Process Safety and Reaction calorimetry

In many batch processes, I keep observing companies hesitant to spend money to obtain reaction data prior to scale up to plant scale. The old adage "we have never done it before and nothing has happened" is often the answer. One incident that happens due to lack of understanding of reaction chemistry is enough to wipe out ALL your gains.An article written in 1991 points out the need for complete data prior to scale up to plant scale. One of the case studies mentioned is quoted below:
"A specific example of this type of approach was given by Homare Shinohara, of Eisai Chemical Co, who described the design of a manufacturing plant for pharmaceutical intermediates based on amino-thiaziazol carboxylic acid, generally known as F-15. Thiaziazol compounds are often used as a side chain at the 7-position of cephalosporin antibiotics. Thiaziazol carboxylic acid chloride (F-15Cl), for example, is being used at Eisai for the synthesis of two new antibiotics currently under development, E-1040 and E-1077. E-1040 is an injection drug, which is said to have the strongest bactericidal activity against Pseudomonas among the cephalosporins currently available, although less efficacious against Staphylococci. It is currently proceeding to Phase III testing. A development of E-1040, E-1077 is described as a fourth-generation cephalosporin having a wide spectrum of antibiotic activity from Gram-positives including Staphylococci to Gram-negatives including Pseudomonas. This compound is currently in e-phase II testing in Japan.
For the production of these compounds F-15 must be chlorinated. However, this intensely exothermic reaction can also produce two kinds of by-products: anti-F-15 acid chloride and phosphoric-amide-F-15 acid chloride. The resultant concentrations of these by-products is directly dependent upon the temperature of the reaction mass.
As a preliminary, the decomposition temperatures of the starting materials and final desired product were determined to confirm their safety. Shinohara's research team then used a Mettler Contalab to firstly determine the conditions required to suppress byproduct synthesis and then measure the heat of reaction to assist in the final plant design. To confirm the results the heats of reaction were also calculated using a Mettler RC 1.
It was determined that the reaction temperature should be maintained below -10ºC and that reaction heats generated depended upon the method of addition of phosphorus pentachloride - continuous, one or two portions. Although at 400 kJ/kg the reaction heats produced with continuous and one portion addition were 50kJ/kg higher than that for a two portion addition, possibly due to the absorption of heat by simultaneous crystallisation, it was decided to base the plant design on a 500-litre, glass-lined reactor with continuous addition of phosphorous pentachloride over a 30-minute period.
On calculation of the heat removal capacity of the jacket on the reactor using brine at -30¡C it was found to be insufficient to maintain the temperature below -10¡C. Further calculations determined the phosphorus pentachloride addition period would need to be extended to 3.3 hours, despite pilot-scale production of 5kg batches being satisfactorily achieved with additions over 30 minutes".
Read the full article with other examples in this link.