Green API Manufacturing - Pharmaceutical Technology

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


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


(IMAGES: IMAGE SOURCE, GEORGE DOYLE/GETTY IMAGES)
When generic competition increased for Neurontin (gabapentin), Pfizer (New York) examined ways to improve efficiency and cost reduction in its manufacturing process for the active pharmaceutical ingredient (API) at the company's bulk-manufacturing facility in Singapore. The company formed a multidisciplinary team of process-development chemists, analysts, and chemical engineers to develop an improved manufacturing process. The result was a more than 50% reduction in costs and a 17% reduction in waste. To develop the new process, Pfizer conducted an in-depth examination of the plant's current systems, processes, and capabilities, and completely reengineered the gabapentin process, which involved developing a green-process route.

Economies of scale


Figure 1: Molecular structure of gabapentin. (Figures 1 and 2 are courtesy of The author)
Ongoing market intelligence made it clear that to sustain a competitive edge, Pfizer needed to challenge its own production capabilities. A green process was the logical approach because it would eliminate or minimize unnecessary processing or materials. All inputs were considered: solvents, raw materials, labor, time, or other factors involving the environmental footprint in the manufacture of gabapentin.


Figure 2: Process route to gabapentin.
The molecular structure of gabapentin is shown in Figure 1. Because the product had been manufactured with an optimized process for many years, part of the challenge was to be able to realize transformational, not simply incremental process changes. The synthesis for gabapentin is shown in Figure 2. The pH of a solution of gabapentin 6K+ is adjusted by the addition of an acid. During the addition, gabapentin crystallizes from solution, and the K. acid byproduct remains in solution. The batch is cooled, and the gabapentin product is isolated. The high solubility of the K. acid in the isolation matrix ensures that it is removed in the mother liquor removal and washing sequence and does not contaminate the product. A series of detailed assessments were made to examine ways to improve the process.

Plant throughput and efficiency. Throughput, or the number of kilograms that could be processed through a certain reactor in a specified amount of time, was examined. Each reactor was assessed to determine its capability within the overall process. The number of steps involved with each reactor was also examined to determine if or where a bottleneck might exist and how that bottleneck may be reduced or removed. This assessment is particularly valuable when special equipment such as a hydrogenator or a low-temperature reactor is involved. A hydrogenator is used in the gabapentin process.


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