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Unblocking a QC bottleneck using protection-deprotection chemistry

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The Problem

· Client came to APC looking to synthesize analytical standards for difficult-to-make, unstable impurities. The inability to access these compounds was creating significant delays in the regulatory filing process.

The Breakthrough

· Using an innovative synthetic approach, APC was able to harness the power of protection-deprotection chemistry to develop a scaled-up synthetic process for each impurity that delivered gram-scale amounts of analytical standards at a purity of > 99%.

The Impact

· The client can now quantify the impurities in the drug substance and include a quantitative method for quality control to regulatory bodies to aid in the filing process.

Accurate and reliable quantification of impurities in drug substances and drug products is not only the cornerstone of quality control but is also an integral part of the regulatory filing process. Some impurities, although well known, do not have commercially available analytical standards due to the degree of complexity required to synthesise them at the high purity needed for analytical quantification.

During a routine crystallisation project, it became evident that the client had no method of quantifying the amounts of two of the impurities present in their drug substance and their final drug product since the impurities were in equilibrium and could spontaneously interchange. This chemical behaviour posed an interesting challenge in synthesising each substance at a purity equal to or higher than 95% without generating the other. Adding to the complexity of this problem, multi-gram high purity material was needed to support validation of the quantification method as well as routine usage during manufacturing.

The chemistry team at APC developed two unique, albeit similar, synthetic pathways for each impurity at small-scale, using silyl protecting group chemistry and column chromatography purification followed by two-step deprotection (including hydrogenation) as a proof-of-concept. Once the feasibility of high purity synthesis was ascertained, the process was scaled up to yield gram-level quantities of highly pure material.

The value to the client was not only the delivery of the required analytical standards, but APC also provided detailed synthesis procedures, enabling the client to synthesise their own standards going forward if required.