(58c) Target Polymorphic Form Development Via Continuous Combined Cooling and Antisolvent Crystallization Using Oscillatory Baffled Crystallizer
AIChE Annual Meeting
2021
2021 Annual Meeting
Pharmaceutical Discovery, Development and Manufacturing Forum
Continuous Drug Substance and Drug Product – Single Unit Operations - Session 1
Monday, November 15, 2021 - 8:40am to 9:00am
Atorvastatin calcium (ASC) is a statin medication that is used as a lipid lowering agent and to prevent cardiovascular diseases. It works by inhibiting HMG-CoA reductase, an enzyme found in liver tissue that plays a key role in production of cholesterol in the body. With cardiovascular diseases being the number one cause of death in the world8, the demand for the statin drugs is quite high, making it a high-volume drug substance and hence a suitable candidate for continuous manufacturing.
ASC is currently manufactured via batch CCAC, which is time intensive and gives wide CSD product at the end of the batch. To overcome this and other disadvantages of batch crystallization, continuous CCAC of ASC was studied in an Alconbury Weston Ltd DN-15 oscillatory baffled crystallizer (OBC) with the aim to improve productivity and CSD of the desired polymorph. An OBC has the advantage of high heat transfer rates and improved mixing that significantly brings down the crystallization time. It also has the advantage of spatial temperature distribution and multiple antisolvent addition points to control supersaturation and hence the crystallization process.
The desired polymorph of ASC form I is crystallized from the mixture of isopropyl alcohol (IPA) and water. First the solubility of ASC form I was found at different temperatures and solvent compositions. The solubility increased as the temperature increased but the solvent composition had a synergistic effect on the solubility. As the desired form is a trihydrate, the saturated API solution was prepared in a high IPA:water ratio and the final solvent composition had low IPA:water ratio.
Three different modes of batch CCAC process were studied to understand the effects of temperature and solvent compositions on the polymorphic outcome. The first mode was direct antisolvent addition in which the antisolvent added to the seeded saturated API solution. In the second mode, reverse antisolvent addition was carried out in which saturated API solution was added to seeded antisolvent. In the third mode, distributed antisolvent addition was tested in which the antisolvent was split into two parts (AS-1 and AS-2). The saturated API solution was added in the seeded AS-1 and then the remaining AS-2 was added to system. The first mode did not yield the desired polymorph, but the second and the third modes gave the desired form. In the first mode, the IPA rich solution did not favor the desired form nucleation, whereas in the other two modes, the IPA concentration was much lower which favored the nucleation of the desired form.
In case of continuous crystallization, there is no direct or reverse antisolvent crystallization as the saturated API and antisolvent streams mix in the OBC tube at a point irrespective of which is added first. However, the ratio of IPA:water at the point of mixing of the two streams was found to have an impact on the polymorphic outcome and the operation in the OBC. The presence of seeds in either saturated API solution or antisolvent also impacted the polymorphic outcome. The splitting of antisolvent into two addition ports in the OBC was found to give the desired form. Through enhanced micromixing and increased heat transfer characteristics of the OBC, the continuous process was found to be 70-fold more productive compared to the batch process. The crystals obtained from continuous OBC operation had narrower CSD compared to that from a batch CCAC process.
Acknowledgement
Dr. Reddyâs Laboratories Ltd. (DRL) is acknowledged for financial support provided through Purdue â DRL fellowship program.
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Publication no.: IPDOIPM-00657