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

Cynthia A. Challener

Advances in solid and liquid formulation techniques are providing more options.
The number and potency of highly potent drug substances are increasing. Formulators working with highly potent APIs (HPAPIs) are increasingly challenged to ensure the safety of both personnel during development and manufacturing and healthcare workers and patients when using the final drug products. That means addressing potential issues with the homogeneity of the formulation, drug content analysis, and proper handling. Advances in microparticle, capsule and syringe technologies, analytical methods, and containment systems are widening the safe formulating options for HPAPIs.


Safety should always be at the forefront of any research and manufacturing operation, according to Thomas R. Tice, senior director of global technical marketing at Evonik Pharma Polymers & Services. For HPAPIs and their pharmaceutical dosage forms, Tice notes that research and manufacturing operations must take place in facilities built on design requirements specific to operations involving potent compounds. It is also necessary to use appropriate personal protective equipment (PPE), train staff, and follow established policies as well as appropriate standard operating procedures to protect workers, contractors, and the community. Bryan Knox, senior director of pharmaceutics with Pharmatek, adds that as the number of potent compounds increases, manufacturing practices are increasingly moving away from reliance on PPE alone, with current practices focusing more on containment at the source to prevent operator exposure. To aid this process, many equipment providers now offer options for containment within the design of the equipment.

“When Pharmatek built its facility specifically for the handling of highly potent compounds in 2007, we chose to invest in a dedicated facility for the development and manufacture of highly potent compounds. The facility utilizes a combination of facility design features, isolator technology, and PPE to prevent cross contamination and to ensure the safety of personnel,” says Knox. Evonik, as a company that offers HPAPI development and manufacturing services for oral and parenteral dosage forms, has developed a comprehensive safety assessment strategy, invested in containment including isolators and dedicated rooms, and adopted process-specific engineering and procedural controls, thus allowing the safe handling of potent compounds according to specific operations, Tice told 


Although highly potent, HPAPIs do not require specific dosage forms. Any formulation strategy for HPAPIs should, in addition to addressing potential issues with proper handling to ensure personnel safety, consider the homogeneity of the formulation and the drug content analysis. “Because unit doses for highly potent drugs typically contain very small quantities of API, ensuring blend and content uniformity and developing accurate analytical methods are particular challenges for low-dose drugs,” says Knox.

There is a precedence in the industry to put highly potent drugs in solution to minimize exposure risk, but with proper environmental, health, and safety systems in place, formulating powders into capsules or tablets is often preferred, according to Knox. Consideration must also be given to the ability to produce a homogeneous product. “Understanding the segregation potential of low-dose drug formulations is an important aspect, because segregation can lead to poor blend and content uniformity, which can affect the manufacturability of the product,” he explains. Assessment of potential segregation should occur during prototype development and initial process development, particularly when using automated equipment where vibration plays a role. Knox also recommends the use of design of experiment (DOE) studies with factorial design to define the design space and avoid potential segregation due to low-dose requirements.


HPAPI formulation processes must be robust and scalable. It is advantageous to have processes that can be scaled down for formulation development such that smaller-scale process equipment can fit into smaller-scale containment and still make formulations representative of what can be made in larger commercial-scale batches, according to Tice. He adds that it is also important to use equipment that can be taken apart and cleaned.

As importantly, appropriate analytical methods with a high level of sensitivity must be identified for the evaluation of low-dose/highly potent drug formulations, regardless of the form of the product. Both excipients and drug product matrices can interfere with detection of HPAPIs due to the high concentration of excipients relative to active ingredient in analytical samples, according to Knox. He notes that ultra-high pressure liquid chromatography (UHPLC) is often preferred over conventional high-performance liquid chromatography (HPLC) for the analysis of highly potent compounds due to its increased sensitivity, which is increased approximately 10 times.

For injectable products, Knox adds that it is crucial to understand the interaction of the packaging contact surfaces with the drug product in solution. In addition, recovery studies should be performed to ensure that the delivered dosage is within acceptable ranges.


While HPAPIs do not have special drug delivery requirements, the dosage form chosen must ultimately address patient safety, compliance, clinical performance, and manufacturability, according to Knox. There are, however, certain dosage forms that provide some advantages because they are more suitable for the lower drug loads associated with HPAPIs.

“Liquid-filled formulations in either soft-gel or hard-shell capsules offer an important oral dosage strategy for highly potent drugs that can cause homogeneity issues when formulated as powders into capsules or tablets,” observes Knox. The technology also has the benefit of being a safer process than the production of capsules and tablets using powders, because dust generation is not an issue.

To obtain capsules and tablets of HPAPIs, fluidized-bed coating technology (Wurster coating), which involves spraying of an HPAPI solution onto nonpareil beads that can then be filled into capsules or pressed into tablets, is an attractive alternative, according to Knox. Mini-tabs can also be used for multiparticulate HPAPI systems where single- or multi-layered coatings contain a functional coat with the active ingredient and a seal coat.

Extended-release parenteral formulations are also well suited for HPAPIs, according to Tice. He specifically notes that extended-release, bioabsorbable poly(lactide-co-clycolide) (PLG)  microparticles reduce side effects, improve therapeutic efficacy, and increase patient compliance. “Like other parenteral formulations, the administration of suspensions of injectable microparticles is limited by the injection volume. HPAPIs are ideal for PLG microparticles because they are dosed at microgram and milligram quantities, which means less API (less mass) is needed to meet the injection volume requirements. In turn, HPAPIs can be delivered from PLG microparticles for weeks and months following a single administration,” he explains. These formulation advantages also apply to extended-release, rod-shaped injectable PLG implants.

Given the safety issues and growing number of options for low-dosage drugs, choosing the right dosage form for an HPAPI can be challenging. Pharmatek takes a data-driven approach to this decision, according to Knox. “Our goal is to look at the least complex dosage-form options first, because conventional approaches save on development time and costs.”  Success can be obtained with dry blending a formulation for filling capsules or making tablets at drug loads in the 0.01% w/w range, depending on the API properties. Dosage strengths at 10 µg or lower often require special considerations, such as oral solutions, liquid-filled capsules, or granulation and coating techniques with the active ingredient dissolved in a spray solution.


Evonik has developed the FormEZE technology, an improved microencapsulation process for the manufacture of PLG microparticles. The continuous, closed-equipment process involves an emulsion-based extraction and affords 20% higher yields with less post-process handling, according to Tice. “This process shortens unit operations time, reduces waste, and can be scaled down from commercial-size manufacturing, all advantages when working with HPAPIs,” he says. The emulsion is generated by a packed-bed column that produces a defined, narrow size distribution of microparticles that allows the use of smaller-diameter needles and affords the administration of more microparticles for drug delivery over longer durations.

Another benefit is that the PLG microparticles made using the FormEZE technology are much easier to administer by injection and safer to use, according to Tice. Because of the size distribution of the microparticles and the assurance of no large particles or agglomerates, they do not clog needles during injection. “When injection procedures are less prone to complications, particularly when HPAPIs are involved, improved safety to the patient and the healthcare worker is achieved,” he comments.

Improvements in capsule availability and manufacturing equipment for liquid-filled hard shells are also of note, according to Knox. “The availability of both gelatin and hydroxypropyl methyl cellulose capsules designed specifically for liquid formulations of HPAPIs and micro-spray sealing and banding technologies have enabled greater application of this delivery technology for highly potent compounds. Opportunities for liquid delivery outside of softgels, which can be an expensive technology to invest in during the early stages of development, represent a real advantage,” he states. In addition, liquid-filled hard shell encapsulation machines now have faster filling and sealing speeds and provide more in-line process checking (temperature, speed, fill weight), as well as automatic in-line feedback with process analytical technology.


  Cynthia A. Challener is a contributing editor at 

Articles

Advances in solid and liquid formulation techniques are providing more options.

New Technologies Enhance the Formulation of Highly Potent Drugs

As demand shifts from high-margin branded drugs in Western regions to low-margin generics in emerging markets, successful bio/pharmaceutical companies are adopting new business models that include significantly more outsourcing and require a deeper understanding of costs all along the value chain. Enterprise resource planning (ERP) systems that have been effective for the internal management of sourcing and production are insufficient for managing the extended relationships and multidirectional communications needed in this new environment. Bio/pharmaceutical companies are therefore turning to cloud-based services to achieve greater transparency and facilitate collaboration.


  The biggest trend driving changes in the market today is the shift from a focus on Western markets to growth areas in emerging regions, according to Diane Palmquist, vice president of product management for GT Nexus, a cloud supply-chain platform provider. “High-margin blockbuster drugs are coming off-patent and mature Western markets are experiencing limited growth. Consequently, the focus has shifted to emerging markets, where the growth rate is higher. However, the demand in these regions is greatest for low-cost, low-margin products, and buying habits are very different (buy the dose, not the bottle),” she observes. The result: bio/pharmaceutical companies need to completely transform their old business models.

The biggest impact can be seen in the higher level of outsourcing now taking place. “Pharmaceutical companies are outsourcing nearly every aspect of the business, including some research-related activities, API manufacturing, drug product formulation, packaging, and logistics,” says K.R. Karu, industry solution director for Sparta Systems, a provider of enterprise quality management solutions. Palmquist adds that currently approximately 40% of industry business is outsourced, and that number is expected to increase to 80% over the next several years.


  As outsourcing has increased, companies have lost control over many aspects of the supply chain. “Companies are still trying to manage interactions with suppliers and service providers through personal communications, which is not only inefficient, but ineffective given the number and complexity of relationships and issues that must be managed,” Karu says. The low margins of today also do not support this approach. ERP systems, which in the past have been used to connect purchasing with production operations, are also not capable of managing the complex interactions between service providers and pharmaceutical companies, according to Palmquist. Furthermore, to meet the demand of emerging markets, pharmaceutical companies must be very responsive and need solutions quickly. ERP systems generally take about 18 months to get up and running, and often by that time the opportunity has been lost.

One of the key issues for bio/pharmaceutical companies is the lack of visibility into contract manufacturers. Often pharma companies do not find out about issues that can impact the delivery of API or finished drug product until much later because the suppliers are trying to solve the problem. The common response, according to Palmquist, is to try and stay on top of potential problems by constantly contacting the suppliers via phone or e-mail, which is not a practical, sustainable, or effective approach.

“The challenge lies in the need to manage a whole host of different suppliers at the same time that the customer base is changing dramatically and bringing an entirely new set of customer expectations. The key to this puzzle is to obtain visibility on both the supply side and the value side, from inventory to quality excursions to government fees,” Palmquist asserts. 


Cloud-based services give bio/pharmaceutical companies the ability to extend their visibility into all parts of the value chain, while at the same time enabling vendors to access the information they need in order to provide optimum services. Raw materials suppliers, contract research organizations, contract manufacturers, brokers, and distributors can all interact simultaneously under very controlled conditions that ensure that important information gets to the only the right people when it needs to, according to Palmquist.


  There are several other practical advantages of using cloud-based systems, according to Karu. Because cloud-based software systems are developed by software experts, they are consistent for all users. Maintenance and upgrades are provided on a continual basis, as well as any necessary validation procedures to meet special compliance requirements for the pharmaceutical industry. There is also no need for investments in extensive information technology infrastructure; the servers are maintained by large companies (think Google and IBM). In addition, redundant systems located around the world ensure non-stop operation. 

Perhaps most importantly, though, is the controlled nature of the interactions through cloud-based systems. “Generally the information that is being shared using cloud-based systems is already being shared via phone calls and e-mails. There are, however, much stronger controls in place in cloud-based systems that ensure that information only goes to the people who should see it. There are no such controls around the use of e-mails with file attachments,” Karu explains


  Overall, according to Palmquist, cloud-based systems offer bio/pharmaceutical companies assistance with achieving assurance of supply. All business activities can be integrated in the cloud and important issues, exceptions, and problems flagged automatically, so that efforts are appropriately focused on resolving potential issues. Not only purchasing systems, but logistics and quality management systems can be linked through the cloud so that the bio/pharmaceutical company is always up to date on what is happening and can readily share information that impacts multiple vendors.

“Moving an established quality system to the cloud and sharing it with raw material suppliers and contract manufacturers makes it possible for these vendors to exchange information immediately. In addition, these vendors can be directly included in specific activities, such as investigations of excursions and remedial actions, leading to much more rapid resolution of problems,” Karu comments. Similarly, cloud computing can benefit other aspects of supply chain management and aid in the rapid response to any type of possible interruption in the supply, from natural disasters to manufacturing malfunctions to distribution issues.


  “The key to success for bio/pharmaceutical companies with such complex supply networks is collaboration across the value chain. Cloud computing is an effective way to enable such relationships,” Karu says. “There is definitely a growing realization in the pharmaceutical industry that suppliers must be thought of as extensions of the company. To be truly successful, we believe that the relationships between bio/pharmaceutical companies and their suppliers should be viewed more like joint ventures, with real transparency of information,” adds Palmquist.

The idea of allowing vendors to see into their business operations is the most challenging aspect of cloud computing for biopharmaceutical companies. “Most companies are at least initially very resistant to letting suppliers see their company information. It is not possible, however, for vendors to effectively participate in quality investigations, audits, and remediation efforts without two-way communication. He adds that the pharmaceutical industry tends to be very conservative about adopting new technology, in part due to concerns about acceptance by regulatory agencies, and cloud computing is no exception. “Both pharmaceutical companies and their suppliers are interested in cloud-based solutions, but neither is convinced that the other is willing to implement them. The greatest challenge at this point, therefore, is to convince the various members of the pharmaceutical industry supply chain to take the first step.


  Companies that have already moved forward with the use of cloud-based services are those that have been pushed fastest towards emerging markets and have realized that ERP systems are insufficient and leave them “flying blind,” according to Palmquist. Pfizer is one example. “Pfizer needed to figure out a way to not only maintain but grow its revenue stream despite having 9 of its blockbuster drugs lose patent protection¾a Herculean task,” she says. Not only did the company need to better manage the supply side, it also needed help tracking costs (taxes, fees, etc.) on the value side in detail, something that was not a concern in the past with high-margin products.

“We expect that more companies will be in this same position and looking for solutions that enable simultaneous, multidirectional communications with numerous members of the value chain. As that occurs, there will also be greater realization that any dollars spent in the supply chain ultimately comes from the pharmaceutical company,” says Palmquist. In the past, it was easy for manufacturers to separate supplier costs from their costs because margins were high. That will no longer be the case as the industry becomes a low-margin business. “As we see in the consumer electronics industry, where every penny is tracked throughout the supply chain, it will be necessary for bio/pharmaceutical companies to look at supplier costs as their costs in order to maximize profits. Connect with suppliers through cloud-based systems will help not only control costs, but also quality and all other aspects of their operations,” she concludes.

For those reasons, Karu anticipates an explosion in demand for cloud-based services in the pharmaceutical industry. “The many-to-many relationships that are possible with cloud-based systems provide a much more efficient mechanism for processing information and managing interactions, which will be critical to the success of pharmaceutical companies in the increasingly challenging business environment they are facing,” he says.

Multidirectional collaboration is critical for the new pharma business model; cloud-based information services can offer a communications alternative.

Pharma Outsourcing Driving Need for Cloud-Based Services

With a quality-by-design approach, robust processes consistently deliver quality product. Small drug manufacturers looking to adopt a quality-by-design (QbD) approach aim to scientifically determine product and process characteristics that will meet specific criteria set after careful analysis of the intended drug application. These critical quality attributes (CQAs) of the final drug product (and often of the API) include the physico chemical properties and performance behavior of the formulated drug (drug substance). The manufacture of small-molecule APIs often requires the production of multiple intermediates using different processes. To consistently achieve these CQAs, it is necessary to ensure that each of these processes is robust. Critical process parameters (CPPs) are, therefore, important components of an effective control strategy for ensuring that the API process consistently delivers product with the appropriate CQAs.


While true CQAs are found in the final specification for a drug product, there are several different aspects of a formulated drug, and particularly the API, that are affected by process parameters. These aspects, therefore, must be linked to the CPPs for each manufacturing process required for the preparation of an API, according to Chris Senanayake, vice-president of chemical development for Boehringer Ingelheim Pharmaceuticals. These characteristics include, but are not limited to, total purity, individual impurity levels, the polymorph(s), solvates, pH, water content, and particle size.

For the API, the most common CQAs are related to impurities from chemical processes and the solid-state properties (e.g., particle size, polymorphism) of the drug substance, according to Gert Thurau, group leader, Technical Regulatory at Roche. It is essential to control impurities for the safety of the drug product, while control of the solid-state properties of the drug substance is necessary to achieve consistent product properties, including bioavailability. “Once these attributes have been defined, it is possible to define what is important to the process and build a process that comes closer to quality by design and is, therefore, highly robust,” he says. The assay and impurity profile of an API are essentially inter-related and are important because low impurity levels translates to safety for patients, while a high assay indicates appropriate efficacy, according to Vishwanath Nadig, associate director of quality assurance for Dr. Reddy’s Custom Pharmaceutical Services (CPS). Nadig adds that moisture content is also important because, in some cases, the presence of moisture may accelerate degradation of the drug substance.

These CQAs should be selected such that if the final product has these attributes, then it will work for its intended purpose. CPPs should then be selected because they have a relationship to the final CQAs and, when controlled, will assure the manufacture or a product with the right CQAs, according to Senanayake. “CPPs are the process parameters that affect the critical quality attributes of the API, and it is important to determine the range for each critical process parameter expected to be used during routine manufacturing and process control,” adds Mark TePaske, director of regulatory affairs, quality, and compliance for Cambrex. Most importantly, it is essential to establish appropriate CPPs for each individual process step because they will ultimately affect the quality of the drug, which in turn can impact efficacy, according to Nadig. “Establishing and meeting CPPs and CQAs allows quality to be built into the process and affords robustness beyond release testing,” adds TePaske.  He also notes that well-defined CPPs ensure that a process operates in a state of control and in a validated state, which is crucial, because process validation is a cGMP requirement.

The definition of the CQAs for the final drug product and API is the first step in a comprehensive risk-based approach to product and process development, according to Thurau. “The starting point of the analysis is typically the quality target product profile, which leads to defining the critical quality attributes for the final product, and in turn, the critical quality attributes for the drug substance. Since the most important CQAs of the final API are the process-related impurities, which mostly result from the starting and raw materials, it is essential to understand the chemistry of the individual process steps,” he explains. In addition to risk assessment, Senanayake adds that prior knowledge, designed experiments, and regulatory expectations all play a role in determining CQAs and CPPs.


Once CQAs are defined, typically during the initial scale-up phase, it is necessary to identify the appropriate CPPs. “At Boehringer Ingelheim, we believe that using a design of experiment (DOE) approach is the best method for demonstrating the interdependency of CPPs and the CQAs for individual process steps,” Senanayake says. Along with general risk assessments, the use of design failure mode and effects analyses (FMEA) is also effective for defining critical parameters of drug products, drug substances, and production processes, according to Nadig. “When applied appropriately, these two approaches are sufficient for defining the important attributes,” he says.

While orthogonal experiments can also be used, Senanayake notes that with DOE, knowledge is gained about the design space for each process that cannot be obtained using screening experiments, although they are useful when determining certain aspects of processes, such as the most effective solvents or catalysts. TePaske adds that once defined, critical attributes should be affirmed experimentally and control limits established, with processes, procedures, equipment and/or facilities revised as needed.

It should be noted that the risk-assessment methods used today are much more rigorous than the processes used in the past. “Historically, process and CQA definition was driven by the process development chemist, and the depth and breadth of the investigations were chemist-dependent,” observes TePaske. As a result, process development was primarily viewed as a laboratory exercise.  He goes on to note that current approaches are more disciplined, and studies are defined by multidisciplinary project teams. “These teams review and reconcile findings and risk assessments, and the concerns of the production, materials, quality, engineering, and other departments involved in manufacturing are integrated into the development process.  In effect, CQA definition and process development have evolved from a laboratory exercise to a global preparation for process validation and commercial GMP manufacturing.” He concludes that this team-oriented approach is the best practice because it integrates the needs of all of the disciplines involved in commercial manufacturing and virtually eliminates the possibility that CQAs and CPPs that cannot be performed in the available facilities and equipment will be defined.


  Based on the results of the quality risk assessment, various reaction and work-up conditions can be investigated, and the products from each process step can be carefully analyzed with regard to their impurity profiles and other properties, according to Thurau. “For example, the structures of the impurities can be determined, and consequently the process conditions can be adjusted to minimize the impurities and/or their fate in downstream steps can be determined. The result is the elimination of the impurities or the determination of safe limits for them,” he explains. He stresses that it is important in this part of the process to be systematic, and to consistently maintain a link between the CPPs being evaluated and the drug product and drug substance CQAs.


  While there are many benefits to a QbD approach and the establishment of CPPs that are linked to final product and drug substance CQAs, there are challenges to implementing such an approach. For Senanayake, the time and resources required remain the biggest barrier to obtaining a useful understanding of a process. “These barriers must be overcome, though, because having thorough knowledge of a process once it has reached commercial manufacturing is critical for success, and therefore, it is necessary to take the time to fully understand the design space,” he asserts.  Thurau agrees that the major limitations are practical in nature and can typically be overcome. He does, however, note that there are some open questions on the definitions and differences in the applicability of the concept by various health authorities. “As registrations for products developed and manufactured using the QbD approach become more detailed and explicit about criticality, the hope is that the increased knowledge will lead to more flexible approaches to change management (do and tell) as opposed to the current set approach (tell and do).

Both Nadig and TePaske point to the need for participation of knowledgeable team members from across different functions of the organization as a challenging aspect of QbD and the establishment of effective CQAs and CPPs. “The multidisciplinary approach requires up-front involvement of disciplines whose primary job responsibility has historically been manufacturing and requires a new way of thinking,” says TePaske. He also adds that the risk-assessment approach often focuses on what can be done, which can stifle innovation.


Despites these barriers and limitations, many companies have recognized the value of a QbD approach and the importance of linking critical process parameters for individual process steps with the critical quality attributes of small-molecule APIs and the corresponding formulated drug products. Boehringer Ingelheim, for example, is monitoring process robustness at each development stage and focusing on understanding how this robustness translates to the commercial scale using batch histories, according to Senanayake. In addition, the company is trying to complete DOEs on the important steps in its manufacturing processes. “Our success to date is demonstrated by our validation efforts and the control charts we have established for individual steps,” he says.

At Dr. Reddy’s CPS, when defining CPPs for each process step, a cross-functional team meets to discuss the key sensitivities of the process parameters and material attributes, which are first weighted in importance, and then tolerances on the variables are established, according to Nadig. DOE screening is then performed to identify the critical parameters, followed by optimization and definition of the design space to understand what will happen to the CQAs under different parameter settings. “Importantly, we are trying to engage senior members from cross-functional teams during these pre-planning meetings so that an exhaustive risk assessment is conceptualized and a mitigation plan worked out,” he comments. The company also emphasizes the importance of clear communications, participation with the customer, and giving weight to all stakeholder concerns throughout the process.


The consequences of not establishing CPPs that are effectively linked to CQAs can be severe. “If the proper controls for an intermediate step in the manufacturing process are not in place, then it is possible for a material to be produced that does not meet specifications for unknown reasons. Such a situation can in turn result in a recall if the intermediate is carried through the entire commercial process. In addition, without proper controls, processes often deliver poor quality product or product of inconsistent quality,” asserts Senanayake. In addition, according to Thurau, if inappropriate process parameters or in-process material attributes are established, the quality of the final product may appear high, but it is the result of testing quality into it, and not of process design and process understanding. Finally, TePaske stresses that operation in a state of control is fundamental to process validation and continued process performance in a validated state. 

With a quality-by-design approach, robust processes can help deliver quality product consistently.

QbD Facilitates Robust API Development

Although significant attention has recently been directed towards biocatalysis as the way forward for commercial-scale asymmetric synthesis, chiral transformations mediated by traditional metal-based and organic catalysts remain important for the manufacture of pharmaceutical intermediates and APIs. In addition, much effort continues to be invested in the development of novel enantioselective methods for the synthesis of building blocks necessary for the manufacture of biologically active molecules. A brief survey of recent literature underscores the breadth of chiral chemocatalysis and interesting new techniques for the selective preparation of asymmetric compounds. Selected examples are highlighted in the following.


Many natural and non-natural amino acids and derivatives contain both nitrogen and sulfur substituents, thus the synthetic methods for the enantiomeric synthesis of building blocks containing these two elements are of significant interest. Scott Denmark and Hyung Min Chi reported an enantioselective route to chiral pyrrolidines, piperidines, and azepanes bearing thiol substituents (1). In their method, terminal and trans disubstituted alkenes with a pendant tosyl-protected amine group are converted to the desired products through the formation of a thiiranium intermediate via Lewis base-catalyzed intramolecular sulfenoamination using a chiral BINAM (1,1’-binaphthyl-2,2’-diamine)-based selenophosphoramide catalyst.

Tsuyoshi Mita and Yoshhihiro Sato at Hokkaido University in Japan reported the asymmetric synthesis of α-amino acids via the stereopsecific carboxylation of optically active α-amino silanes, which were obtained through the enantioselective silylation of N-tert-butylsulfonylimines using a Cu-secondary diamine complex (2). The carboxylation proceeded under 1 atmosphere of CO

. Spirocyclic oxindolo-β-lactams were prepared in high yields with excellent diastereo- and enantioselectivities by Song Ye at the Chinese Academy of Sciences (3). In this case, ketenes were subjected to an N-heterocyclic carbene (NHC)-catalyzed Staudinger reaction with isatin-derived ketimines using NHCs with free hydroxyl groups as the catalyst.


  Chiral fluorinated compounds are also of interest, because incorporation of the highly electronegative fluorine atom can have an impact on the physico-chemical properties of APIs. Gregory Fu and colleagues at the California Institute of Technology tackled the challenge of preparing chiral tertiary alkyl fluorides, and particularly α-fluorocarbonyl compounds (4). They reported a method for the asymmetric synthesis of tertiary α-fluoroesters via the catalytic asymmetric coupling of aryl alkyl ketenes with commercially available N-fluorodibenzenesulfonimide and C

ONa as a nucleophile using a chiral ferrocenyl PPY (4-pyrrolidinopyridine) catalyst. The alkoxide was crucial for freeing the catalyst from an acylated intermediate. Meanwhile, Qing-Yun Chen and Yong Guo at the Chinese Academy of Sciences reported the asymmetric synthesis of tertiary α-fluoro ketones via the Tsuji-Trost reaction of racemic acyclic α-fluorinated ketones using a palladium/phosphinooxazoline catalyst (5). The desired products were obtained in up to 90% yield with up to 90% enantiomeric excess (ee). 
  
  The preparation of chiral compounds with trifluoralkyl groups is also important for drug development. Liang Hong and Rui Wang at Lanzhou University in China developed a practical method for the enantioselective introduction of a monofluoroalkyl group into the oxindole framework (6). The reaction of a wide range of 3-bromooxindoles and α-fluorinated β-keto gem-diols afforded the desired products with diastereoselectivities of >20:1 and enantioselectivities of 93-99%. Xufeng Lin and colleagues at Zhejiang University reported the first highly enantioselective iso-Pictet-Spengler reaction of C-2-linked 

-aminobenzylindoles with trifluoromethyl ketones (7). The reaction is mediated by chiral spirocyclic phosphoric acids as organocatalysts, and the benzazepinoindoles bearing trifluoromethylated quaternary stereocenters were obtained in up to 98% yield and up to >99.5% ee.


  Asymmetric hydrogenation is one of the most widely used enantioselective chemocatalytic reactions used at commercial scale. Even so, advances in this technology, including its application to a widening range of substrates, continue. A recent example was reported by Xumu Zhang at Wuhan University in China (8). His group developed a Rh-DuanPhos ((1

-(1,1′)biisophosphindolyl) complex for the synthesis of chiral cyclic allylic amines with up to 99% ee from cyclic dienamides. The products are ideal building blocks for the preparation of chiral, cyclohexane derivatives with multiple substituents. Meanwhile, Virginie Ratovelomanana-Vidal at PSL Research University and Zhaoguo Zhang at Shanghai Jiao Tong University reported the enantioselective synthesis of γ-hydroxy amides with up to 99% ee via the asymmetric hydrogenation of γ-ketoamides in the presence of a Ru-Xyl-SunPhos-Daipen catalyst (9).


  Functionalization of chiral intermediates can also be achieved via asymmetric C-H insertion reactions. In 2013, the H.M.L. Davies group at Emory University reported the enantioselective synthesis of highly functionalized 2,3-dihydrobenzofurans from derivatives of veratrol and anisole via two sequential enantioselective C-H insertions involving an intermolecular carbene insertion catalyzed by rhodium followed by an intramolecular C-H alkoxylation reaction catalyzed by palladium (10). The products could also be further functionalized via a palladium-catalyzed intermolecular Heck-type sp2 C-H functionalization reaction.


Carbon-carbon (C-C) coupling reactions have become key tools in the synthesis of pharmaceutical  and other fine chemical intermediates, and chiral C-C coupling reactions are highly valued. Several new methods have been reported recently, including the diastereo- and enantioselective coupling of alcohols and vinyl epoxides to form asymmetric quaternary carbon centers, which was developed by Michael J. Krische at the University of Texas at Austin (11). In this iridium-catalyzed reaction, primary alcohol oxidation leads to reductive C-O bond cleavage in isoprene oxide to generate aldehyde-allyliridium pairs that combine to form products of tert-(hydroxy)-prenylation, many of which are observed in terpenoid-type natural products. Notably, the reaction proceeds without the use of premetalated reagents or unwanted stoichiometric byproducts.

Meanwhile, Brian M. Stoltz at the California Institute of Technology prepared (trimethylsilyl)ethyl ester protected enolates via fluoride-induced “thermodynamic” enolate formation and used them in palladium-catalyzed asymmetric allylic alkylation reactions to obtain α-quaternary six- and seven-membered ketones and lactams (12). The reaction expands the scope of allyl substrates beyond traditional β-ketoesters and has a high tolerance for reactive functionality.

Two rhodium-catalyzed enantioselective C-C coupling reactions were also recently reported. Vy M. Dong at the University of California, Irvine reported the enantioselective cross-coupling of aldehydes and α-ketoamides via intermolecular hydroacylation to provide α-acyloxyamides using a new Josiphos ligand (13). Separately, Chen-Guo Feng and Guo-Qiang Lin developed the enantioselective rhodium-catalyzed 1,2-addition of arylboronates to cyclic N-sulfamidate alkylketimines, which provides chiral sulfamidates that can be readily reduced to chiral β-alkyl-β-aryl amino alcohols (14).

Finally, Amir Hovedya at Boston College reported the copper/NHC-catalyzed enantioselective allylic substitution of di- and trisubstituted alkenes with readily accessible (pinacolato)alkenylboron compounds to generate 1,4-dienes bearing an asymmetric tertiary carbon (15). The reaction tolerates a wide range of olefins and provides the desired products in up to >98% yield with >98:2 selectivity for the SN2′ vs. SN2 addition and a 99:1 enantiomeric ratio (er). The group also demonstrated the applicability of the reaction in the synthesis of several natural products.


  Multicomponent reactions are attractive because they often enable the synthesis of complex intermediates in an atom-economical manner from basic starting materials. These reactions are even of more interest when they proceed with high stereo- and regioselectivity. At the Universidad de Oviedo in Spain, Francisco J. Fañanás and Félix Rodríguez developed a one-pot, gold phosphate-catalyzed, three-component coupling reaction of alkynols, anilines, and glyoxylic acid that generates sprioacetals with incorporated α-amino acid functionality (16).


  Cascade reactions, like multicomponet reactions, are attractive because they provide direct access to complex structures in one pot with few or no undesirable byproducts. Adrien Quintard and Jean Rodriquez of Aix Marseille Université developed a cascade reaction involving the enantioselective reaction of allylic alcohols with diketones catalyzed by an iron catalyst with iminium activation followed by chemoselective acyl transfer (17). The γ-chiral alcohol products (3-alkylpentanols) are obtained in up to 96% yield with a 96:4 er and are useful for natural products synthesis.

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A literature survey underscores the breadth of chiral chemocatalysis and interesting new techniques for the selective preparation of asymmetric compounds.

New Techniques Advance Asymmetric Synthesis

A survey of the recent literature reveals numerous advances in asymmetric chemocatalysis.

Asymmetric Synthesis Continues to Advance

With a quality-by-design approach, robust processes consistently can help deliver quality product.