Dilevalol hydrochloride

Undertaking manufacture of early launch bulk actives for Marketing was always controversial. It occurred in one case (see presentation on dilevalol hydrochloride) and, as it happened, the early launch manufacturing strategy saved enormously, by... 

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... 

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 impurity profile (synthesis related impurities) was actually better for dilevalol than for the parent compound, labetalol, reflecting the benefits of further purification during the DBTA resolution step. Thus, although dilevalol hydrochloride contained traces of DBTA itself, no tertiary amine impurities or brominated dilevalol could be detected—both types of impurity are present at very low levels in labetalol. 

Would the dilevalol hydrochloride obtained by this Scheme contain any new impurities which would complicate the Regulatory registration process ... 

Could the work needed to demonstrate and prove that the simplified process gives dilevalol hydrochloride acceptable to Regulatory Affairs and the FDA be done in the time frame needed to update the IND prior to NDA filing ... 

Dilevalol DBTA Salt to Dilevalol Hydrochloride. Very little improvement in the RR composition results from the transformation of dilevalol DBTA salt to dilevalol hydrochloride. Ethyl acetate was used as the solvent vehicle in early work. In a search for a more stable solvent methyl isobutyl ketone (MIBK) was selected as the best alternative. DBTA was removed by extraction into water with sodium hydroxide (DBTA of excellent quality was recovered from the aqueous phase in high yield >90%). The MIBK solution of dilevalol was then treated with hydrochloride acid to precipitate dilevalol hydrochloride (Scheme 9). The pH needed for maximum efficiency in the crystallization of dilevalol hydrochloride was 0.5 (this is in sharp contrast to the pH required for maximum efficiency in the crystallization of labetalol hydrochloride—pH 3.0). It should also be noted that dilevalol hydrochloride could not be handled in stainless steel equipment. Hastelloy, plastic or ceramic equipment was employed to eliminate the risk of coloration of dilevalol hydrochloride by traces of iron compounds. The plant equipment layout for this step is shown in Figure 5. 

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. 

The work carried out on the dilevalol hydrochloride step was undertaken in close collaboration with Schering Manufacturing in Ireland, who contributed greatly to the establishment of the IND/NDA process conditions for final API preparation. The more aggressive process conditions of temperature, coupled with the use of a pH < 1, as employed in the MIBK-based production process, were examined in depth. It... 

FIGURE 5. Equipment for conversion of dilevalol DBTA salt to dilevalol hydrochloride... 

The product of the simpler synthesis was compared in detail with the product of the RR-amine process. In particular, the Research Quality Control Unit searched for the presence of different polymorphs and new impurities (e.g., the dialkylation byproduct from the first step). They compared the stabilities of both products and also compared the hardness and dissolution rates of tablets made from both products. Since the DBTA resolution, crystallization, and product isolation steps, as wll as the final dilevalol hydrochloride preparation step, were the same for both the RR-amine process and the simpler synthesis, it was anticipated that these steps should protect against the introduction of new impurities or changed physical parameters in the final crystalline product. Such proved to be the case. 

Additional needed process equipment was evaluated, selected, purchased, and set up. Automation opportunities were defined, and process control instruments were tested, purchased, and installed. An existing clean (HEPA-filtered) area was upgraded for the final isolation of the dilevalol hydrochloride made in New lersey—this was needed to serve the requirements for the parenteral dosage form. 

Detail of the 50-60°C crystallization of dilevalol hydrochloride from MIBK/ water. A comprehensive comparison report with the earlier process using 25°C hydrochloride crystallization temperatures was provided. 

For the manufacture of dilevalol hydrochloride (and other APIs), Schering created needed process and control documentation and set up formal compliance programs to ensure GMP guidelines were met. Major programs for ensuring GMP compliance include ... 

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... 

The process evolved to one in which the converting enzyme was isolated and used in a batch process with a small amount of pyridoxal 5-phosphate as co-factor and pyruvate as the amine acceptor.12 This process was in a pilot plant phase when dilevalol hydrochloride was withdrawn from the market. 

Alternative Routes to Dilevalol Hydrochloride. The major disadvantage of the NDA... 

Since this process involved an Aspergillus fermentation as the last chemical transformation step, considerable concern was expressed concerning possible contamination of the dilevalol hydrochloride with such as citrinin or allergenic proteins. All test carried out by the time dilevalol hydrochloride was withdrawn were negative. However, a full testing program had not been completed. 

The withdrawal of dilevalol hydrochloride represents a unique milestone. As far as the author is aware, this is the first case wherein a deliberately produced chiral API may have demonstrated more toxic liability than the racemic mixture. 

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