Optimization Strategies for API Synthesis and Formulation Development

November 2, 2006
Patricia Van Arnum

Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Pharmaceutical Technology, Pharmaceutical Technology-11-02-2006, Volume 30, Issue 11

Optimizing formulation and API synthesis is critical for product success. Technology providers advance chemocatalysis for olefin metathesis and asymmetric reactions in API synthesis. And pharmaceutical majors share insights in formulation development.

As pharmaceutical manufacturers face continual pressure to hasten products to market, strategies for improving the drug-development and manufacturing processes become critical. In pharmaceutical chemical development, ways to optimize manufacturing economics of active pharmaceutical ingredients (APIs) through higher product yields, improved reaction conditions, or waste-reduction are increasingly important. At the same time, formulation scientists face the demand of optimizing formulations as part of a strategy of bringing new chemical entities to market or extending the life cycle of established products.

Advances in catalysis for synthesizing intermediates and APIs

Catalysis plays a critical role in optimizing a synthesis for APIs and pharmaceutical intermediates. Advances in catalysis recently have broadened the use of olefin metathesis in pharmaceutical applications.

Olefin metathesis is the technology that was recognized in the award of the 2005 Nobel Prize in Chemistry, given to Robert Grubbs, professor of chemistry at the California Institute of Technology (Pasadena, CA), Richard R. Schrock, professor of chemistry at the Massachusetts Institute of Technology (Cambridge, MA), and Yves Chauvin, honorary director of research at the Institut Francais du Petrole (Ruel-Malmaison, France).

Olefin metathesis involves the interchange reaction of alkylidene groups between alkanes, explains Jürgen Krauter, marketing and sales manager at Degussa Homogeneous Catalysts (DHC), part of Degussa AG (Düsseldorf, Germany). Depending on the particular substrate and transformation, metathesis is formally grouped into several types, he explains.

These types (Figure 1) include: straight swapping of groups between two acyclic olefins (cross metathesis); formation of cyclic olefins (ring-closing metathesis); polymerization of cyclic olefins (ring-opening metathesis polymerization); and formation of dienes from alkenes and alkynes (enyne metathesis).

Figure 1

The catalyst is an integral tool in promoting these reactions, and the ligands in the catalyst are the key focus in chemical development. DHC, for example, recently developed and launched a second-generation metathesis catalyst for pharmaceutical applications. The product ("catMETium IMesPCy") is an alkylidene-ruthenium complex with a N-heterocyclic carbene ligand.

Ruthenium-carbene complexes with diphosphine ligands have extensive uses in organic synthesis. These complexes not only exhibit high reactivity in olefin metathesis reactions but also are highly tolerant toward many different functional groups, explains Krauter. When one of the phosphine ligands in the coordination sphere is replaced with an N-heterocyclic carbene, reactivity is improved and the stability of the resulting ruthenium complexes is improved.

"The development of these so-called second generation catalysts has broadened the scope of olefin metathesis significantly," says Krauter. He explains that nucleophilic carbenes of the imidazolylidiene type are stronger σ-donor ligands and show little tendency to dissociate from the metal center. These ligands bearing sterically demanding substituents on their N-atoms are able to stabilize the catalytically relevant intermediates against decomposition pathways.

Degussa owns the composition of matter patent for the catMETium IMesPCy catalyst. To support this position, Degussa has taken licenses under patents generated by Wolfgang A. Hermann, professor at Technische Universität (München, Germany) and field-of-use licenses under patents generated by Steven Nolan, professor at the University of New Orleans (New Orleans, LA). Degussa is using a business model for catMETium IMesPCy under which the kilogram price is all inclusive with no additional license fees.

Materia, Inc. (Pasadena, CA) is another company specializing in olefin metathesis in pharmaceutical applications. The Nobel Prize winners Grubbs and Schrock serve as scientific advisors to Materia. Materia is a company co-founded by Grubbs and current Materia CEO Michael A. Giardello, who served as a postdoctoral fellow with Grubbs.

Materia was founded in 1997 as Advanced Sports Materials. It initially focused on metathesis polymer technology. Its technology platform was later broadened to include asymmetric metathesis catalyst technology for pharmaceutical applications and its "OrganoCatalysis" technology for producing chiral building blocks, intermediates, and APIs.

CMOs add capabilities in pharmaceutical chemical development

Advances in chemocatalysis

The OrganoCatalysis technology, which was developed by David MacMillan, professor at Caltech, uses small organic molecules to serve as general catalysts for asymmetric transformations of other substrates. The technology is based on the finding that certain organic functionalities, such as the iminium ion, mimic the substrate activation found in Lewis acid-catalyzed transformations, and therefore the catalyst mechanism effectively serves as an analog to Lewis acid coordination.

Materia has used this technology in several reactions, including asymmetric variants of Friedel-Crafts alkylation, 1, 4 conjugate additions, Diels-Alder reactions, and 1,3 dipolar cyclo-additions, says John Kibler, Materia's director of corporate development. The enantioselective synthesis of (-) ketorolac, a nonsteroidal antiinflammatory drug, is an example of a process using both Materia's metathesis and OrganoCatalysis technology.

Catalytic process for sitagliptin

Designing a catalyst for optimizing a synthesis also may improve manufacturing economics by increasing yield and reducing waste. Merck & Co., Inc. (Whitehouse Station, NJ) was recognized earlier this year for a green chemistry approach for the synthesis of sitagliptin, the API in "Januvia," a dipeptidyl peptidase-4 inhibitor to treat Type II diabetes. The drug was approved by the US Food and Drug Administration in October 2006.

Sitagliptin is a chiral β-amino acid derivative, and in collaboration with Solvias AG (Basel, Switzerland), Merck forwarded an approach for the asymmetric catalytic hydrogenation of unprotected enamines to synthesize sitagliptin using a ferrocenyl ligand in the catalyst.

Merck discovered that hydrogenation of unprotected enamines using rhodium salts of a ferrocenyl-based ligand as the catalyst produces β-amino acid derivatives of high optical purity and yield. Merck applied the method in the final synthetic step. The dehydro precursor to sitagliptin used in the asymmetric hydrogenation is prepared in a one-pot procedure. Following hydrogenation, Merck recovers and recycles over 95% of the rhodium. The reactive amino group of sitagliptin is only revealed in the final step, and therefore there is no need for protecting groups. The new synthesis has only three steps, increasing the overall yield by nearly 50%, and reducing the amount of waste by 80% (1).

Solvias also recently licensed the rights to manufacture, market, and distribute the MeOBIPHEP catalyst technology from Roche (Basel, Switzerland), which may be used in asymmetric reactions.

Strategies in Formulation Development

API synthesis is only part of the battle. Researchers from Johnson & Johnson, Pfizer, Bristol-Myers Squibb, and GlaxoSmithKline share insights into formulation.

Developing a good formulation is as important as synthesizing the API itself. That point was recently underscored by Merck & Co. Inc.'s decision to revise its filing plans for MK-0524B, an investigational fixed-dose combination of MK-0524A and simvastatin, as the company continues to work on developing the fixed-dose combination formulation.

MK-0524B is a key drug in Merck's late-stage pipeline. Analysts had projected 2010 sales of $780 million (2) as Merck is positioning the drug as a follow-on to "Zocor" (simvastatin), its cholesterol-lowering drug whose US patent expired in 2006, and "Vytorin" (ezetimibe and simvastatin), the combination therapy from Merck and Schering-Plough Corporation (Kenilworth, NJ). Merck says it has not yet determined a new filing date for the fixed-dose combination of MK-05424B.

The setback underscores the importance of successful formulation development. That topic was addressed at the Annual Eastern Pharmaceutical Technology Meeting (EPTM) (see sidebar, "About EPTM") with several scientists from major pharmaceutical companies offering insights for formulation development.

Phase-appropriate strategies for formulation development

"Understanding key physical and chemical properties and other factors that can affect the oral exposure in the early stage of the discovery and development process can ensure developability and avoid many potential formulation-development issues," says Lian-Feng Huang, associate director of pharmaceutical sciences at Johnson & Johnson Company (New Brunswick, NJ), who presented at EPTM. In early-stage drug development, Huang suggests using phase-appropriate formulation strategies based on three phases: research to hits; lead optimization; and candidate selection to first-time-in human (FTIH).

Each of these phases has its own formulation needs. In the research-to-hit phase, formulations are needed for in vitro and in vivo efficacy studies to identify potential lead compounds. Exotic formulations or standardized dosing vehicles with strong solubilizing power are sometimes used to ensure proper identification of good hits. "Common limitations at this point are limited or no drug substance, poor purity, and limited understanding of key physicochemical properties," says Huang.

When developing formulations for lead optimization, key needs are developing formulations for in vivo efficacy studies, for toxicology studies, and for supporting a pharmaceutical developability assessment, outlines Huang.

For formulation development for FTIH, key factors to consider are the indication, the clinical study plan, the drug substance availability, and the complexity of potential formulations, i.e., the compound developability. One of the decision factors facing a pharmaceutical company as a drug candidate approaches clinical development is whether to develop a simple formulation or to proceed with more sophisticated formulation approaches. Simple formulation options may be powder in a bottle, powder in capsules, suspensions, or solutions. More sophisticated formulation approaches include prototype solid-dosage forms and special delivery systems. There are advantages and disadvantages for each approach.

"The advantages of using a simple formulation is that it requires minimum drug substance and minimum development work and can offer greater flexibility for dose adjustment," says Huang. "The disadvantages are that a simple formulation may not be feasible for out-patient studies, depending on the therapeutic area of the drug and the country where the studies are conducted. Also, using a simple formulation may make formulation development the rate-limiting step in late-stage drug development."

A simple-formulation approach is appropriate to use with high-risk compounds with low success rates as not to waste resources. Also, "Simple formulations should be considered with compounds with large dose ranges that require significant flexibility in dosing," she says.

Simple formulations also are appropriate when the drug substance is in very limited supply and for compounds with low development risk. "Simple formulations may also be an attractive approach when multiple compounds will be going into FTIH, but only one will be developed into a market formulation," says Huang.

Huang also outlines the pros and cons of developing a prototype solid-oral dosage form for FTIH. "The advantages are that prototype formulations can be more easily developed into market formulations, and therefore are more efficient and less risky," she says. The disadvantages are that it requires more drug substance, more time, and more resources. It also will waste resources as most compounds will be terminated after Phase I studies based on expected attrition rates in drug development today.

With the advent of many technologies and predictive tools for solid-dosage form development, developing a prototype formulation for FTIH may eventually consume less time, less drug substance, and fewer resources, notes Huang. Until then, both approaches will remain popular depending on a company's risk management.

Other decision factors in formulation development

Another consideration to address in early-product development is whether to develop a modified-release form of the drug. "Only a few years ago, controlled release was more or less restricted to managing product life cycle," explains Avinash Thombre, research fellow, Pharmaceutical Research and Development at Pfizer, Inc. (New York, NY), who also spoke at EPTM. "Some internal formulation development for controlled release was maintained by large pharmaceutical companies, primarily as a backup, and controlled-release technologies were frequently licensed-in from small drug-delivery companies."

That mindset has changed. "Today, controlled release is considered for more and more drug candidates earlier in their development," says Thombre. "There is recognition that controlled-release formulations represent a cost-effective way to progress candidates, and the focus is on rapid progression of a drug candidate to proof-of-concept with the most appropriate formulation."

In assessing the viability of developing a controlled-release form, Thombre outlines several key elements: physicochemical factors such as dose, dose and solubility ratio, and stability; biopharmaceutical factors such as absorption mechanism and regional permeability; and pharmacokinetic factors such as plasma half-life and presystemic and first-pass metabolism.

On a delivery basis, hydrophilic matrix tablets, osmotic technology such as asymmetric membrane technology and swellable core technology, multiparticulates, and microspheres are examples of controlled-release technologies that may be used in developing a formulation.

Thombre presented two case studies to show how to assess the feasibility of developing controlled-release formulations of drug candidates, including the utility of pharmacokinetic simulations and the use of dose-solubility maps and other factors to help select the most appropriate controlled-release technology (3).

Predictive tools and technologies

Just as important as developing a formulation strategy early in the drug development process are the techniques and tools used to used to evaluate the performance of the solid-dosage form.

Solubility versus dissolution rate. A useful framework for assessing the probability of success of oral-drug absorption and bioavailability is the Biopharmaceutics Classification System (BCS). The BCS (see Table 1) classifies drugs substances based on permeability and solubility (4).

Table I: The Biopharmaceutics Classification System

The predictive value of the BCS is less clear, however, when a drug converts to a lower solubility form on exposure to an aqueous solution, explains Robin Bogner, associate professor of pharmaceutics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut (Storrs, CT), who also spoke at EPTM. Such conversions may include: solvent-mediated transformations of metastable polymorphs to more stable polymorphs; soluble salts to lower solubility salt forms or their corresponding free acids or bases; anhydrous to less soluble hydrates; and amorphous to crystalline forms.

In such cases, an important question is whether dissolution rate or solubility is a better predictor for bioavailability enhancement. Bogner maintains that dissolution rate is superior to solubility in assessing forms that convert during dissolution. Moreover, the dose is an important parameter in determining whether or how fast conversion takes place. In terms of methods, a flow-through cell recently designed at the University of Connecticut will allow assessment of hydrodynamic and other conditions that affect conversion while allowing direct observation of the surface.

Microenvironmental pH. Modulation of the microenvironmental pH through pH modifiers is another consideration in maximizing solid-dosage form stability and in vivo performance, an issue addressed by Munir Hussain, senior research fellow, pharmaceutical R&D, Pharmaceutical Research Institute at Bristol-Myers Squibb Company (New York, NY), who spoke at EPTM. The microenvironmental pH in a solid-dosage form may be assessed using several methods.

About EPTM

In the slurry method, hydrogen activity is measured in suspension where water concentration is much higher than that in the solid. A second method is diffuse reflectance visible spectroscopy, which is based on the premise that the microenvironmental pH is equivalent to the pH of a standard solution with the same degree of probe ionization. It uses a pH indicator dye molecule with a pH-dependent degree of ionization.

Once the microenvironmental pH is assessed, a pH modifier can modulate the microenvironmental pH to maximize the stability of the solid-dosage form or enhance oral absorption of weakly basic drugs. "Careful selection of the pH modifier, its concentration, and the manufacturing process used to incorporate the pH modifier is necessary to enhance stability or in vivo performance," says Hussain.

As an example, a Bristol-Myers Squibb drug candidate that showed chemical instability in a tablet dosage form was stabilized by the inclusion of 5% sodium carbonate in the formulation, which resulted in a microenvironmental pH in the tablet that was similar to the pH of maximum stability in solution. Another example, BMS-561389, a Factor Xainhibitor, showed gastric pH dependent oral absorption was presented. Adding tartaric acid as a pH modifier in the tablet formulation resulted in oral bioavailability that was independent of gastric pH.

In vivo tools for evaluating dosage forms. To aid in the evaluation of new chemical entities, specialized tools may be used to evaluate the dosage form. Alan F. Parr, director of the product line extension group at GlaxoSmithKline (GSK, Research Triangle Park, NC) outlined at EPTM how GSK uses specialized technologies to evaluate the in vivo performance of a drug and its dosage form. These technologies include gamma scintigraphy, regional absorption tools, and a swallowable camera.

Gamma scintigraphy noninvasively images the transit or deposition of a dosage form to its intended site of delivery in vivo by incorporating short-lived gamma-emitting radioisotopes. It may be used in preclinical and clinical studies. The technique correlates in vivo behavior with pharmacokinetics. This technique can be applied to most formulation types, and the technique labels the dosage form, not the drug. In vitro tests are performed to establish that the release of the drug is similar to the release of the isotope, explains Parr.

Company Web sites

"The largest use of gamma scintigraphy is to explain unexpected pharmacokinetic results due to the inconsistent behavior of the drug," says Parr. It also may be used to evaluate the in vivo behavior of various formulations, the effect of food on the in vivo behavior of various formulations, the effect of excipients on gastrointestinal (GI) transit, and the in vivo behavior of various formulations. Gamma scintigraphy may be used to rapidly screen viable formulations of a given compound as well as determine the development plan for a modified-release formulation for the compound, says Parr.

Companies such as Scintipharma, Inc. (Lexington, KY) and Bio-Images Research, Ltd. (Glasgow, Scotland), which was founded in October 2000 as a spinout from the Universities of Strathclyde and Glasgow, specialize in this technique.

GSK has used tools for radiofrequency-activated, nondisintegrating drug delivery in formulation development. These tools are capable of noninvasive controlled delivery of drug formulations for determining regional differences in drug absorption and bioavailability.

Examples of this technology are Innovative Devices LLC's (Raleigh, NC) "InteliSite" and "Companion"capsules. With these technologies, radiolabeling permits determination of the capsule location within a specific region of the GI tract via gamma scintigraphy. "When the capsule reaches the desired location in the GI tract, external activation opens the capsule," explains Parr. "The release and degree of dispersion of the solution (InteliSite) or powder (Companion) contents from the capsule can be visualized using the gamma camera," says Parr. Plasma samples are collected, analyzed, and then correlated with the site of the drug release. GSK has used the Companion capsule to evaluate the regional absorption of roughly 15 compounds.

GSK also has used a swallowable camera, "PillCam" (Given Imaging, Inc., Duluth, GA) to observe the in vivo behavior of various dosage forms such as matrix tablets and to evaluate the physical effects of dosage forms on the GI mucosa.


1. US Environmental Protection Agency, "Presidential Green Chemistry Challenge Awards," (Washington, DC, 2006), www.epa.gov/greenchemistry/pubs/pgcc/winners/gspa06.html, accessed Oct. 2, 2006.

2. P. Van Arnum, "The Outlook for New Molecule Entities," Pharm. Technol. 30 (10), 63–70 (2006).

3. A. G.Thombre, "Assessment of the Feasibility of Oral Controlled Release in An Exploratory Development Setting," Drug Discovery Today 10 (17), 1159–1166 (2005).

4. US Food and Drug Administration, Office of Pharmaceutical Science, "The Biopharmaceutics Classification System (BCS) Guidance, http://www.fda.gov/cder/OPS/BCS_guidance.htm, accessed Oct. 10, 2006.