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Cedarburg Pharmaceuticals Inc. Case History #20042
Collaboration with Cedarburg Proves Successful in Achieving Technical Transfer and 16-Step Synthesis.
Project Background
A virtual pharmaceutical company faced a three-phase challenge. The company had acquired a product from a major pharmaceutical company. Thus, a significant technical transfer of information, related to both the drug substance (API) and drug product production, was required. Requirements included:
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Completion the synthesis from intermediates available from the major pharmaceutical company to provide 25 g of API, and purify part of it as a reference standard. Develop analytical methods required to qualify this standard. |
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Development of the synthetic steps to provide a safe, economical commercial process for scale up. Previously, the final product was isolated by freeze drying (lyophilization), which was expensive and provided no improvement in product quality. A procedure to crystallize this product was sought. One of the key steps involved reduction of a double bond. Hydrogenation alternatives were to be looked at, and if time permits, asymmetric hydrogenation. The improved process was to be demonstrated on a 100 g scale incorporating the necessary analytical methods and in-process controls. |
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Synthesis of 3 kg of cGMP product utilizing outsourcing pilot plant facilities. We recommended a sixteen step synthesis that involved collaboration with Cedarburg's technical consultant and alliance partner, Dixie Chemical. The decision to involve Dixie was based on the resource requirements for this large project, Dixie's expertise on several synthetic steps of this convergent synthesis, and the larger volumes potentially required at the commercial scale. |
Project Results - Overview
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The effort to prepare 25 g of API from existing intermediates (37 g prepared), of which part was further purified to be a reference standard, was successful. |
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Approximately 100 g was synthesized for lyophilization studies on schedule. |
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The yields of many steps were improved, increasing volume productivity and substituting a more efficient catalytic hydrogenation procedure in place of hydride reduction. |
Project Results - In-Depth
The effort to prepare 25 g of API from existing intermediates (37 g prepared), of which part was further purified to be a reference standard, was successful. However, this requirement was complicated by the introduction of a new analytical method with increased sensitivity. Despite the requirement to meet a higher standard, a reference standard was prepared which was significantly purer than any previously prepared material.
The development efforts were coordinated between Cedarburg Pharmaceuticals and Dixie Chemicals by Cedarburg's project manager. Dixie focused on each leg of the convergent synthesis up to a stable intermediate, including the preparation of two key reagents.
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Cedarburg completed the synthesis of each arm of the convergent synthesis and undertook the critical combination of these components to make the final API. |
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As with earlier attempts by the pharma company, our efforts to crystallize the final product were not successful. Approximately, 100 g was synthesized for lyophilization studies on schedule. |
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Dixie initially evaluated the route obtained from the major pharma company, and then undertook a program of improving critical steps in the synthetic scheme. They were successful in improving the yields of many steps, increasing volume productivity and substituting a more efficient catalytic hydrogenation procedure in place of hydride reduction. |
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Time did not permit an investigation into asymmetric hydrogenation methods, which will be addressws in the future. |
The third phase of the project was modified at the customer's request. Instead of scaling up the process to make 3 kg, the customer wanted three batches of cGMP product as soon as possible to be used in upcoming clinical trials. Not only was the overall purity of the product increased, but also the amounts of individual impurities were to be lowered (recall that no final recrystallization procedure was available).
Dixie was contracted to make the key intermediates under cGMP, which would be converted at Cedarburg to the final API. While the first two batches met the customers assay specifications, one impurity remained at unacceptably high levels. The third synthesis was delayed while a team of synthetic and analytical chemists worked to solve this problem. Conditions for minimizing this impurity were found, and the last GMP batch met all of the customer's requirements (i.e. quantity, assay, and impurity levels).
The successful conclusion of this project was due to the thorough initial planning of each phase, the tracking of each team's progress on their timelines and frequent communication through bi-monthly meetings, e-mails and telephone conversations. Communication on the team's progress to the customer resulted in their confidence that the project was on track, such that they rarely participated in the meetings. The project has now moved to the next phase, where Cedarburg and Dixie will be synthesizing multi-kilogram quantities for qualification and validation batches in our respective pilot plants.
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