Dilevalol hydrochloride development

Distillation is one of those unit operations that assumes its importance based on the scale of operation. Clearly, distillation is one of the most important operations in a petroleum manufacturing plant where separations of closely boiling liquids require sophisticated distillation column design, built upon detailed theoretical plate determinations, material of construction issues, and secondary distillation requirements. In the pharmaceutical industry, the recovery and recycle of a solvent (versus incineration) depends on process scale. Further insight into the problems that might be faced in recovering solvents (and reagents) is provided in the section entitled Dilevalol Hydrochloride Development of a Commercial Process. ... 

The use of a Kraus-Maffei type of containment unit is described in the case study entitled Dilevalol Hydrochloride Development of a Commercial Process (q.v.). The... 

CASE 1 DILEVALOL HYDROCHLORIDE—DEVELOPMENT OF A COMMERCIAL PROCESS... 

The old process for the manufacture of albuterol5 requires the use of a number of chemicals, particularly formaldehyde and bromine, which are classified as extremely hazardous substances (and subject to reporting requirements under EPCRA and CAA—see later). Clearly, we preferred not to handle these. At the time, albuterol manufacture, because of its small volume, was being carried out in Chemical Development plants. Because we were enjoined to reduce wastes as part of our RCRA and EPCRA commitments, we initiated a search for a better and simpler process. Such a process evolved from our work on the manufacturing process for dilevalol hydrochloride (q.v.). Scheme 1 summarizes our first new process starting with low-cost methyl salicylate.6... 

The conditions used in the hydrochloride formation/crystallization step were somewhat different when MIBK/water was used in place of ethyl acetate. In particular, hydrochloride formation needed to be carried out by adding concentrated hydrochloric acid to the MIBK solution of dilevalol base at ca. 55°C (versus ca. 25°C for ethyl acetate). In this way, oiling out of the hydrochloride salt was avoided. A small amount of citric acid was included in the crystallization system to chelate any traces of iron which may be introduced. The amount of water in the system is more than sufficient to dissolve the small amount of citric acid—in early versions of the process, using much less water, precipitation of some citric acid caused a slight discoloration of the dilevalol hydrochloride. The crystallization conditions were carefully chosen to produce a crystal which filtered and washed well, which dried well (to MIBK <0.5%) and which gave a bulk density (ca. 0.3 g/ml) which met Pharmaceutical Development s criteria for operation of their tabletting process. 

At the time of the FDA s pre-approval inspection (our first) of the Chemical Development dilevalol DBTA manufacturing operation (dilevalol hydrochloride itself was manufactured in Schering s Ireland facility), Chemical Development received an FDA 483 notification stating that the full-time use of the butanol/water recrystallization process for dilevalol DBTA salt was in violation of the NDA. The NDA stated that the recrystallization process was registered for use only when the first crystallization of the DBTA salt gave a product outside specification the FDA interpreted this to mean no more than about 10% of the time. Since the process had evolved... 

---