single-use bioreactors. The SP200 units have collected over 2000 samples in more than 240 accumulative days of operation with no contamination or loss of sample integrity.”

MAST systems have been placed in nine client facilities (15 total units installed) with more than 2400 sterile samples collected without loss of sterility.  “The major MAST product modules have moved out of the beta testing stage and are being sold to early adopters as pre-commercial products,” says Pepper. 


New MAST technologies are still being beta tested, including a module to automatically remove cell from the whole broth, leaving the clear supernatant. This module would send clear samples to analytical devices that require cell-free samples, such as liquid chromatographs and mass spectrometers, so that these instruments can be integrated for real-time data collection and processing. 

In the near future, Bend Research plans to install the first multiplexed MAST system capable of collecting samples from up to eight bioreactors and sending those samples to as many as four analytical devices. “This solution should gain a lot of traction in the laboratory setting where banks of bioreactors are running at the same time,” says Pepper.


The MAST platform offers the ability to collect reproducible samples more frequently and automatically without operator involvement, which reduces the risk of contamination and operator exposure. The ability to integrate analytical results from numerous sources provides more insight into cell behavior and the impact of process parameters, enabling the use of more sophisticated process-control strategies.  

“Our intention with the MAST platform is to help biopharmaceutical companies gain insight into what actually occurs in a bioreactor by providing a means for understanding how bioprocess variables affect overall product quality,” comments Graham. “We believe that by coupling the right tools, the MAST platform provides in-depth guidance for optimization of the reactor environment in order to meet cell needs for the production of the target product. Ultimately, we hope that the MAST platform will provide the meaningful real-time analytics, process measurements, and novel data management techniques that will enable the development of predictive control models that in turn will drive increased product consistency and batch-to-batch reproducibility,” she concludes. 

Cynthia A. Challener, PhD is a contributing editor to 

The Modular Automated Sampling Technology platform allows sampling of bioreactors.

Automating Online Sampling of Bioprocesses

Reliable systems to transfer bioprocess samples directly from bioreactors to analytical devices while maintaining process sterility are crucial for biopharmaceutical companies to effectively take advantage of process analytical technology (PAT) and gain a more fundamental understanding of what is happening within bioreactors.  
   
  Bend Research (part of Capsugel Dosage Form Solutions) has collaborated with major biopharmaceutical companies, including Pfizer, Eli Lilly, and Boehringer Ingelheim, to develop the Modular Automated Sampling Technology (MAST) platform. MAST consists of a sterile sampling system, a sample scheduler and navigator for automated sampling and delivery of samples to various analytical instruments, and a data-management system for collecting and analyzing the results, and if desired, providing feedback to the bioreactor for direct adjustment of reaction conditions.

The MAST platform includes the Sample Pilot, a sterile sampling unit that consists of a sampling module and an associated programmable logic controller (PLC). The SP100 Sample Pilot modules collects 50-mL samples for monitoring of pilot- and commercial-scale manufacturing operations, and the SP200 takes incremental 5-mL samples for analysis of development-scale reactions and reactions that run in smaller laboratory-scale bioreactors and pilot-scale, single-use bioreactors. Each sample assembly consists of proprietary valves and a pump and is designed to draw samples from the bioreactor and push them out to user-defined destinations, according to Clint Pepper, a director at Bend Research. "Because we use positive displacement, rather than pulling the samples out with a vacuum, it is possible to deliver even viscous culture samples with high cell densities to analytical instruments more than 50 feet away."

To maximize the potential of sterile biopharmaceutical sampling, the MAST platform design includes software systems for managing sample scheduling, delivery of the samples, processing of the analytical results, and adjustment of bioreactor parameters if desired. The MAST Sample Scheduler and Navigator modules will work together to facilitate sample collection from bioreactors and transfer to analytical testing systems. 


  The steam-sterilized SP100 module has been successfully demonstrated in five different bioreactors in three different facilities. "During recent development runs on pilot-scale bioreactors, the MAST platform and SP100 successfully delivered more than 480 samples without contamination, including more than 200 cumulative days of successful operation at the 30-L to 500-L scales in both cell culture and microbial applications," reports Pepper. "The sanitant-sterilized SP200 module has been deployed in five different facilities ranging in scale from bench reactors to large-scale, single-use bioreactors. The SP200 units have collected over 2000 samples in more than 240 accumulative days of operation with no contamination or loss of sample integrity."   MAST systems have been placed in nine client facilities (15 total units installed) with more than 2400 sterile samples collected without loss of sterility.  "The major MAST product modules have moved out of the beta testing stage and are being sold to early adopters as precommercial products," says Pepper. 

The MAST platform offers biopharmaceutical manufacturers several advantages, according to Pepper, including the ability to collect reproducible samples more frequently and automatically without operator involvement, which reduces the risk of contamination and operator exposure. The ability to integrate analytical results from numerous sources provides more insight into cell behavior and the impact of process parameters, enabling the use of more sophisticated process-control strategies.  

Cynthia Challener, PhD, is a contributing editor to 

This article was excerpted from an article that will appear in the July issue of 

The Modular Automated Sampling Technology platform takes online samples from bioreactors and transfers them directly to analytical devices.

Advances in Real-Time Bioreactor Sampling

Advances in catalysis have had a tremendous impact on the pharmaceutical industry, enabling the synthesis of highly complex small-molecule intermediates and APIs in fewer steps, with increased atom economy, and often with high selectivities and yields. There are issues with many of the most widely used catalytic systems, however, including the cost, availability, and toxicity of many of the precious metals used to form the catalysts and the need for expensive and complex ligands to achieve the desired transformations. There has been much interest, therefore, in the development of alternative catalysts derived from abundant, nontoxic metals and simple ligand systems. New base metal catalyst platforms are also of interest because they may enable new chemistry not previously observed with traditional precious metal catalysts. Select examples with potential applications in pharmaceutical synthesis are discussed below.


  There is a finite supply of metals in the Earth’s crust, and humans are consuming many of them at an ever-increasing rate. As a result, the availability of certain transition metals for use in the production of catalysts is becoming increasingly limited due to growing demand for these materials in other applications, including the newer organic light emitting diode displays in smart phones and televisions and renewable energy systems, such as fuel cells, wind energy, and photovoltaics. 

In fact, in 2012, the British Geological Survey updated its risk list for the supply of chemical elements or element groups that are of importance to human society (1). The availability of each element was determined by considering its abundance in the Earth’s crust, the location of current production and reserves, the political stability of those locations, and the recycling rate and substitutability of the element. The rankings give an indication of which elements might be subject to supply disruption, most likely from human factors such as geopolitics or resource nationalism, along with events such as strikes and accidents. At the top of the list with the highest risk of supply disruption are the rare earths, platinum group metals, niobium, and tungsten. It should be noted that the demand for the elements (outside of their substitutability) was not considered in this analysis.

The platinum group metals are of particular interest to the pharmaceutical industry, because many important catalysts rely on platinum, palladium, ruthenium, rhodium, iridium, and osmium. These metals are expensive and experience high price volatility. The price of platinum, for example, ranged from $1400-$1500/ounce in March 2014, and has varied more than 5-fold in the last few years, according to Paul Chirik, the Edward S. Sanford Professor of Chemistry at Princeton University. With respect to platinum supply, he notes that the amount of platinum produced each year is only approximately 6% of the quantity of gold mined annually.


  Some researchers are raising the question of whether or not a reaction can truly be considered sustainable if such rare (and at times toxic) metals are required. According to Amir Hoveyda, Joseph T. and Patricia Vanderslice Millennium Professor of Chemistry at Boston College, even if a transformation is otherwise green (i.e. minimal/no solvent, high atom economy, no need for heating/cooling, little downstream processing requirements), it can’t be realistically considered as sustainable if a catalyst based on a rare transition metal is required. Hoveyda also notes that to be industrially practical, reactions must proceed in a reasonable period of time, ideally within six to eight hours, and catalysts must provide high selectivities and high yields.


  One reaction that Hoveyda has focused on is the copper-catalyzed synthesis of enantiomerically enriched homoallylic amines and alcohols, which are important intermediates for the preparation of many different biologically active molecules. As an alternative, his group has developed a transition metal-free route to enantiomerically pure amines and alcohols with inexpensive, easily prepared derivatives of the amino acid valine as catalysts for the reaction of a wide range of readily available unsaturated organoboron reagents with imines and carbonyls. In addition to not requiring any rare transition metal salts, the reactions are generally complete in six hours, require low catalyst loadings, and provide high yields and enantioselectivities. The effectiveness of this new set of catalytic reactions, according to Hoveyda, is due to the use of a proton and internal hydrogen bonding.


  Chirik, meanwhile, is developing alternative catalysts based on cobalt and iron, which are far more abundant than the precious metals. In addition, while most precious metal catalysts require two-point substrate binding for inducing high levels of enantioselectivity in asymmetric hydrogenation, because iron and cobalt are a new catalyst type, they have yet to exhibit this limitation, he points out. For example, Chirik’s cobalt asymmetric hydrogenation catalysts formed using simple and inexpensive chiral amine ligands are relevant to the pharmaceutical industry. In fact, Chirik developed the catalysts through a collaboration with Merck &  Co. that included high-throughput experiments. Notably, the cobalt catalysts are effective for the hydrogenation of both functionalized and unfunctionalized olefins in high yield and high enantiomeric excess. 

In a second example, Chirik’s group has developed iron catalysts that mediate both inter- and intramolecular [2π + 2π] reactions of alkenes and alkynes to form cyclobutenes. What is interesting about this system is that it is effective for unactivated olefins and is also selective for 2+2 cycloaddition even in the presence of a diene that can undergo Diels-Alder (4+2) cycloadditions. According to Chirik, such selectivity is unique to iron and results from its ability to engage in radical chemistry with the supporting ligand.


  A third strategy for the development of alternative catalysts involves mimicking the behavior of enzymes. Such research is being performed by Robert Morris, a professor at the University of Toronto, who has developed new iron catalysts that perform what he calls “metal-ligand bifunctional catalysis,” in which the ligand and metal both play an active role in the catalytic cycle. Notably, he has shown that with the right choice of ligands, the electronegativity of the iron center can be adjusted such that it is close to that of carbon and thus able to form covalent bonds, particularly iron-hydrogen bonds. Surprisingly, carbon monoxide, which is often a poison to catalysts, is a required ligand as it is for nature’s hydrogenases.

Such catalysts are effective for the asymmetric transfer hydrogenation (ATH) of ketones and can be simply prepared from relatively inexpensive diamines and phosphine aldehydes, which self-assemble (promoted by the metal through a template effect) to form imines that bind to the metal. Morris notes that the catalyst is effective at low loadings and the iron can be readily oxidized upon exposure to air and then precipitated, allowing for simple purification. A third-generation family of these iron-based catalysts was reported in 2013 and should be available for purchase soon (2).  These catalysts are more active than any known catalyst for ATH and as selective as more expensive conventional ruthenium-based systems.

The catalyst may also be applicable for direct hydrogenation under a mild hydrogen pressure, and the reverse of the asymmetric transfer hydrogenation reaction may be useful for the kinetic resolution of racemic alcohols.


  Carbon-carbon coupling reactions have become widely used in organic synthesis, including the commercial manufacture of numerous pharmaceutical building blocks and key intermediates. Robin Bedford, professor of catalysis at the University of Bristol, has been investigating the potential for using iron catalysts to mediate these important transformations. In the past, coupling reactions involving iron have generally been Grignard reactions of “hard” nucleophiles. Bedford wanted to expand the repertoire to other “softer” nucleophiles (e.g., zinc) that are used in coupling reactions catalyzed by platinum and palladium.

What his group found was that the choice of ligand was crucial for creating iron catalysts that are effective for both the Negishi coupling of benzyl halides and phosphates with diarylzinc reagents and Suzuki couplings of arylboronates with alkyl and allyl halides and 2-halopyridines. Most importantly, the best ligand is the simple, inexpensive, bis(diphenylphosphino)ethane (dppe) ligand. The key, according to Bedford, is to prepare the catalyst in the correct manner. “One of the important lessons we learned in this work was that it is important to understand the identity and role of the active catalytic species and how ligands interact with iron in order to generate the desired species,” Bedford states.


  Iron is not generally thought of as a good metal for the preparation of catalysts because of its electronic structure. Platinum group metals, which are heavier metals with no unpaired electrons, have always been thought to form stronger bonds with ligands, according to Patrick L. Holland, a professor of chemistry at the University of Rochester. On the contrary, his group has shown that complexes based on metals with unpaired electrons can follow similar reaction mechanisms, and often do so more rapidly, as long as a balance is maintained between the weakness and activity of the ligand-metal bonds. 

Holland has developed special bidentate ligands that are designed to afford the high-spin electronic configuration in complexes with first-row metals. For example, his group has developed an iron(III) imido complex that oxidizes hydrocarbons and transfers a nitrene (NR) group to organic substrates.

“We believe that properly designed complexes of iron and other first-row metals can serve not only as alternatives to transition metal catalysts for the mediation of established reactions; given their unusual reactivity, they may also provide access to novel transformations,” observes Holland.

“Risk list 2012: An updated supply risk index for chemical elements or element groups which are of economic value,”

 Accessed Apr. 10, 2014.
  2.	W. Zuo et al., Science, 342 (6162), 1080-1083 (2013). 

Industry seeks alternatives to costly and toxic precious metals used to form the catalysts for organic synthesis.

Alternatives to Precious Metal Catalysts Sought

Transition metal-containing catalysts are widely used in organic synthesis, but many are based on expensive, rare metals. Researchers are seeking more sustainable alternatives.

Seeking Alternative Catalyst Solutions

Solid dosage forms are preferred for the delivery of APIs, but many therapeutic agents do not readily form stable crystalline materials or the crystals have poor solubility. Cocrystals alter the physical properties of APIs without chemical modification while maintaining the benefits of a crystalline solid form, and thus may provide a viable solution for some of these difficult APIs. Cocrystals can also be synthesized using numerous different methods, some of which use little solvent or are solvent-free and have the potential to provide real cost advantages. As a result, the potential for cocrystals is significant.

This potential is tempered, however, by the industry’s reaction to FDA’s classification of pharmaceutical cocrystals as “drug product intermediates” (DPIs) rather than APIs in its April 2013 regulatory guidance on cocrystals (1). This decision is generating significant discussion within the industry about the risks associated with the practical development of cocrystals. Based on the public comments on the draft guidance, manufacturers would prefer cocrystals to be considered drug substances rather than drug product intermediates. As the industry moves toward adopting the FDA guidance, the risk associated with developing cocrystal-based products appears to be increasing rather than decreasing. There are questions, for example, about expiration dates for drug products that incorporate cocrystals manufactured using processes that are consistent with API (drug substance) materials but regulated as DPIs. In addition, FDA is the only agency to date to formally define a regulatory scheme for cocrystals. If other agencies around the world take a different approach, it could become difficult for companies to develop cocrystal-based products that satisfy global regulatory requirements. The European Medicines Agency (EMA), for example, could consider cocrystals to be drug substances rather than DPIs.


“The selection of a specific crystal form for a given API is a profoundly important step from clinical, legal, and regulatory perspectives: the dissolution rate and intrinsic solubility of different crystal forms is variable and can strongly influence bioavailability; stability to temperature and humidity are critically dependent upon crystal packing; and the unpredictability (i.e., lack of obviousness) of crystal structures and physical properties means that there are legal issues and challenges in terms of obtaining and maintaining patent protection for an API,” says Ning Shan, director of preclinical development at Thar Pharmaceuticals. 

Highly lipophilic APIs have dissolution problems that may be overcome using a cocrystal because the new crystalline lattice being formed often has different dissolution properties compared to those of the crystals of the API alone, according to Chris Frampton, chief scientific officer of SAFC Pharmorphix. The formation of a new crystal lattice with a pharmaceutically acceptable coformer can overcome development hurdles, such as compaction problems and difficulties with hygroscopicity. In addition, for non-ionizable APIs, for which it is not possible to make a salt, the option to form a cocrystal can be advantageous over exploring exotic formulation methods or changing the API molecular structure to include the acid or base functionality required for salt formation, which can have an impact on the activity of the API. There is also the potential to use cocrystals as a lifecycle management tool, because their use can delay or divert generic competition.


Defining cocrystals as drug product intermediates, in which the coformer is treated as an excipient and the cocrystal is effectively considered to be a formulated material, has several consequences. A potential advantage could be in the area of cocrystal synthesis. Traditionally, APIs are crystallized from an organic solution, and such processes often require the use of large quantities of solvent. Utilization of solvent is common in drug substance manufacturing plants, but not in drug-product manufacturing facilities where DPIs are manufactured. Because cocrystals can be produced using solventless solid-to-solid or slurry conversion processes that are well documented in the literature, they are ideally suited for production in DPI facilities, according to Scott L. Childs, president and CSO of Renovo Research. “These novel synthesis techniques have been used to scale up cocrystals at gram scales and for screening purposes for many years. Now that cocrystals are classified as drug product intermediates, it is possible to consider these methods for cocrystal synthesis on the commercial scale,” he explains.  “The ability to prepare cocrystals using solventless synthesis methods in drug-product manufacturing facilities, which is where amorphous dispersions and other enabling formulations are manufactured, provides the opportunity to use ‘greener’ production methods and realize better manufacturing economics and reduced development times,” Childs adds.

The FDA guidance generally creates the opportunity for the application of non-traditional synthesis techniques to the preparation of cocrystals. There are processes being developed that have potential for application to the industrial-scale manufacture of cocrystals, such as methods using hot melt extrusion, continuous oscillatory baffled crystallizers, and resonant acoustic mixing techniques (2-4). Some solventless methods rely on various grinding techniques and melting approaches, according to Marcel Hoffmann, chief science officer with Crystallics. “Gaining an understanding of cocrystal formation and their interactions at the molecular, particle, powder, and product level is necessary in order to improve the manufacturing processes for this type of drug,” he adds. If the industry embraces the FDA guidance with respect to the manufacture of cocrystals in drug-product manufacturing facilities, there could be a significant shift in cocrystal manufacturing away from solvent-based processes and towards solventless processes, according to Childs.


Defining cocrystals as drug product intermediates has also created significant concerns. According to Hoffmann, depending only on differences in pKa, the same counter ion would form a salt with one API and a cocrystal with another API, and the two substances would be treated differently from a regulatory perspective. “In addition,” he notes, “this definition opens the door for generic companies to develop cocrystals and follow a 505(b)(2), or even bioequivalence route, rather than a more costly new chemical entity route.” 

Shan does point out, though, that a cocrystal still has the same active moiety as the original drug. “Even so, under the patent protection of the original drug, a cocrystal version of the same drug cannot circumvent the original patent,” he notes. “However, a cocrystal with desired properties can be patented, IP protected, and marketed, as mentioned previously in the context of life-cycle management.”

The FDA approach may not be consistent with the approach that other world regulatory agencies adopt for cocrystals, according to Childs. “If novel cocrystal manufacturing is enabled via the FDA guidance, but the same manufacturing approach causes a regulatory problem in other world markets, then that creates risk,” Childs observes. “There is currently no clear answer regarding how the FDA approach will fit in with the rest of the world, which is making it difficult to get buy-in and investment into this new technology from a very risk-averse industry,” he adds.

Shan further notes that the requirement in the FDA guidance that the developer of a cocrystal drug product must provide “assurance that complete dissociation of the API from its excipient occurs prior to reaching the site of action for pharmacological activity” could be a real challenge. 


At SAFC Pharmorphix, the ability to perform crystal structure analyses on really small crystals has been advantageous. “Knowing the crystal structure makes it possible to see how the two materials come together to form a supramolecular complex. Then we can go back to our list of potential coformers, tune them slightly, and follow an iterative process to develop the optimum cocrystal,” observes Frampton.

Renovo, meanwhile, has developed a new approach to formulating cocrystals that uses the improved cocrystal solubility more effectively. Traditionally, as is commonly done with salts, cocrystals are used in 

preclinical studies as “neat” material (pure crystalline powder), according to Childs. This approach is not optimal, because cocrystals are highly susceptible to solvent-mediated transformation into the poorly soluble form of the API when dosed as neat material.  

“We have developed a new approach, demonstrated with a danazol cocrystal, that utilizes solubilizing excipients and precipitation inhibitors to create an optimal supersaturation level and controlled dissolution event,” Childs explains.  The model system achieved a 10X increase in the area under the concentration time curve (AUC) in animal studies using the formulated cocrystal, compared to only a 1.7X increase in the AUC using the neat cocrystal solid.  “The results of this study suggest that the appropriate formulation of cocrystals can be an important part of the cocrystal development process,” he says. Childs believes that the concepts outlined in this study present a viable roadmap for moving cocrystals forward because it suggests that formulated cocrystals can directly compete with more established drug-delivery technologies such as amorphous dispersions and lipid-based solubilizing formulations.  


Despite these significant regulatoryconcerns, interest remains in cocrystals. “Looking at the ratio between salt formation and cocrystal studies that Crystallics carries out on behalf of its customers, it is clear that the pharmaceutical industry is still hesitant to make cocrystals their final marketed products,” notes Hoffmann. He does, however, point to Esteve’s cocrystal of Tramadol and Celecoxib as one example of a cocrystal that is progressing towards a new drug approval. There is hope that a successful application of this cocrystal will pave the way for others. Crystallics is in fact seeing a renewed interest in the development of cocrystals, with most projects focused on tuning the physicochemical properties of the API, particularly solubility and dissolution rate. 

“I am convinced that pharmaceutical cocrystals are here to stay,” Hoffmann asserts. “With increasing research, our understanding will rapidly grow and cocrystals, unlike other bi-component crystals, offer the possibility of crystal engineering. Predicting the physicochemical properties up front is the holy grail of drug development,” he comments.  Frampton points out, though, that the current lack of predictability of cocrystal formation is necessary to some degree. “As soon as it is possible to predict cocrystal structures, we have a problem. Patent applications for salt forms are already being questioned on the grounds that they are predictable and obvious due to the pKa of the API and the limited list of pharmaceutically acceptable salt formers. The lure of the cocrystal remains the questionable and unexpected successful outcome.”

Childs adds that although additional advancements are needed to help the field mature, the science does not appear to be the limiting factor in the uptake of cocrystals by the pharmaceutical industry, but rather it is the perceived risk associated with cocrystals that seems to be slowing progress with respect to their industrial application. “With the appropriate time, effort, and investment, cocrystals can be used to consistently create improved pharmaceutical products. In specific situations, cocrystals should be able to compete directly with amorphous dispersions in terms of efficacy, but offer a superior product because of the lower risk and improved stability of the crystalline state compared to the amorphous state,” he concludes. 

Guidance for Industry: Classification of Pharmaceutical Co-Crystals

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, 2014 Advance Article, DOI: 10.1039/C4CE00154K.
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  Cynthia A. Challener is a contributing editor at 

The perceived risks associated with cocrystals may be slowing progress of their industrial application.