Kromasil^® notes

A brief history of preparative liquid chromatography

Traditional preparative liquid chromatography was born in 1903 when the Russian botanist M. Twsett made the first separation of carotene pigments. The columns he used were made of glass, they were packed with gravels and were basically operated at atmospheric pressure. This situation kept unchanged for many years, until the 1960’s when organic chemists began to use stainless steel columns operated at a few bars.

A major event in the history of preparative chromatography happened in 1974 when Roussel Uclaf (a former pharmaceutical French company, now owned by Aventis) patented the concept of dynamically compressed columns (columns equipped with a piston and allowing to compress the chromatographic bed), thus opening the door to the birth of Modern Preparative Chromatography (MPC).

MPC is a real revolution in the history of chromatography and one could probably also say in the history of the pharmaceutical industry. MPC makes use of Dynamic Axial Compression (DAC) columns packed with micro particles (typically 10 µm) of silica-based robust material and operated at medium/high pressure (30-70 bar). Right after it was invented, MPC found a major application in the pharmaceutical industry: the “polishing” of insulin. By polishing it is meant the removal of impurities structurally very close to the insulin molecule. This requires high efficiency columns (in terms of number of theoretical plates). This started at the end of the eighties at pharma company Ely Lilly (Indianapolis, USA). In 1989, Lilly published for the first time the purification of insulin by MPC. Since this date, MPC has experienced a worldwide recognition in the pharmaceutical industry and a formidable growth. If insulin polishing is probably still the largest application, there is a very large number of molecules in the pharma industry (Active Pharmaceutical Ingredients, APIs) which are purified today using PMC. And there are many reasons to believe that the future of MPC is very bright considering the more and more drastic conditions put on purity by the relevant authorities, the greater and greater complexity of APIs and the development of the technique itself, both practically (with alternatives such as SFC – Supercritical Fluid Chromatography, SMB – Simulated Moving Bed, etc.) and theoretically (with more and more powerful optimisation and control tools). It must also be mentioned that with more than 500 million people with diabetes today to be treated, insulin will be needed in large quantities and MPC will continue to be extensively used.

What is behind the great story of MPC is the High Performance Concept. This is basically the use of columns offering a large number of theoretical plates (a few thousands) in a (relatively) short time. As a matter of fact this is quite similar to the situation with analytical columns.

It is an interesting coincidence that the two companies which really promoted the High Performance Concept started their businesses at the same time (1986): Eka Chemicals introduced its Kromasil line almost at the same time as Prochrom (later acquired by Novasep) acquired the Roussel Uclaf licence and introduced its DAC columns line and ancillary equipment specifically designed for the pharmaceutical industry. A long and successful story for these companies!

As a final word, it is worth noting that MPC is probably one of the very few chemical processes (the only one?) that can be directly scaled up without any specific adjustment: a process developed with a column of a few mm internal diameter can be scaled up more than 100,000 times! This is certainly a very important explanation to the success of MPC in the industry.