Green API Manufacturing - Pharmaceutical Technology

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PharmTech

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PharmTech Europe

Green API Manufacturing
Pfizer uses green-chemistry in a second-generation manufacturing route for gabapentin.


Pharmaceutical Technology
Volume 33, Issue 9, pp. 46-48

Material usage. Mass balance, or the amount of raw materials, solvents, or reagents used per kilogram of product, and the related costs were also examined. Key questions in this evaluation were:

  • How is the material used in the process (i.e., is it converted or does it have to be recovered)?
  • If recovered, how and at what point in the synthesis is the material recovered?
  • Can the material be reused or is it treated as waste?
  • If recovery or reuse is involved, is the recovery or reuse economical or can such costs be minimized?

Implementation. The reengineered process also had to be adaptable not only to the Singapore facility, but to all Pfizer plants that produced gabapentin. These process-design changes would have to be made with little or no costs as part of a mandate to cut costs while reducing environmental impact.

With these considerations in mind, several challenges existed:

  • Producing gabapentin at a low cost in large quantities
  • Using less capacity, labor, and energy while reducing chemical use and waste and maintaining robust processing and quality
  • Reducing carbon-dioxide emissions consistent with Pfizer's standards
  • Ensuring consistent quality and no increase in impurities as a result of the new process
  • Fitting the new process within existing physical-plant capabilities.

Second-generation process

Solvent reduction. Reducing the amount of organic solvents in the first-generation gabapentin process was a key focus. Because gabapentin has relatively high water solubility, the main challenge was to ensure maximum product recovery from an aqueous crystallization matrix. To achieve this goal, a new reagent that had the ability to be functional in water was needed to eliminate the need for organic solvent carriers.

Two reagents—sodium hydroxide and potassium hydroxide—were examined. The sodium hydroxide generated a salt that was far less soluble and had the potential to be a contaminant in the final product. Potassium hydroxide was an ideal answer because of its high water solubility of the corresponding salt. It also simplified the purification process by eliminating distillation steps. In the earlier process, distillation was required, which required large quantities of solvent. In the new process, there was no distillation; the product was crystallized directly from the reaction solvent, which in this case was water. Distillations are slow, consume a lot of capacity, and are energy-intensive. Eliminating the distillation step and using water as a solvent resulted in significant savings.

Maintaining formulation characteristics. The new process also had to maintain the ability of the API to be formulated either by powder flow or compaction as was the case with the original process. These parameters were satisfied based on the reagents selected for the new process and the way this facilitated crystallization in the water-based solvent.

Lessons learned

Certain key points drove the project's success. First, scientists and engineers must understand all the financials of their own processes and designs and be able to target and easily quantify any improvements. This evaluation can be challenging because it is outside normal technical training. A firm knowledge of target expenditures, materials, operator costs, labor, overhead, and waste are critically important. In addition, keeping the manufacturing process as simple as possible and striving for the most efficient processes using innovative chemistry and technology is important. A well-established process may have hidden value if a financial focus and innovative science are applied. The improved efficiency and cost savings introduced in the second-generation process for producing gabapentin allowed Pfizer to remain competitive in the manufacture of gabapentin. This fact is a valuable lesson for process chemists and engineers.

For more on this topic, see "A Green Manufacturing Route to Testosterone."


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