Rethinking the process

Graham Lampard visited Bede, a company founded out of an academic idea, which is using X-ray analysis to help in drug formulation analysis and product control

Too often academics are accused of living in the clouds, without consideration for the real world. Having been in academia for 30 years, Keith Bowen, group director of technology for Bede, could have been one of them. However, when he and Professor Brian Tanner, of Durham University, had an idea about X-ray analysis, rather than write a learned paper about it, to collect dust on university bookshelves, they formed a company, and Bede was formed.

The company is named after the Venerable Bede, an English scholar, scientist and historian.

Twenty-five years later, Bede is a leader in X-ray analysis solutions, and the holder of a worldwide group of companies, with bases in Denver in the US, Shanghai, China, and the Czech Republic.

The first use of the analysis was for the semiconductor industry, where the necessity for an automated tool to produce a 12 inch silicon wafer robotically led to the development of the Bede FAB series. The analysers are fabrication-line (fab-line) metrology (the scientific study of measurement) tools, with complete automation in wafer loading, alignment, measurement and interpretation of the product wafer.

The high intensity beam, delivered by a patented X-ray microsource, enables diffraction data to be collected from areas on patterned wafers as small as 0.3mm². The analyst can then determine numerous parameters including thicknesses, roughness, composition, polycrystalline stress, texture and phase identification.

further growth

Having become market leader for X-ray analysis in that industry, Bede decided that expansion was necessary to achieve further growth. It chose pharmaceuticals because, as Bowen put it: 'The pharma industry is a little behind the semiconductor in automation, but a little ahead in the regulation.'

And the synergy between the two industries is helpful; both need consistency and excellent repeatability, something Bede developed in supplying the electronics industry. Another example is 21CFR Part 11 traceability, the architecture for which is integral in Bede's products.

Bowen said that in drug design the correct polymorph is very important. For instance, the anticancer drug Etoposide, a DNA synthesis inhibitor, in its most stable solid form has a very low bioavailability due to its poor solubility. However, there is a new metastable polymorph that has an increased solubility by a factor of about two. And using X-ray analysis can elucidate structures. To enable pharmaceutical companies to do just this, both in the finished product and during process, Bede developed the BedeMonitor. It is one in a range of new pharmaceutical instruments from Bede that helps ensure the correct polymorph is crystallised.

crystallisation monitoring

It is an on-line X-ray diffraction instrument designed to measure powder patterns from in-process materials. An example is the monitoring of crystallisation of products and intermediates from solution. The equipment can be configured to suit different applications and measurements with appropriate choice of components.The monitor is connected to the crystallisation tank via a closed-loop, and therefore controls in real-time the crystallisation of compounds. The risk of producing undesired polymorphs is minimised as the process can be stopped at an early stage if the incorrect enantiomer is produced.

The thermally controlled cell allows the sample to be recirculated through the measurement zone. This could, of course, be a sub-sample from a larger stream. Thermal regulation is particularly important in crystallisation processes as temperature can directly affect the formation of crystals: the cell and sample pipe work are jacketed with temperature control fluid. The Microsource, a compact, high brightness X-ray source, is also a development.

new consortium

The monitor was developed as a result of Bede's appointment as a key member of a new consortium called Control and Scale up of Batch Crystallisation for Organic Speciality Chemical Products - or 'Chemicals Behaving Badly', as Bowen put it - an Engineering and Physical Sciences Research Council (EPSRC) supported research programme.

The project aims to improve in-line measurement techniques for controlling the production of high value-added chemical components in the pharmaceutical and agrochemical markets; other project members include Malvern Instruments, Pfizer, GSK and AstraZeneca.

An advantage of having a group of companies under one umbrella is the ability to call on experts. Reflex s.r.o., based in Prague in the Czech Republic, is Bede's technology provider for detectors and X-ray optics as well as its expert in mirror optics. It produced the Sollimator, technology that dramatically improved light transmission from the source by replacing metal foil slits with thin glass foils that increased transmission from around 30% of the light source to 75-80%.

size determination

Originally developed for the astronomical industry, the technology is now included in the BedeAnalyst, a powder X-ray diffractor designed primarily for the high performance powder diffraction of pharmaceutical samples.

The instrument can determine in a single measurement composition, uniformity or particle size distribution during production, formulation or in the finished product and it has a tablet mapping facility.

Special attention has been given to peak accuracy, resolution and symmetry, and to low angle performance. This means the instrument can be used for demanding powder applications on any material, such as Rietveld refinement for structure analysis.

A typical use would be analysis of non-steroidal anti-inflammatory drug tablets. Work carried out using the Analyst showed that with a particular formulation the product degraded after only two hours' atmosphere exposure, which may affect its pharmacokinetics.

Tablet mapping can use either transmission or reflection modes, depending on the quantity to be measured, but the real advantage is that the test is non-destructive, with automated data collection and analysis, and Bede-designed graphical representation. The analyser could also be used to show whether generic drugs have the same API as the patented version, or to determine the distribution of the api in the generic compared with the patented drug, i.e. tablet mapping. Again, variation may affect the pharmacokinetics of a generic compared with the patented version.

Given the increasing levels of legislation and testing demanded by the regulatory bodies, both instruments are set to help pharma companies better control of their drug production, which should ensure Bede's influence extends far beyond the laboratory.