			As China emerges as a significant supplier of pharmaceutical ingredients, it must assure other countries of the safety of its excipients. China's State Food and Drug Administration (SFDA) intends to revise its excipient-control regulations to protect consumers at home and abroad. The agency has begun to meet with international trade organizations such as the International Pharmaceutical Excipients Council (IPEC) to hear industry's concerns. The author describes the contacts between SFDA, IPEC, and other international bodies. The article explains what SFDA has learned and how it may adjust its regulations for the future.			

As China's role in the global pharmaceutical market increases, the Chinese State Food and Drug Adminstration (SFDA) and many China-based pharmaceutical manufacturers and excipient producers are beginning to collaborate with their international counterparts on excipient-control issues. Compliance with appropriate good manufacturing practices (GMPs) throughout the entire excipient distribution supply chain and an understanding of international regulatory and pharmacopeial excipient controls are critical components for ensuring that pharmaceutical excipients are safe and of acceptable quality. The recent tragedies related to contaminated glycerin and other products sourced from China underscore the need for safe excipients. 

China's proposed new license requirements for the manufacture and use of excipients

During the last two years, several regulatory developments related to the manufacture, importation, and use of excipient ingredients in China have taken place. In the past, China has required certain types of licenses for the manufacture and use of excipients in the country. Recent proposed changes to the registration requirements, however, could significantly affect the future availability of excipients produced in China for the country's domestic market and for export. 

SFDA issued new Drug Excipients Registration Application Materials requirements on June 21, 2005. The regulation covered various excipient-registration requirements, including those for imported excipients. In December 2005, SFDA revised these requirements and proposed a new set of regulations to control excipients used in products marketed in China. The regulations would establish new GMP and manufacturing rules for excipients produced in China and new requirements for obtaining an import license for pharmaceutical excipient ingredients that are produced outside of China. 

To obtain an import license under these proposed regulations, excipient manufacturers would be required to provide additional detailed information concerning the manufacture of their pharmaceutical ingredients and specific additional data to substantiate the excipient's safety for its intended use. The regulations would apply to new excipients and commonly used compendial excipients that have been used for years in China. The level of data and information that the proposed regulations would require significantly exceeds what has been previously required in China. The requirements also exceed the amount of information generally required in other major market countries, especially for compendial excipients. The proposed regulation would require the pharmaceutical manufacturer to obtain a copy of the license for each excipient in its formulation from each of its excipient suppliers to support the use of these excipients in drug products made in China. 

Proposed regulations for excipients that are produced domestically in China are similar to those for excipients that are imported into China from foreign manufacturers. Domestic excipient manufacturers must meet a higher quality and GMP standard than China has typically required in the past, and they must supply more information to SFDA about their products and processes. In addition to the current requirement of being registered with SFDA, excipient manufacturers would also be routinely inspected for GMP compliance. The regulations as applied to domestic Chinese excipient manufacturers will significantly affect these domestic excipients' availability and cost. Additionally, the proposed import license requirements would potentially increase costs significantly for all multinational excipient companies who intend to supply their excipients to China. The requirements could cause some companies to stop supplying the Chinese market because of cost and intellectual-property concerns. 

The licensing requirements for imported excipients are somewhat different from those for domestic Chinese manufacturers and contain many criteria that are especially difficult for many excipient manufacturers to meet (see sidebar, "SFDA's proposed requirements for obtaining an import license"). 

SFDA proposed requirements for obtaining an import license			

In the past, excipients used in China were regulated in the same manner as drugs or active pharmaceutical ingredients (APIs). The domestic implementation of licensing requirements was somewhat inconsistent for excipients, however. SFDA proposes to separate the regulation of excipients to facilitate improved control of quality for both domestic and imported excipients. The goals of their proposed excipient regulations are to improve the quality of excipients, minimize safety risks, and to align SFDA regulations with international standards. In developing the excipient regulations, SFDA has proposed to use the basic principles of its drug regulations as a foundation for excipient regulation. The proposed regulations, however, do not recognize the significant differences between excipients, APIs, and drug products in terms of typical international regulatory requirements. 

The International Pharmaceutical Excipients Council of the Americas (IPEC-Americas), a trade association of manufacturers of excipients and drug products, has led an industry coalition representing excipient producers and users that works with SFDA to clarify the requirements for obtaining a Chinese import license and to assist SFDA in achieving its goal of improved excipient quality and safety. IPEC-Americas representatives have attended meetings with SFDA to discuss the differences between excipient regulations in the US, Europe, and Japan and the proposed excipient regulations in China. A coalition coordinated by the International Pharmaceutical Excipients Council (IPEC) has requested several changes to the proposed regulations to achieve better harmonization with international standards and requirements. The IPEC Coalition includes IPEC Americas, IPEC Europe, and the Japanese Pharmaceutical Excipients Council (JPEC). 

The IPEC Coalition, in collaboration with the US Department of Commerce, presented the industry's concerns to SFDA at a meeting of the Joint Commission on Commerce and Trade (JCCT) in March 2006. This discussion, along with several follow-up meetings in April 2006, resulted in a fairly favorable first step toward improved excipient regulation. The IPEC Coalition and other participants provided SFDA with information about the regulation of excipients in the US, Europe, and Japan and identified problem areas in SFDA's proposed regulations that would significantly affect both excipient manufacturers seeking import licenses and pharmaceutical companies who would use these materials in China.  

SFDA informed the participants that, unlike in most developed countries where pharmaceutical manufacturers essentially regulate their use of excipients with limited regulatory agency oversight, China's government must be responsible for excipient quality. SFDA believes that many Chinese pharmaceutical manufacturers do not have good systems in place to properly qualify excipient suppliers and control excipient quality. SFDA believes that the government must step in to provide adequate protection to Chinese consumers. Accomplishing this goal may require some type of excipient licensing system, according to the agency. 

On the other hand, SFDA wants to draft regulations based on appropriate international standards and does not want to impose unrealistic regulations on imported excipients. The agency expects to be able to review the same type of information used to establish excipient quality and safety that is required by international regulatory authorities during the drug-registration process. Since most regulators outside China do not require significant detailed information to be submitted for compendial excipients, SFDA may relax its proposed license requirements for these types of materials. 

SFDA and the Coaltion agreed that detailed safety and manufacturing information should be required for the licensing of new excipients and that the regulations should reflect the different needs for evaluating compendial excipients versus new excipients. 

SFDA stated that it will study the excipient GMPs and other guidelines provided by the IPEC Coalition to further revise its excipient regulations. SFDA expressed a desire to learn from other countries' success and to use that experience to develop excipient regulations for China. SFDA also noted that although the new excipient regulations have been proposed, no firm implementation date had been set, and that it was unlikely that they will be finalized until 2008. SFDA will use the time to carefully review and assess the documents supplied to them, as well as the various presentations made during its meetings with IPEC Coalition representatives. 

One outcome of the 2006 meetings was the recognition of the need to hold an excipient conference in China to discuss how excipients are regulated globally. Such a conference would facilitate SFDA's collaboration with industry for a mutually beneficial resolution of the licensing requirements. In 2007, the IPEC Coalition has continued to help SFDA develop excipient regulations that are science-based and achievable without causing undue regulatory burden that may result in some excipient manufacturers exiting the marketplace. 

IPEC–CCPIE excipient-control strategies conference

More than 150 people participated in an International Excipient Control Strategies Conference in Beijing on March 13–14, 2007. The conference was organized by the China Center for Pharmaceutical International Exchange (CCPIE), IPEC Americas, IPEC Europe, and the Japanese Pharmaceutical Excipient Council (JPEC), with help from the Research and Development-Based Pharmaceutical Association Committee (RDPAC) in China. The meeting attracted at least 30 SFDA division directors and other agency personnel, plus many Chinese and international excipient and finished-drug manufacturers. 

The conference was designed to provide the pharmaceutical and excipient industry, SFDA, and several major pharmacopeias an opportunity to interact on topics related to the control of excipients used in pharmaceutical products marketed in China and the rest of the world (see sidebar, "Goals of the International Excipient Control Strategies Conference"). 

Goals of the International Excipient Control Strategies Conference			

Speakers at the conference included Zhang Wei, director of SFDA's Department of Drug Registration; Wang Ping, deputy general secretary of the Chinese Pharmacopeia; Dr. Agnes Artiges, director of the European Pharmacopoeia; Dr. Kiyomi Ueno, director of the Japanese Pharmacopeia's standards division; Dr. Roger Williams, chief executive officer of the US Pharmacopeia (USP); and Dr. Catherine Sheehan, USP's director of excipients. Several industry speakers from IPEC member companies described how pharmaceutical excipients are evaluated for safety and controlled for quality throughout Europe, Japan, and the US. Song Ming Xian, director of the regulatory division of the Sichuan Provincial Food and Drug Division, summarized current SFDA excipient GMP regulations and described the need for a Chinese industry association dedicated to improving excipient quality. 

Zhang Wei, director general of SFDA's registration department, gave the opening speech, which provided interesting information about what direction SFDA may take when it revises the draft excipient regulations. He provided his vision of how SFDA might regulate excipients in the future. 

In his speech, Wei addressed many of the issues that the IPEC Coalition had raised regarding SFDA's draft regulation, and he indicated that more flexibility is warranted. Wei recommended that the licensing requirements for the most common compendial excipients could potentially be eliminated and that a DMF-type system be established for premixed and coprocessed excipients. He stressed, however, that a detailed licensing system would need to be set up to control excipients intended for injections because of the high level of risks associated with these materials. 

SFDA's concepts regarding this regulation have changed significantly since the agency proposed its original draft. At that time, it appeared that the agency would publish a regulation that would create great difficulties for industry without benefiting consumers. The ongoing dialogue between the IPEC Coalition and SFDA seems to have influenced the debate over the regulations in a positive way. 

All the speakers described how excipients are controlled from various perspectives in each major market region. The excipient conference provided a valuable overview of global excipient regulations. 

After the conference, Wei reported that the expected redraft of SFDA's excipient regulations in China would be postponed until 2008 and that some changes might be based on comments made to the agency. 

IPEC discussed the formation of an industry-based excipient working group in China, which is currently being explored. IPEC proposes to organize an excipients organization in China that would be similar to other IPEC groups. Each group originally formed after a major excipients conference at which it became obvious that such a group would benefit the industry, pharmacopeias, regulatory agencies, and consumers. IPEC hopes to form an excipients working group in China in late 2007 and has continued working with SFDA since the March 2007 conference on excipient controls. 

IPEC Americas worked with the US Department of Commerce to enable SFDA to visit two excipient-manufacturing facilities and one API-manufacturing facility. SDFA representatives conducted visits during their trip to the Annual JCCT meeting in Washington, DC, on April 9–12, 2007. SFDA wanted to tour excipient and API facilities to see how US manufacturing facilities for excipients and APIs meet GMPs. The agency also wanted to understand how manufacturing processes for these materials are controlled in the US. 

The seven-person SFDA delegation and its hosts from the US Department of Commerce toured three US ingredient-production facilities at the invitation of IPEC-Americas members. On April 9, the group toured Colorcon's "Opadry" manufacturing facility in West Point, Pennsylvania, and saw FMC's "Avicel" manufacturing facility in Newark, Delaware. On the next day, the group visited Johnson & Johnson's Wilmington, Delaware, plant, which produces APIs for the company's finished drugs (see sidebar, "Officials visit drug-manufacturing facilities"). 

Officials visit drug-manufacturing facilities			

These productive visits helped establish a good working dialogue between SFDA, the Department of Commerce, and the US pharmaceutical and excipients industry. The SFDA representatives were impressed with the level of GMP controls in place at the abovementioned companies. They planned to use the information they gained to modify the excipient and API control strategies they will implement in China. 

Recent events affect SFDA's improvement plans

Since the April meetings, several international events have highlighted concerns about the quality and safety of excipients and other food ingredients and products sourced from China. More than 100 people died in Panama after taking drugs that were contaminated with Chinese-produced glycerin that was adulterated with diethylene glycol, a poisonous chemical used primarily to manufacture antifreeze. Chinese-produced toothpaste that contained diethylene glycol was found in various US locations. Many pets in the US died from Chinese-sourced pet food ingredients that had been contaminated with melamine. Various other quality problems involving Chinese products have surfaced and received much media coverage. In addition, several high-profile corruption charges have been made against former SFDA officials. Some charges resulted in the imposition of the death penalty. 

These events have put tremendous pressure on the Chinese government and SFDA to immediately eliminate corruption and strengthen regulatory controls of the manufacture of food and drug products, including excipients and food additives. SFDA has taken several measures to exercise oversight, but the magnitude of the problems will require much of the agency's resources in the coming months. It is uncertain how these problems will affect the timing of SFDA's planned revisions to its excipient regulations and SFDA's desire for flexibility in harmonizing regulations with international agencies. 

IPEC will continue to work closely with SFDA to help the agency improve its excipient-control systems and establish a sound approach to maintaining excipient safety and quality for products produced in China for the domestic and international markets. 

SFDA has invited IPEC to participate in an upcoming SFDA internal training program in October 2007. IPEC will provide training to SFDA inspectors and reviewers regarding international excipient-control strategies, excipient GMPs, and DMF systems. IPEC will provide a full-day seminar for SFDA personnel on Oct. 29, 2007. 

IPEC hopes to announce the formation of an IPEC Excipient Working Group in China at the SFDA training session. The working group would act as a focal point for collaboration on excipient issues between SFDA and the domestic and international excipient and pharmaceutical industries. 

IPEC Americas is also helping the US Food and Drug Administration establish improved excipient-control systems for the importation of excipients from China and other countries. FDA formed a task force in response to the recent tragic events and is trying to determine the best approach to prevent these tragedies from occurring again. FDA asked IPEC Americas for assistance because IPEC has drafted many excipient-control guidelines such as the 

IPEC–Pharmaceutical Quality Group Excipient GMP and Auditing Guidelines,

IPEC Good Distribution Practices Guideline,

IPEC Americas Certificate of Analysis Guideline,

IPEC Americas Significant Change Guideline for Bulk Pharmaceutical Excipients.

IPEC Americas' latest effort is the development of an 

Overall Excipient Qualification Guideline

 that outlines a process for qualifying the entire excipient supply chain from the manufacturer to the user. This guideline reflects the international concern about excipient safety. IPEC Americas plans to launch the first phase of this guideline at its Regulatory Affairs Conference on Sept. 10–11, 2007. 

The ongoing collaboration of industry groups such as IPEC with SFDA and FDA will effectively provide appropriate excipient controls that benefit the consumer by improving drug safety and quality. This collaboration and dialogue will also ensure that new regulatory requirements are reasonable and do not create non-value-added costs in the system that would unnecessarily increase drug prices without providing any further improvements in safety to the consumer. 

 is chairman of the International Pharmaceutical Excipients Council of the Americas. He also is director of global regulatory affairs at Colorcon, 1936 West Point Pike, West Point, PA 19486, tel. 215.699.7733, 

Articles

As China emerges as a significant supplier of pharmaceutical ingredients, it must assure other countries of the safety of its excipients.

Excipient Control Strategies in China

	Screening and detecting polymorphism when developing and manufacturing active pharmaceutical ingredients (APIs) is an ongoing challenge for pharmaceutical manufacturers. 

 is the ability of a compound to exist in more than one crystalline structure. Different solid forms can possess different properties, including solubility, which can in turn affect the bioavailability of the drug.  

"The investigation of polymorphic forms of a drug substance is valuable to the pharmaceutical industry, as the differences in the physical properties of different solid forms can be problematic in the later stages of development and formulation," says Chris Frampton, chief scientific officer at

(Cambridge, UK). "Different solid forms can show differences in properties such as aqueous thermodynamic solubility, melting point and hygroscopicity, which in turn can affect bioavailability, processability, and stability, respectively."

One of the more well-chronicled examples of polymorphism occurred in ritonavir, the API in  "Norvir," a protease inhibitor developed by A

 (Abbott Park, IL). The drug was approved in 1996, and in mid-1998, Abbott encountered manufacturing difficulties with the capsule formulation, according to the company's 1998 annual report. Ritonavir  exhibited conformational polymorphism of two unique crystal lattices that had  significantly different solubility properties (1). The formation of the polymorph caused Abbott to pull the drug from the market and reformulate.  

A recent analysis by SSCI, the solid-state chemistry business of 

(Greenwich, CT), showed that of 245 compounds it has screened, 89% had multiple solid forms (see Figure 1). Approximately 50% of the compounds showed polymorphism, 37% were hydrates, and 31 were solvates, outlines Stephen Byrn, head of the scientific advisory board of Aptuit and head of the Department of Industrial and Physical Pharmacy at Purdue University.  

Other research conducted by Professor Ulrich Griesser at the University of Innsbruck shows a lower incidence of multiple solid forms in organic molecules: polymorphism (36%), hydrates (28%), and solvates (10%) (2).  

"The difference in prevalence of 51% versus 36% probably reflects the fact that many organic chemists do not search for polymorphs when preparing new compounds," explains Byrn. "In contrast, compounds submitted to SSCI/Aptuit are drug candidates. Another factor that may explain the differences in prevalence of polymorphs is the fact that SSCI/Aptuit would tend to get problem compounds, including materials that have a large numbers of polymorphs." 

A review of several APIs and new chemical entities (NCEs) shows not only the prevalence of other solid forms but also  the challenges in detecting these forms.  

 The polymorphism of acetaminophen shows the challenges in screening for polymorphs (see Figure 2). 

"The crystal structures for two known crystal forms of acetaminophen (monoclinic and orthorhombic) have been published," explains Frampton (3, 4). "The monoclinic form is the thermodynamically stable crystal form at room temperature with respect to the orthorhombic form. Evidence for a third, metastable, form has been published (5, 6). To date,  however, it has not been possible to isolate any crystalline material to enable a full crystal structure or physicochemical property determination."  

The problem with acetaminophen was the repeated failures of research groups  to isolate the orthorhombic form using the method of slow evaporation from ethanol as described by Haisa 

. (3), explains Frampton. Eventually, it was discovered that the orthorhombic form could be produced from solution by using seeds of the orthorhombic modification that were isolated from melt-crystallized acetaminophen (7). 

"It is clear that in this case, conventional solvent-screening techniques of the time would fail to produce any evidence of the less-stable orthorhombic form since it was only possible to produce seeds of the orthorhombic form under somewhat extreme conditions," says Frampton. "Given that the crystal structures of the two modifications were available, it was reasonably straightforward to identify the pure forms from their X-ray powder diffraction (XRPD) patterns (see Figures 3a and 3b). The form assignment from XRPD was subsequently confirmed by single-crystal X-ray analysis. 

 Sodium diclofenac (see Figure 4) is a nonsteroidal anti-inflammatory drug that shows polymorphism. The sodium salt of the drug is manufactured by Novartis as "Voltaren." Frampton says there are three known anhydrous crystal modifications of the free base: two monoclinic forms (

"Sodium diclofenac has also been shown to readily form stable hydrate phases when crystallized from aqueous miscible solvents," explains Frampton (11). "Although these hydrated materials are not technically polymorphic phases since they are solvates, they do present interesting solid-form challenges."

He explains that the current literature reports a sodium diclofenac pentahydrate  phase that was derived from the results of a single crystal X-ray diffraction study (11). The pentahydrate phase was based on the crystalline asymmetric unit of the structural model containing two molecules of sodium diclofenac and 10 molecules of water in the monoclinic space group P2

/m. The results of the structural investigation, however, showed that the solved structure had a disordered sodium-water linkage and a high overall crystallographic 

A decision framework  for on polymorphism for generic drug applications 

"We were prompted to reinterpret the single-crystal X-ray data after repeated thermogravimetric analysis (TGA) and Karl Fischer (KF) measurements indicated that the water content was reproducibly always slightly less (e.g., 21.48% and 21.0% from TGA and KF, respectively) than the theoretical content of 22.07% based a fully hydrated pentahydrate structure," says Frampton. These values equate to 4.83 and 4.69 moles of water respectively. Figure 5 shows an example TGA. 

"Redetermination of the single-crystal X-ray structure reveals that the structure contains only a pseudomirror plane, and as such, the true space group of the structure is 

/m. The asymmetric unit of the structure now contains four molecules of sodium diclofenac and 19 molecules of water, yielding an overall stoichiometry of a 4.75 hydrate," says Frampton. 

All the atoms in the crystalline asymmetric unit are now fully ordered, and all hydrogen atoms, including those on the 19 water molecules, were located in the Fourier difference maps and were included within the refinement. The theoretical water content for a fully hydrated 4.75 hydrate is 21.19%, which is in accord with the other analytical data, Frampton explains. The structure now has a much-improved crystallographic 

"It is important to stress in this case that the correct result was only obtained after the consideration of all the analytical data and that we should not be surprised by the noninteger value of the water content," he says. A further hydrated species, a triclinic 3.50 hydrate, was also identified in the study.  

. (Monza, Italy) for certain respiratory disorders, shows the challenge in polymorph screening and the potential opportunities for discovering and patenting a polymorph.  

Andolast is administered as a dry powder for inhalation. "When a product is used in the form of micronized powder for the treatment of respiratory tract disease, the particle-size distribution (PSD) of the inhaled drug is crucial to its performance," explains Markus von Raumer, product manager of the solid-state development unit at 

 (Basel, Switzerland). "Physical chemical characteristics play a fundamental role in the case of inhaled drugs not only for the solubility issues shared with oral drugs but also due to the aggregation phenomena, which can impact negatively the performance of the powder, ultimately affecting its pharmacological activity," he says (12).  

During the early pharmaceutical development of andolast, deviations in the consistency of the API's physical chemical characteristics were observed, and a review of the solid-state issues was required, explains von Raumer. These deviations related to: batch-to-batch PSD variability (which affected released fraction and therefore drug efficacy); batch-to-batch variability in hygroscopicity (which affected released fraction and hence manufacturability); and batch-to-batch variability in chemical–physical characteristics that reflected in flow and blend properties (which affected manufacturability and therefore product cost).  

Analysis of the complete batch history, combined with fresh physicochemical analysis of key samples, revealed several issues. Deviations occurred independently upon the supplier, upon the batch scale, and upon the batch purity. For all batches, the same chemistry and the same isolation procedure was used.  

"Sequential to compilation of historic data, the crystallization conditions and a crystallization process investigation was carried out," says von Raumer. The screening was based upon product precipitation from several water-miscible solvents changing concentration, water content, and temperature. Phase-equilibration experiments were carried out as well. In these experiments, material from the previous batches was slurried in different solvents, at different water concentrations, different temperatures, and for different times. Crystallization from different media gave different solids, in terms of XRPD, Fourier transform (FT)-Raman spectra, and hygroscopicity.  

Crystallization in thermodynamic conditions, however, afforded the same product when a proper amount of water was present, points out von Raumer. This product was not hygroscopic, was stable, and its water content determined by KF was about 20%. Crystallization under kinetic conditions, especially when the water activity in the medium was poor, afforded a hygroscopic product with KF lower than 20%. This product was not stable and converted under appropriate conditions into a stable product with KF of approximately 20% and XRPD and Raman results identical with the precipitated product. All the products obtained from crystallization trials that gave KF around 20% displayed the same XRPD spectrum. 

"According to the above experiments, it was proven that andolast disodium crystallized in only one preferred hydrated form: the penthaydrate. All other hydrated forms were not stable and converted under appropriate conditions into the pentahydrate," notes von Raumer. "The single-crystal structure was resolved, and molecular-mechanics simulation showed that, upon water removal, a certain degree of distortion was introduced within the crystal structure, with the distortion being proportional to the number of water molecules removed."  

From this solid-state study, a new crystalline form, andolast pentahydrate, was revealed, which displayed certain superior properties, says von Raumer. Andolast pentahydrate is not a hygroscopic solid, is stable to mechanical milling, and is stable to as much as 85% relative humidity. It also can consistently be prepared according to a standard process, has constant mechanical properties such as flowability, and has advantages in formulation in comparison with previous material because of a better performance in delivered dose, fine particles delivered, and fine-particle fraction. Aside from improved performance, the new crystalline form of andolast also led to patent applications in the United States  and Europe (13, 14). The European patent application calls for an expiration date of 2026 compared with the original expiration date of 2010 that is specified in an earlier patent (15).   

"While the development of the andolast drug product was hampered due to inconsistencies and was slowed down by a non-negligible factor, the actual situation allows for a rapid continuation with a possibly much longer time horizon of exclusivity," says von Raumer. "This situation once again demonstrates the utility and opportunities that are created by carefully investigating the solid-state aspects of drug candidates." 

XRPD is the most common analytical method used in polymorph screening, although certain researchers use Raman spectroscopy as their primary screening method. "Each method has its value, and more recently SAFC-Pharmorphix has been experimenting on the use of both methods in combination for polymorph and cocrystal screening using a combined X-ray powder diffractometer with a Raman attachment," says Frampton.  "This instrument has been developed in collaboration with Bruker AXS, and a patent covering this technology has recently been published (16). This technology has been further enhanced by a new release of the clustering program, Polysnap2, which can cluster any two-dimensional data and produce weighted combinations." SAFC-Pharmorphix has an active collaboration with Professor Chris Gilmore and his group at the University of Glasgow (Glasgow, UK).   

In a typical study, a crystallographer places a compound in a range of solvents and subjects them to a range of crystallization conditions in hopes of obtaining single crystals, Aptuit's Byrn explains. He points out that the number of solvents used in the screening varies. A small polymorph screen should include 8–10 solvents (17). "A more complete screen would require more than 50 solvents," he adds. In recent research, Xu and Redman-Furey outlined an approach to narrow their selection of 57 solvents to 20 (18). Byrn points out that in a related study, Miller suggested an approach of finding the most stable polymorphs by slurring compounds in a variety of solvents (19). 

"We now know that solvent-based crystallizations alone do not find all of the forms. In several cases, solvent-based polymorph screens have missed very important solid forms," explains Byrn. In another example, Yu discovered the second most stable form of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile  (ROY) using a melt-recrystallization technique (20). "It is well established that ROY had previously been screened by all of the best-known high-throughput techniques, and this form had not been found," explains Byrn, adding, solvent-free techniques such as drying, sublimation, and amorphous crystallization can produce new forms not discovered by solvent-based crystallization.  

Byrn offers several examples of techniques used to find polymorphs. In a study at Aptuit/SSCI, nabumetone was recrystallized from a wide range of solvents under different conditions. About 250 experiments were performed, yielding Form I. When nabumetone was recrystallized in capillaries, a procedure known to produce very high supersaturations, a new form was discovered in about 70 of 400 crystallizations. Analysis of these crystallization conditions shows that the appearance of the new form depends on superaturation and quiescence and not on solvent content, Bryn explains.   

In another study, SSCI/Aptuit compared the polymorphs formed in a common high-throughput technology with those from capillaries and traditional crystallizations under a broad range of conditions. "It was clear that the plate crystallization technology, which is commonly used in high-throughput polymorph screens, tends to overproduce one form relative to other methods," says Byrn.  

Although XRPD is the most common technique used in the overall solid-state characterization of pharmaceutical materials, other techniques are needed to understand the form, determine how it behaves under stress conditions, discern the relationship between forms, and decide which form is suitable for development.  

"The powder pattern will tell you if it is crystalline but will not provide critical information such as solvation state, melting point, water uptake, solubility, and physical stability, for example," explains Byrn. "Thermal data such as differential scanning calorimetry, thermogravimetry, and hot-stage microscopy are used to determine melting temperature, solvation state, desolvation, and form changes upon drying. This information can be directly related to processing such as drying." 

Gravimetric vapor sorption is used to measure water sorption and desorption, which can lead to environmental handling guidelines to prevent hydrate formation or dehydration upon exposure to various relative humidity conditions. Other methods such as infrared, Raman, and nuclear magnetic resonance (NMR) spectroscopies can often show specificity between forms that may be more difficult to see with XRPD.  

"These techniques, along with XRPD and others, are commonly used for quantitative solid-state method development to quantitate the amount of different forms present in API or drug product or confirm that only one form is present. It is usually desired to have only one form produced, but processing such as drying, milling, and granulation, can commonly lead to multiple forms, indicating that an understanding of form changes during the process and better control of the process is needed,"explains Byrn. 

He points to recent advances in screening methodology using Raman microscopy to determine the presence of multiple forms in the same crystallization vessel. "Additionally, NIR is finding some use as a tool for differentiating polymorphs during screening. Finally, the developments of X-ray microscopy at Argonne National Laboratories [Argonne, IL] and other synchrotron sources promises to increase our ability to detect solid forms in small samples."  

Other spectroscopic methods may be used in detecting polymorphs. "Like infrared spectroscopy, where the absorption of infrared energy is characteristic of a particular molecular vibration, the absorption of the radio-frequency radiation is characteristic of the magnetic environment of the nuclei, explains SAFC-Pharmorphix's Frampton. When applied to solids, cross-polarization magic-angle spinning solid-state nuclear magnetic resonance spectroscopy (CPMAS SS NMR) can give useful information regarding the crystal structure and polymorphic form of the compound. It also can also reveal the degree of crystallinity of the sample under investigation, he says. "Crystalline samples yield narrow lines as equivalent nuclei are in a constant magnetic environment dictated by the crystal structure, whereas amorphous solids usually yield broader lines reflecting the range of environments found in the solid. CPMAS  SS NMR spectroscopy can also give valuable information on the crystalline asymmetric unit of the crystal structure." 

 1. J. Bauer et al., "Ritonavir: An Extraordinary Example of Conformational Polymorphism," 

Identifying polymorphs is a crucial part of the drug-development process as researchers forward select methods to improve detection.

Advancing Approaches in Detecting Polymorphism

	As contract manufacturing organizations (CMOs) and pharmaceutical ingredient suppliers gather for CPhI Worldwide in Milan Oct. 2–4, the outlook for outsourcing is mixed. Companies are proceeding with select investments in small-molecule manufacturing, cautioned by increased competition from Asian suppliers and consolidation pressures. Asian suppliers continue to make inroads into the global outsourcing market as certain companies add small-molecule and formulation capacity. And for those CMOs also positioned in contract biologics manufacturing, the outlook is strong. 

A positive sign for the contract primary manufacturing market is the recent performance of one industry leader: 

  (Basel, Switzerland). Led by growth in its biopharmaceuticals sector, Lonza reported a 45.2% increase in its first half 2007 sales to CHF 642 million ($532 million) in its biopharmaceutical and exclusive synthesis business. Biopharmaceutical sales almost doubled to CHF 400 million ($332 million). Capacity utilization in its biopharmaceutical business was above 90%, according to the company's first half results.  

 Reflecting strong growth in its biopharmaceutical business, Lonza is investing in microbial and mammalian cell-culture production. Following its $460-million acquisition of 

 's (East Rutherford, NJ) bioproducts and biopharmaceutical business in February, Lonza named Hopkinton, Massachusetts, as the global US headquarters for its microbial biopharmaceutical business and announced plans to invest more than $30 million in its Hopkinton site to support growth plans for microbial process development and manufacturing. The Cambrex acquisition netted Lonza additional biopharmaceutical services capabilities and small-and mid-scale microbial manufacturing capacity to complement existing microbial capacity in Visp, Switzerland. Lonza started producing current good manufacturing practices (CGMP) batches at a new 15,000-L microbial biopharmaceutical line in Visp, and a second line is mechanically complete. 

  In March 2007, Lonza began construction of its second large-scale mammalian facility in Singapore. The final build-out of the facility is expected to be completed and operational in 2011. The $350-million facility will have four mammalian bioreactor trains, each with a flexible capacity of 1000–20,000 L, inclusive of purification units.  

In May 2007, Lonza broke ground for a new $300-million, 330,000-ft

facility for biopharmaceutical manufacturing technologies, support systems, and warehouses in Portsmouth, New Hampshire, where the company has commissioned its largest-scale mammalian cell-culture plant to date. Lonza is adding a 5000-L bioreactor to the existing facility, which has 93,000 L of capacity. It also increased its capacity by acquiring 

 's (South San Francisco, CA) mid-scale mammalian biopharmaceutical production plant in Porriño, Spain, in late 2006.  

Lonza further added to its biopharmaceutical toolbox in August with the acquisition of the "AggreSolve" technology and service business of 

protein-analysis platform that can be applied to solving the problems posed by protein aggregation. Zyentia was founded in 2002 as a spinoff from the University of Oxford, based on technologies around protein folding and aggregation first developed in Oxford then in Cambridge by Professor Chris Dobson and coworkers. 

  On the small molecule side, Lonza's exclusive synthesis business reported sales of CHF 242 million ($200 million) in the first half of 2007, down slightly from sales of CHF 257 million ($213 million) in the same period last year. The company attributed the decline to a transformation of its plant in Kourim, Czech Republic and deferred delivery schedules.  

  Lonza is proceeding with select investments in its small-molecule business. It is building a new CHF 80 million ($66 million) large-scale plant for manufacturing highly potent active pharmaceutical ingredients (APIs) at its facilities in Visp. It already has  small-scale facilities in Visp.  

Lonza also is building a commercial-scale plant with supporting development and analytical laboratories in Visp for producing antibody drug conjugates. The plant will initially be capable of producing over 100 kg of antibody drug conjugates per year, and future expansion plans are built into the design. Stage I is expected to be on line in 2008. Lonza now operates laboratory-scale production and will bring small-scale pilot facilities on stream in 2007.  

  Like other CMOs, Lonza is building its position in Asia. The company completed a small-scale manufacturing plant for APIs in Nansha, China. The plant was scheduled to go on stream in August. In addition, the company is constructing a new large-scale API facility in China. Production is expected to begin in the second half of 2008.  

 (East Rutherford, NJ) shifted its portfolio earlier this year, with the key move being the divestiture of its bioproducts and microbial biopharmaceutical business to Lonza for $460 million. It also sold its small-molecule API manufacturing facilities in Cork, Ireland, and Landen, Belgium, to International Chemical Investors S.A. With those moves, Cambrex now operates small-molecule research and manufacturing facilities in Charles City, Iowa; Karlskoga, Sweden; Milan, Italy, and North Brunswick, New Jersey. 

In July, Cambrex began construction of a mid-sized CGMP manufacturing facility for small-molecule APIs and intermediates in Karlskoga. The plant is scheduled for completion by early 2009.  

The company is also building new laboratory space to augment its existing high-potency development facilities at its site in Charles City, Iowa. The project includes the construction of an 11,500-ft

-facility with five new process development/kilo laboratory production suites for high-potency APIs and enhanced facilities for analytical development and quality control activities. The facility is scheduled to be completed by early 2008. 

  (Langfeld, Germany) is investing EUR 30 million ($40.4 million) to modernize manufacturing facilities in Leverkusen and Dormagen, Germany. Saltigo also is investing EUR 10 million ($13.5 million) to convert an existing plant in Leverkusen into a multipurpose CGMP facility for manufacturing APIs and intermediates. The facility will include four modular units with total capacity of more than 200 metric tons.  

As competition from Asian CMOs intensifies, Western-based CMOs are responding by enhancing their positions abroad.  

  (Hyderabad, India) formed a new contract-drug development company, 

  (Hyderabad). Aptuit Laurus will consist of a 160,000-ft

  research and development facility in Hyderabad, a large-scale manufacturing plant that it is currently under construction in Pharma City, Vishakhapatnam,  and Aptuit's existing informatics development and support group in Bangalore.  

Aptuit has further committed to invest approximately $100 million during the next four years to build upon Aptuit Laurus's development, manufacturing, and informatics capabilities.  

Aptuit has been actively building its contract drug-development portfolio. Recent acquisitions include SSCI, a solid-form research firm, and EaglePicher Pharmaceutical Services, which provides small-molecule synthesis capabilities, including high-potency actives. 

 (St. Louis, MO) made several moves in 2007. It acquired 

  (MMB, Carlsbad, CA), a biopharmaceutical contract manufacturing organization, to further enhance the biologics capabilities within its SAFC Pharma business segment. MMB's core expertise is in the development and clinical manufacturing of viral products. 

SAFC also completed the construction of two new protein API facilities at its St. Louis manufacturing facility: a 25,000-ft

  CGMP purification and manufacturing suite for transgenic plant and other nonanimal derived protein APIs and a 6000-ft

  facility for purification of animal-derived protein APIs. The expanded capacity seeks to meet increased demand for large-scale supply and will meet late-stage clinical trial and commercial manufacturing needs for transgenic and naturally-sourced APIs. 

SAFC completed the initial phase of a two-stage expansion at its SAFC Pharmorphix research facility in Cambridge, United Kingdom. SAFC Pharmorphix provides solid-form characterization and research. The company also expanded Pharmorphix's capabilities into the United States with a new laboratory at SAFC's high-potency API facility in Madison, Wisconsin.  

Mid-to small-sized CMOs are investing in production and service capabilities.  

  (Heerlen, The Netherlands) API and intermediates manufacturing facility in South Haven, Michigan. The acquisition provides kilo-, pilot-, and commercial-scale capacity and also provides Albemarle with certain projects for generic APIs.  

Ricerca Biosciences. Ricerca Biosciences LLC

  (Concord, Ohio), a contract drug-development company, is embarking on a growth strategy in which it hopes to double its revenues by 2009. Earlier this year, it completed a financial restructuring that includes new equity and term facilities totaling nearly $50 million. That financing will help Ricerca to implement a multiyear business plan, which includes a $15-million investment to add chemistry and biological laboratories to its site in Concord, Ohio.  

  (Craigavon, UK) expanded its analytical services offerings in bioanalysis, characterization, stability testing, structure confirmation, and batch release.  at its facility in Elvingston, Scotland.  

The company also started a collaboration for fill-and-finish services with the Center for Pharmaceutical Science and Technology (CPST) at the University of Kentucky, which became a private laboratory, Coldstream Laboratories. Coldstream will provide IV formulation and sterile fill of cytotoxics and potents for clinical-trial applications. CPST opened a new $17-million sterile manufacturing facility in May 2006. By 2011, the Coldstream facility is projected to have annual revenues of $15 million and employ up to 50 science-based and other professional staff. The collaboration positions Almac Sciences in upstream offerings in cytotoxics; it also offers contract manufacturing of high-potency APIs at its facility in Craigavon, Northern Ireland.  

Earlier this year, Almac Sciences also teamed with with 

 (Pasadena, CA) under which Almac Sciences will provide process development and manufacture for a select group of chiral intermediates and APIs based on enzymatic technology developed by BioCatalytics. BioCatalytics was subsequently acquired by 

 (Redwood City, CA), which specializes in biocatalysis for small-molecule synthesis.  

Last November, Almac Pharma Services completed a $10.5-million expansion of its formulation activities with the addition of extended formulation development services for solid-oral dosage forms from preclinical to pilot scale. 

  (Germantown, WI), a pharmaceutical chemistry outsourcing company, partnered with Arlington Capital Partners with the aim of building a drug-development organization focused in three primary areas: APIs, formulation, and regulatory consulting services.  

  In keeping pace with moves by CMOs to offshore locations, 

 (Albany, NY) acquired the assets of Ariane Orgachem Pvt. Ltd. in Aurangabad and Ferico Laboratories Ltd. in Navi Mumbai, India, giving the company two API and intermediates facilities in India. AMRI also acquired additional land for expansion and plans to invest approximately $15 million to expand and upgrade manufacturing capabilities during the next three years. 

  (RSIL) formed a joint venture, Evotec-RSIL Ltd., in Thane, India, to design, synthesize, and manage compound libraries as a service. In addition, Evotec expanded its sterile-pharmaceutical manufacturing facility in Glasgow, UK. The company doubled its capacity for the aseptic GMP manufacture of clinical trial material. 

  Regis Technologies (Morton Grove, IL), which offers chromatography services and custom-synthesis , recently expanded its development area to include an additional 7000 ft

 of synthetic laboratories and offices.  

Just as Western companies invest in India, Indian CMOs are raising their position in the global outsourcing market. 

  (Noida, Uttar Pradesh, India) acquired 

  (Spokane, WA), a contract manufacturer of sterile injectables. The move strengthens Jubilant's contract research and manufacturing services (CRAMS) business and provides the company with another US-based manufacturing facility. Jubilant also has a solid-dosage form manufacturing facility in Salisbury, Maryland.  

Jubilant provides CRAMS for advanced intermediates, fine chemicals, APIs, and dosage-forms as well as drug-discovery and development services. In 2007, the company booked orders of $60 million for its CRAMS business, up from $40 million in 2006.  

In June 2007, Jubilant commissioned a new dosage-form FDA-compliant manufacturing facility at Roorkee, Uttarakhand, India. The facility has annual manufacturing capacity of 1.6–1.8 billion tablets and 150 million capsules.  

Jubilant Organosys has manufacturing facilities in seven locations: Gajraula (Uttar Pradesh) for advanced intermediates and fine chemicals; Nanjangud (Karnataka) for API manufacturing; Roorkee (Uttarakhand) for dosage forms; Salisbury, Maryland, for solid-dosage forms; Spokane, Washington, for sterile injectables; and Nira, Maharashtra, and Samlaya, Gujarat, India. The company also is a large producer of pyridine and pyridine derivatives and recently increased production capacity of pyridine and picolines to 42,000 tons per year.  

  (Mumbai, India) is continuing a $100-million investment program in formulation development and manufacturing services. The company has invested roughly $50 million over the past three years as part of its early-phase (development) and late-phase (manufacturing) formulation services in the UK and India, and it plans a similar investment over 2007–2009. The investment includes a new sterile supplies pilot plant in Mumbai, India, which is scheduled to come on stream in the fourth quarter of 2007.  

The company's focus on formulation services and final-dosage forms follows the addition of capabilities in this area from NPIL's 2006 acquisition of 

 's (New York) API and formulation manufacturing facility at Morpeth, UK. As result of the Morpeth acquisition, NPIL Pharma has annualized aggregate drug-formulation capacity of 3 billion tablets, 500 million low RH (<8%) tablets, 270 million hard-gelatin capsules, 180 million ophthalmic liquids, 48 million glass vials, and 30 million ampules.  

In custom manufacturing, NPIL formed a new dedicated unit, NPIL Innovations or NPIL(i), to focus on developing and applying new technologies used in process development and production of APIs. The unit focuses on biocatalysis, chemocatalysis, and flow processing, including its catalyst-based racemization technology.  

  (Brussels) fine-chemicals and vitamin businesses for an undisclosed sum. The deal includes Solvay's Veenendal, The Netherlands, facilities, as well as the intellectual property rights for fine chemicals, vitamin D, and vitamin D analogues.  

The Solvay acquisition is the latest move by Dishman to acquire Western production assets. In 2006, it acquired the CMO 

  (Bubendorf, Switzerland), which included capabilities for high-potency APIs. In February 2006, it acquired I03S, Ltd. a company specializing in ozone chemistry, and in 2005 acquired the UK-based contract research company Synprotec, Ltd.  

  In China, the contract research and manufacturing firm 

  (Shanghai) is raising its position in the global market. The company is planning an US initial public offering (IPO) priced to raise roughly $120 million. Wuxi PharmaTech's operations are grouped into two segments: laboratory services (consisting of discovery chemistry, service biology, analytical, pharmaceutical development, and process development services) and manufacturing (manufacturing of advanced intermediates and APIs) to 70 pharmaceutical and biotechnology customers, including nine of the top 10 pharmaceutical companies, according to the company's prospectus.  

Contract manufacturers and pharmaceutical ingredient suppliers proceed with select investments in biologics manufacturing, small-molecule synthesis, and formulation as the industry prepares for CPhI Worldwide in Milan.

CMOs Make Select Investments in Primary and Secondary Manufacturing

			Single-enantiomer drugs represent an increasingly large share of new chemical entities, leading to approaches in asymmetric synthesis. Asymmetric hydrogenation is an atom economical and scaleable method for the manufacture of commercial chiral compounds.  Developing efficient methods to produce the chiral ligands and catalysts on a large scale is essential to effectively commercialize this technology. The authors examine methods to manufacture select catalyst systems and their application in commercial-scale asymmetric hydrogenation.			

Single-enantiomer compounds accounted for 75% of the new small molecule pharmaceuticals approved by the US Food and Drug Administration in 2006. Half of these products are made by purely synthetic means, and asymmetric chemocatalytic methods such as asymmetric hydrogenation are being used more frequently to synthesize single-enantiomer compounds.  

Asymmetric hydrogenation was first demonstrated almost 40 years ago, with the landmark literature reports published independently by the groups of Knowles and Horner in 1968. Both groups indicated that a rhodium catalyst, modified with a chiral phosphine ligand, was capable of inducing asymmetric hydrogenation in a suitable prochiral substrate. While working for Monsanto, Knowles developed the first commercial application for the manufacture of L-DOPA (see Figure 1), a drug used for treating Parkinson's disease (1). This pioneering work led to Knowles sharing the 2001 Nobel Prize for Chemistry with Noyori and Sharpless. 

During the 1970s, there were no more than a handful of chiral ligands reported, and none of these were commercially available on large scale. The ligand system and synthesis for any given application had to be developed 

, thereby creating significant barriers in using asymmetric hydrogenation. Most systems also were neither modular nor widely applicable over a broad range of substrates, making systematic selection of a suitable catalytic system difficult to predict. Noyori introduced the BINAP catalysts in the 1980s, and these catalysts led to Takasago developing many commercial processes for manufacturing β-hydroxy esters [used in the Lipitor (atorvastatin) side chain], alcohols, and carbapenem intermediates using ruthenium-BINAP systems (2).  

During this period, a greater range of catalytic systems and substrates was established, so systematic employment of chiral catalytic technology was possible to a significantly greater extent. The largest-scale rhodium-BINAP process is the allylic isomerization of diethylgeranylamine to provide (R)-citronellal, an intermediate used to manufacture (–)-menthol, which is produced on a scale exceeding 1000 metric tons per year (2).  

The commercial success of the BINAP technology encouraged many companies and research institutes to search for novel ligands outside the scope of the BINAP patents. Hoffmann-La Roche, for example, developed the MeO-BIPHEP ligands and catalysts and applied these ligands in the manufacture of vitamins and pharmaceutical intermediates. The side chain of tetrahydrolipstatin (orlistat) (see Figure 1) is manufactured using an asymmetric hydrogenation process, with a ruthenium MeO-BIPHEP catalyst (3).  

By the 1990s, there were many more catalyst systems established for asymmetric hydrogenation, applying a diverse range of ligands, using rhodium, ruthenium, and iridium metals, and finding applications in pharmaceutical, agrochemicals, nutraceuticals and the flavor and fragrance industries. The two ligand systems with the greatest impact developed in the 1990s were DuPhos (1,2-bis(2,5-dialkylphospholano)benzene) by Burk (4) and Josiphos by Togni and Spindler (5). The JosiPhos ligand system is used in the largest-scale asymmetric hydrogenation process known to date: for the manufacture of the herbicide Dual Magnum[(

)-metolachlor] (see Figure 1), which is produced on a 20,000-metric-ton scale per year (6). The actual iridium Josiphos catalyst required was not known at the start of the research project, but was discovered as the development of (

)-metolachlor proceeded. Chirotech, now part of Dowpharma, obtained the exclusive license to the DuPhos, BPE (1,2-bis(2,5-diphenylphospholano)ethane) and 5-Fc (1,1'-bis (2,5-diphenyl-phospholano) ferrocene) technology for commercial pharmaceutical applications from DuPont. Chirotech subsequently developed numerous asymmetric hydrogenation processes, and the DuPhos ligands and catalysts were also offered for sale on commercially relevant scales (>100 g–multi-kilograms) (7).   

There are in excess of 3000 ligands known for asymmetric hydrogenation processes, though only a handful of these are truly available on a kilogram scale within a reasonable lead time (8). Four drugs, recently approved by FDA are reported to use asymmetric hydrogenation in their manufacture (see Figure 2). Rozerem (ramelteon) (9) and Aptivus (tipranavir) (7) were approved in 2005, Januvia (sitagliptin) (10) in 2006, and Tekturna (aliskiren) (11) in 2007. These approvals confirm that asymmetric hydrogenation has matured and become an accepted addition to commercially relevant technologies for pharmaceutical manufacture. 

Rhodium DuPhos applications and ligand synthesis

The DuPhos technology has a broad substrate scope, and Chirotech has reported asymmetric hydrogenation processes for tipranavir (7), candoxatril (7), pregabalin (7), unnatural α-amino acids (12), and succinates (13) (see Figure 3). To further develop and potentially commercialize such processes, however, require the Me-or Et-DuPhos rhodium precatalysts to be produced on multikilogram scales. 

Prior to the commercialization of the DuPhos technology, Chirotech developed methods to produce the ligands and catalysts on a multigram scale, with practical but moderate yields. These methods satisfied the laboratory scale and early development needs for the compounds shown in Figure 3. As demand for these catalyst systems increased toward multi-100s grams and then to kilograms, it was clear that the initial synthetic methods were not practical in terms of yield, purity, and economics. In the first instance, Chirotech addressed the ligand synthesis and made improvements over the original routes. Hexane-2,5-diol was originally obtained using an electrochemical Kolbe coupling of single enantiomer 3-hydroxybutyric acid, but this method did not scale up well with severe fouling of the electrodes being observed (14). 

Chirotech then developed an in-house method constituting a bioresolution approach starting with the 1:1 racemic/meso diol (15). Using inversion techniques on a monobutyrate derived from the meso diol, a good yield of the (

) enantiomer was obtained, but the yield of the (

) entantiomer was lower. With the introduction of highly efficient alcohol dehydrogenase enzymes and ready availability of hexane-2,5-dione, both enantiomers of hexane-2,5-diol are commercially available on the requisite scales. For security of supply reasons, Dowpharma still operates its own protected bioresolution route. 

In the original synthetic protocol for the DuPhos ligands, 1,2-bis (phosphino) benzene was deprotonated with 

-BuLi, followed by addition of the cyclic sulfate and then further 

-BuLi (see Figure 4) (14). This approach gave the ligands in good yields and purities. Upon scaling up this process to produce kilogram amounts, yields were not reproducible, and higher levels of impurities were formed. These problems were readily solved by an inverse addition procedure, whereby 

-BuLi is added to a mixture of 1, 2-bis (phosphino) benzene and the cyclic sulfate. This process is readily scaleable, giving high purity ligand in excellent yields on multikilogram scales (16). This process also has been applied to other 1,4-diols to give access to ethyl and isopropyl phospholane ligands, as well as the related 1,3-diols for the proprietary phosphetano ligands, FerroTANE (Dowpharma, Midland, MI) (17). 

For some asymmetric hydrogenation catalyst systems, it is acceptable to make the precatalyst 

 from a metal complex and the ligand. We have the general approach that it is better to preform and isolate the ligand–metal catalyst complex so it can be charged to the reactor as a defined species. This approach results in more robust and reproducible reactions, with greater quantification (important for CGMP manufacture) and no debate as to whether the precatalyst complex has completely formed. Initially, standard established literature methods were used to make the Rh-DuPhos complexes: (1,5-cyclooctadiene) Rh(I) acetylacetonate] is converted into the sparingly soluble Rh bis(1,5-cyclooctadiene) tetrafluoroborate complex (18), and the ligand reacts with this intermediate to provide the precatalyst complex in solution. Addition of an antisolvent is required to precipitate the desired product (see Figure 5). This method worked well for a range of diphosphine ligands, but provided material in modest yields (~70%) and variable product form. Obviously, failing to isolate 30% of valuable ligand and metal precursor is neither desirable nor economical.  

A further problem with this method was that the product form was variable, from robust deep red crystals to orange-yellow amorphous powders. Although all of these forms performed well in asymmetric hydrogenation reactions, the powdered materials had shorter shelf life and were prone to degrade more easily than the crystalline material. Further process development led to a scaleable process that delivers crystalline rhodium precatalysts in very high yields (91–97%) with excellent chemical purity and substantially improved chemical and physical stability.  

The new process involves taking [(1,5-cyclooctadiene) Rh(I) acetylacetonate] in an ethereal solvent (see Figure 6a), treating it with an alcohol solution of strong acid, such as tetrafluoroboric acid, to give a soluble bis-solvato species (see Figure 6b), which is then reacted with an ethereal solution of the bisphosphine ligand (see Figure 6c). Shortly after the addition of the ligand crystallization of the precatalyst complex is observed. This protocol controls the rate of nucleation at higher temperatures through rate of ligand addition, such that granular, free-flowing precatalyst is deposited in exceptionally high yields (19).  

The difference in quality of the precatalyst formed using this process is noteworthy (see Figure 7). The original catalyst fabrication process often provided an orange amorphous powder that performed well in the asymmetric hydrogenation reaction, but had poor long-term stability. This material had to be handled very carefully under rigorously inert conditions, as the larger surface area made it more prone to atmospheric oxidative decomposition. The new process provides a deep red crystalline material, and allows the crystal size and reproducibility to be controlled to produce high-quality product (see Figure 7). This material can be readily weighed in air, as long as it is stored under nitrogen, has a long shelf life (>12 months), and provides reproducible results in asymmetric hydrogenation. 

As our early needs were for both enantiomers of [Me-DuPhos Rh (COD)]BF

, we first applied this procedure in manufacture. Very high yields of crystalline precatalyst (>95 %) on batch sizes from 2–2.5 kg per run (see Figure 8) were obtained, with the ability to increase the batch size as required. This process is operated routinely and consistently produces high-quality product, a major advance when compared with the original precatalyst synthesis.  

With this process working well for rhodium Me-DuPhos complexes, Dowpharma investigated the synthesis of other related bisphosphine complexes. This methodology could be applied to the manufacture of a wide range of precatalysts, all giving crystalline products in high yield and quality (see Figure 9). Unsurprisingly, the crystalline form in each case is subtly different, and the crystallization protocol requires tailored optimization for each product. The basic process, however, is retained for each precatalyst produced. To date, we have applied this method to more than 20 bis-and mono-phosphine systems (19). 

Applications of ruthenium- based catalysts

Ruthenium catalysis is complementary to rhodium catalysis as it is effective in differing substrate classes. Dowpharma's position in this area includes ruthenium DuPhos/BPE systems and Diphosphine RuCl

 Diamine systems for asymmetric ketone hydrogenation, developed by professors Noyori and Ikariya. Chirotech in-licensed the Noyori technology from the Japan Science and Technology Corporation (JST) in December 2000. 

Limited representatives of the DuPhos ligand family have been developed for ruthenium catalysis. Among these ligands, the i-Pr-DuPhos Ru (TFA)

 system is good for the asymmetric hydrogenation of acrylate derivatives. This catalyst outperforms other ruthenium-based catalysts, including biaryls, for the asymmetric hydrogenation of tiglic acid, a γ-amino acid derivative (20) and furoic acid (see Figure 10). The latter process to (

)-3-furoic acid was scaled up for clinical supplies. 

Single-enantiomer drugs represent an increasingly large share of new chemical entities, leading to approaches in asymmetric synthesis.

Pharmaceutical Technology-09-01-2007

Excipient Control Strategies in China

Advancing Approaches in Detecting Polymorphism

CMOs Make Select Investments in Primary and Secondary Manufacturing

Manufacture of Asymmetric Hydrogenation Catalysts