Ring The Changes

The more we discover about the human body and its physiology, the more complex our methods of affecting it become.

 

Pharmaceutical active ingredients, the main weapon in modern medicine's arsenal against disease, are now designed to target specific cells in the body; specific molecules found on those cells; specific groups of atoms on those molecules.

 

The shape of these molecules is vital to their chemistry and the way they act on their targets. This presents the chemists and the process engineers within the pharmaceutical industry with a daunting task: finding ways to make exactly the right molecule, in large quantities, under the mildest possible conditions, and while consuming the minimum resources.

 

Catalysis is a vital tool for this job, and homogeneous transition metal catalysis (TMC) is becoming increasingly important for pharmaceutical chemistry. These are based around the design of an array of organic molecules — ligands — which form complexes with transition metals. Through their shape and chemistry, these complexes direct the chemical building blocks into their final forms.

 

TMC's strength is that it can direct the formation of chiral molecules predictably and efficiently. Introduced into industrial chemistry towards the end of the last decade, it is now a standard technique for pharmaceuticals, dramatically simplifying the syntheses of some molecules and making previously impossible syntheses a routine matter.

 

Dynamic Synthesis, the custom synthesis division of German speciality chemicals producer Dynamit Nobel, is an old hand at TMC.

It concentrates on chemistry involving three types of reactions: asymmetric hydrogenation, where hydrogen is added across a double bond to create chiral centres; C—C coupling, the directed formation of bonds between carbon atoms which is vital for building up large, complex molecules; and closely related to these reactions, the carbonylation family, which produces oxygen-containing molecules such as organic acids, amines, esters, amides, aldehydes and ketones.

 

Most of Dynamic Synthesis's TMC operations are carried out by its Basle-based subsidiary, Rohner. The company's origins, like those of many European chemical companies, lie in the dyestuffs industry.

 

The Eastward movement of this industry to its new centres in Asia led to companies seeking new markets, and Rohner opted to use its expertise in making complex aromatic molecules in the related field of pharmaceuticals. This market had very different and exacting requirements from the dyes, explains Rohner's TMC project leader Adriano Indolese, which has led to many changes, both in terms of business and in technology.

 

The latter can be seen clearly at Rohner's manufacturing centre, with the installation last year of new equipment to carry out large-scale hydrogenation reactions in compliance with current good manufacturing practice (cGMP). Costing SFr13million, the hydrogenation train is centred around a 4000litre reactor vessel.

 

'We often need to promote reactions in acid media, so we needed to make the vessel from acid-resistant Inconel 686 alloy,' Indolese says. The vessel can also withstand temperatures in the 10°-160°C range and pressures up to 60bar.

 

The high pressure tolerance of the reactor was particularly important, because it enables the company to boost the efficiency of some of its reactions, Indolese says. For example, a fairly simple reaction, such as hydrogenation , has dramatically different results if carried out at different pressures.

 

Another major factor in the design of the reactor was the type of stirrer used. 'We found that the best design had angled vanes to promote circulation of the reaction mixture — it flows down in the middle of the reactor and up at the sides,' Indolese says. The train also includes a catalyst filtration section, a crystalliser, inverting filter centrifuges and stirred pressure filters for product separation, and a vacuum paddle dryer and pressure filter dryer.

 

The catalysts themselves are as vital a part of the process as the reactor and other equipment.

 

Dynamic Synthesis has a collaboration with Solvias, another Basle-based company which was part of Novartis until a management buy-out in 1999. Now acting as a catalysis technology provider, Solvias develops the catalyst for specific reactions, carrying out screenings, separations, and determining the optimum reaction conditions, then licensing the catalyst technology to chemical manufacturers like Dynamic Synthesis, which scale-up the process to production level.

 

Marc Thommen, product manager at Solvias, explains that the economics of catalytic chemistry can often extend beyond the control of process engineers. Catalysts frequently require valuable metals whose cost can outweigh other factors. 'The price of rhenium can be far more important than losing 3% in enantiomeric excess,' he comments.

 

One example of this was a project to find a catalyst that would reduce a double bond in a large crystalline free acid, creating a chiral centre in the molecule while preserving all of its other chemistry.

 

The molecule was needed for a drug about to enter phase III clinical trials, so a large quantity was needed. The client needed a workable catalyst within six weeks, Thommen says. The reaction needed a rhenium catalyst, but the team needed to home in on an effective ligand to direct the hydrogen to the right position on the substrate molecule. A screening process narrowed down the choice from an array of ligands based around a ferrocene species.

 

Tuning the substituents on the organic part of the ligand improved enantiomeric excess from 62% up to 95%. The final choice delivered this excess with 100% conversion in less than eight hours, below 80°C, and with a substrate to catalyst ratio of over 5000.

 

A multi-kilogramme consignment of the catalyst has now been manufactured and delivered. 'A real-world target requires a real-world catalyst,' Thommen comments, 'and I've never seen a ligand developed and supplied so quickly.'