Scale-up and Production

In a pilot campaign, altogether 17,392 kg of 3 were produced in 182 batches, each run in a 630 L hydrogenation reactor. The average yield was 92.2%, the average content was 99.0%, with 0.5% of the isomer 4. In all 1% yield was lost in 19 of the total 182 batches due to incomplete conversion. This was almost certainly caused by incursion of oxygen, probably in the H2 or N2 lines. All attempts to revitalize a reaction that had stopped, through addition of fresh catalyst, were unsuccessful. The toluene solvent was successfully recycled after distillation under N2. 

The optimized parameters from the lab experiments were only slightly modified as follows  

In order to minimize the risk of a failed batch on the production scale, the S/C ratio was lowered to 4200 1. The TOF (Turn Over Frequency) was 700 per hour. 

For the second production campaign of (J )-(S)-PPFP( Bu)2, the (R)-hydroxyethyl-ferrocene 7 was formed directly by borane reduction of acetylferrocene using (S)-MeCBS-oxazaborolidine catalysis [7] (see Fig. 8). Typically in laboratory studies, after conversion to the acetate with acetic anhydride a 91% yield with 88% ee was obtained. On a production scale 149 kg of crude 7 were prepared in 14 batches in a 500 L reactor in 88% yield, and 86% ee. 

The diastereoselectivity reached, even on a production scale, was remarkable. Although the chiral phenylethyl substituent certainly enhanced the selectivity of the hydrogenation, the results with the prochiral benzyl-substituted analogue were also very impressive. A licensing agreement was rapidly reached between Lonza and Ciba-Geigy for the commercial production. As a result of turbulence in the market price of (d) - (+) -biotin, Lonza did not continue with its production after the first campaign. 

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New synthesis ofTATB, scale-up and product characterisation. Proc. 31st Ind. Ann. Conf. of ICT, Karlsruhe, Germany, June 27-30, pp. 37/1-37/10. 

Mintzer, H. Scale-up and production considerations for therapeutic aerosols. Aerosol Age 30(3) 22-24 (1985). 

Selected excerpts and figures from M. Levin, Tablet Press Instrumentation for Product Development, Process Scale-Up and Production Quality Control, Education Anytime, CD-ROM Short Course, AAPS 1999 are reprinted with permission. 

Chemical or enzymatic hydrolysis of the chiral cyanohydrin gives access to 2-hy-droxycarboxylic acids. The most prominent examples are (S)- and (R)-mandclic acids, which are mainly used for racemate resolution. Other chiral acids, such as (R)-2-chlorom an del i c acid, are used as precursors for pharmaceuticals (see Fig. 11). Scale-up and production of (R)-2-chloromandelic acid was successfully performed with a space-time yield of 250 g/L/d (ee = 95%). 

It is of worthy of note that the International Conference on Harmonization (ICH, Guideline Q6A of the October of1999) includes under the heading of polymorphs single entity polymorphs molecular adducts (solvates, hydrates), amorphous forms . The FDA currently requires that pharmaceutical manufacturers investigate the polymorphism of the active ingredients before clinical tests and that polymorphism is continuously monitored during scale-up and production processes [42], The... 

This is the most demanding area for the chenfist. The requirements for scale-up and production are very different from those in medicinal chemistry/discovery and need a very different approach to chemistry. Yields for steps in a process are very frequently increased dramatically by intensive process research -improving literature reactions with reported yields of 20-30% up to a usable 80-90% is not uncommon. 

The requirements of scale-up and production are very different from those in medicinal chemistry and drug discovery and may lead to a very different approach to chemistry. The number of steps in the synthesis is a major determinant of cost, as are, of course, the costs of starting materials and reagents. Standard preliminary targets are for 90% hplc yields in each stage, with purification by crystallisation or possibly distillation in some cases chromatographic purification on a production scale, which may be in ton quantities, is very rare. 

The present paper will describe a number of issues related to optimization and quality assurance during scale-up and production of the Statoil Co/Re/alumina catalyst. 

Many facets of the container/closure system should be taken into consideration to expedite the development, scale-up, and production processes for lyophilized materials. It is important to remember that just as every drug product is unique, so is its packaging requirements. A thorough evaluation early in the development process will help to avoid problems later in the cycle. 

Caspeta L, Nieto I, Zamilpa A, Alvarez L, Quintero R, Villarreal ML (2005) Solanum chrysotrichum hairy root cultures characterization, scale-up and production of five antifungal saponins for human use. Planta Med 71 1084—1087... 

Thijssen J (2007) The impact of scale-up and production volimie on SOFC manufacturing cost, 4 Feb 2007. http //www.netl.doe.gov/technologies/coalpower/fuelcells/publicationsAIT% 20Manufacturing%20Study%20Report%20070522.pdf. Accessed 10 Jan 2011... 

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