Process Optimization

Which parameters are screened? In process optimization, the most promising route based on the results of the process screening is selected. The yields from each step should be good at this point. However, there remain many challenges in developing a process from the chosen synthetic route. To improve process efficiency, the space-time yield should be optimized, the work-up developed, and the workflow streamlined. These effects can be achieved by minimizing in-between isolation steps, using the same solvent for different steps, or recycling solvents. In addition, if the planned process will have conditions that are extreme in some respect, for example temperature, corrosion, or heat production, it is advisable to have a specific vessel in mind while optimizing the reaction. Some important parameters to take into consideration are the kinetics of the reaction, the effects of differing rates of addition, stirring speed, the effects of heating and cooling ramps on the reaction rates, and the impurity spectrum.

An efficient work-up sequence often determines the total process performance. Therefore, during process optimization, the batch size should be sufficient to allow representative extractions, filtrations, or distillations. We have set up a dedicated laboratory to determine the relevant design parameters from small batches.

What are the requirements for the parallel optimization equipment? The vessel should have a volume of 50-250 mL, a mechanical stirrer, an independent heating/ cooling aggregate as well as an accurate temperature control. Calorimetric analysis is advantageous at this stage; reflux condensers and metering pumps for the re-actants are necessary as peripheral equipment.

Examples of commercially available multiple reaction stations for process optimization Well-known systems for process optimizations are the Auto-Mate from HEL, the FlexyLab from Systag, the MultiMax from Mettler-Toledo and the Surveyor from Argonaut (Table 30.3).

The workstations mentioned above have the following features in common: an independent temperature control for each vessel, a PC-based control, and data analysis software. For the basic system, they all have a price of between 100,000 and

Tab. 30.3. Workstations for parallel process optimization.

Workstation

Number of

Vessel size (mLj, agitation

Temperature

Price

Internet;

simultaneous

control, individual

categorya

http:/¡www

reactions

(yes/no)

Systag, FlexyLab

4 (up to 6)

250 mL mechanical

Yes (—80)—280 °C

D

Systag.ch

HEL, auto-MATE

4 (up to 16)

20-100 mL mechanical

Yes (—80)—350 °C

D

Helgroup.co.uk

Mettler Toledo, MultiMax System

4 (up to 16)

50 mL magnetic

Yes (—50)—180 °C

D

Mt.com

Argonaut, Surveyor

10

45 mL magnetic, vertical

Yes (—40)—150 °C

E

Argotech.com

HEL, auto-MATE High pressure

4

100 mL, stainless steel, 200 bar

Yes (—80)—350 °C

E

Helgroup.co.uk

a Price categories: A = <10 T€; B = 10-25 T€; C = 25-75 T€;

D = 75-125 T€; E = 125-175 T€. b Numerous names of companies and equipment used in this table are registered trademarks.

a Price categories: A = <10 T€; B = 10-25 T€; C = 25-75 T€;

D = 75-125 T€; E = 125-175 T€. b Numerous names of companies and equipment used in this table are registered trademarks.

150,000 euros. At the time of writing, the Auto-mate from HEL has been on the market for about 2 years and has users in most pharmaceutical and fine chemical companies. It has four mechanically agitated vessels per unit (volume 50-100 mL), the opportunity to monitor calorimetric data, and a whole set of extension equipment at an additional charge. From the chemist's view, the transparent glass setup has the advantage that one can recognize color changes or precipitations in the reaction mixture. Recently, the Automate has become available in combination with an x, y,z robot for automated sample collection and handling - named DUET.

The four FlexyLab reactors are of larger size (volume 250 mL) and can be run completely independently. They come with two mass-controlled liquid dosage units with flow inducers for each reactor. The reactor head has two standard NS 14/NS 19 glass joints, convenient for attaching standard laboratory equipment. The temperature difference between the two reactors can be up to 200 K, depending on the cooling aggregate.

The MultiMax from Mettler-Toledo is a compact system with four 50-mL reactors and a dispenser box for one reagent. Three standard glass joints in the reactor head allow the attachment of additional equipment, and agitation is carried out with a stirring bar. Additional features such as mechanical stirring and additional dosage units may be added; the STAVEX program for statistical experimental design and the possibility of equipping the system with online in situ FT-IR analysis are useful additional features.

The Surveyor has been developed by Argonaut Technologies for process development chemists. It has ten transparent Teflon reaction vessels with a volume of 75 mL and an integrated x, y,z robot. The typical magnetic Argonaut agitation system provides good mixing even of viscous media and suspensions (although the transfer quality to common plant stirrers has not been examined). Online sampling and the integrated HPLC analysis (not included in the basic station price) are interesting for determining reaction kinetics, an important issue during the process optimization. With ten parallel reactors and a working volume of 45 mL, this system could also be useful as a process-screening workstation.

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