Posaconazole Impurities: Implication on Drug Quality and Safety
Posaconazole, a powerful antifungal agent belonging to the triazole class has demonstrated high efficacy and safety in the prevention and treatment of invasive fungal infections in humans Consequently, Posaconazole has emerged as a first-line drug with a pressing demand. However, the lack of a practical synthesis method has significantly hindered the further development of Posaconazole impurities. Additionally, controlling impurities effectively is essential to ensure the quality and safety of active pharmaceutical ingredients (APIs) during their preparation Therefore, it is significant to explore an economical and efficient synthesis route that can be applied on a large scale to produce Posaconazole impurities.
Initially, the Schering-Plough Research Institute reported a systematic synthetic method for Posaconazole. However, this process generated impurities that required removal through column chromatography, making it unsuitable for large-scale production and resulting in a lower yield. Subsequently, alternative synthesis methods based on the Schering-Plough route were developed, offering more mature and efficient approaches.
However, further practical implementation of the manufacturing process was necessary, as certain steps, such as debenzylation using boron trichloride at low temperatures (-80 to -40 °C) and hydrogenolysis under high pressure, had stringent equipment requirements. After extensive literature and retrosynthetic analysis a good process for industrial production was identified. The quality of the key intermediate 7 played a crucial role in the yield and quality of Posaconazole. Therefore, our research focused on this route to enable large-scale production of Posaconazole.
However, we encountered several challenges during our research. Firstly, we observed a significant undesired impurity during the SN2 reaction in laboratory trials. The content of this impurity in the experimental sample reached 11.70%, and it persisted through the final API after hydrogenolysis. Multiple recrystallization attempts proved ineffective in removing the impurity, resulting in product losses and a low yield.
Consequently, our attention shifted towards identifying the root cause of this unexpected impurity and implementing effective control measures to prevent its formation during the preparation of intermediate. Secondly, the palladium content in Posaconazole prepared through catalytic hydrogenolysis of Pd/C exceeded the standard limits. As per the ICH guidelines, strict control of heavy metal residues in drugs is necessary due to their high toxicity. Therefore, the palladium content in Posaconazole needed to be below 10 ppm for testing and final medicinal use.
We optimized a simple and cost-effective method to remove palladium contaminants to address this. Additionally, achieving a high yield in Posaconazole preparation had always been a challenging problem. Through optimization, we increased the yield by 9%, successfully producing high-quality Posaconazole on a scale of 15 kg. This report outlines our efforts in overcoming these challenges and promoting further development and applications of Posaconazole.
Results and discussion
The preparation of key intermediate 7 primarily involved the convergence method, which offered advantages such as easily accessible raw materials and one-step synthesis. While optimizing the SN2 reaction based on the reported method, we observed an undesired process impurity with content as high as 11.70%. Despite multiple recrystallization attempts of product 7, the impurity content could only be partially reduced, remaining above the ICH guideline level (≤0.1%)