Case study 4

API particle synthesis


The OmnipaqueTM and VisipaqueTM X-ray contrast media are used throughout the world. GE Healthcare is the market leader with a share of approximately 40% of the global market, which is growing by 6-8% annually. The Lindesnes site in Norway is the company’s only facility producing the active pharmaceutical ingredients iohexol and iodixanol. These active ingredients were developed in Norway and have been manufactured at the Lindesnes site since 1982 and 1990, respectively, so the product patents expired many years ago.

The switch from discontinuous to continuous processes is considered particularly important because iohexol and iodixanol are now produced in very large discontinuous reactors (up to 40 m3 ), making it difficult to operate under homogeneous conditions.

This case study focuses mainly on the synthesis and crystallization of the important intermediate 5-acetamido-N,N‘-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, hereafter referred to as compound 541. For simplicity, pharmaceutical intermediates such as compound 541 will be grouped under the general heading of active ingredients. Crystallization of compound 541 is the final step in Fig. 1.8 and is accomplished by addition of hydrochloric acid, followed by distillation and cooling.

In recent years, GE Healthcare has been investigating the transfer of crystallization from batch to continuous mode. In collaboration with Prof. Xiong-Wei Ni from the Harriot-Watt University (partner in this project) and other external partners, crystallizations were performed in a COBR. The number and location of injection points for the hydrochloric acid was an important area of investigation, as this resulted in significant scaling and misfiltration characteristics of the crystals.

Objectives of SIMPLI-DEMO

SIMPLI-DEMO aims to develop crystallization into a COBR pilot plant.

In addition, the use of microwaves and ultrasound can benefit the production process in several ways. The interaction of microwaves with very polar solvents such as MeOH/H2O can increase the solubility of the intermediate compound, thereby reducing the volume of solvent required, making the whole process more compact and the downstream distillation less energy consuming.

  • Microwaves can also be used to rapidly evaporate the solvent at the end of the synthesis step to shorten the process time and produce high supersaturation. Finally, the novel COBR with internal MW antennas developed under the SIMPLIFY project is also expected to benefit the synthesis process in terms of more efficient descaling.
  • In particular, the new COBR/MW provides the flexibility to adjust local heating and local temperature, and thus local supersaturation level, as needed. In addition, Ultrasound has been shown to have great potential for improving crystallization processes.
  • Ultrasound can be used for three purposes in this case study, to achieve the reduction of induction time and increase of nucleation rate, to reduce scaling by intense micromixing, and to use cavitation bubbles as nuclei.