(58c) Target Polymorphic Form Development Via Continuous Combined Cooling and Antisolvent Crystallization Using Oscillatory Baffled Crystallizer

In recent years, continuous manufacturing has received much interest across the pharmaceutical industry, academia and regulatory bodies due to its potential to lower the cost of manufacturing while maintaining consistent quality^1-3. The regulatory bodies, such as the U.S. Food and Drug Administration (FDA), have been encouraging pharmaceutical companies to adopt continuous manufacturing to ensure uninterrupted supply of high-quality drugs to patients⁴. One of the important links in continuous manufacturing is crystallization unit operation. Most often crystallization governs the critical quality attributes of active pharmaceutical ingredient (API) such as purity, crystal size distribution (CSD), yield, polymorphic form, morphology, etc. In continuous crystallization, the controlled state of operation helps in achieving consistent quality drug substance. Continuous cooling only crystallization on model compounds has been extensively studied^5-6, but a very few papers have been published on continuous combined cooling and antisolvent crystallization (CCAC). It is common in pharmaceutical industry to use antisolvent to improve yield, but the solvent composition can impact the polymorphic outcome of the drug substance⁷. Therefore, designing a continuous CCAC process to solve the challenges of API crystallization in a highly regulated environment is a complex engineering problem. In this work, continuous CCAC of a commercial drug substance, Atorvastatin calcium, via oscillatory baffled crystallizer will be presented.

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. Reddy’s Laboratories Ltd. (DRL) is acknowledged for financial support provided through Purdue – DRL fellowship program.

Reference:

1. McKenzie, P., Kiang, S., Tom, J., Rubin, A. E. & Futran, M. Can Pharmaceutical Process Development Become High Tech? AIChE J. 52, 3990–3994 (2006).
2. Plumb, K. Continuous processing in the pharmaceutical industry: Changing the mind set. Chem. Eng. Res. Des. 83, 730–738 (2005).
3. Lee, S. L., O’Connor, T. F., Yang, X., Cruz, C. N., Chatterjee, S., Madurawe, R. D., Woodcock, J. Modernizing Pharmaceutical Manufacturing: from Batch to Continuous Production. Journal of Pharmaceutical Innovation, 10(3), 191–199 (2015).
4. Pharmaceutical CGMPs for the 21s Century - A risk-based approach. Food Drug Adm. 32 (2004).
5. Chew, C. M., Ristic, R. I., Dennehy, R. D., & De Yoreo, J. J. Crystallization of paracetamol under oscillatory flow mixing conditions. Cryst. Growth Des., 4(5), 1045-1052 (2004).
6. Ristic, R. I. Oscillatory mixing for crystallization of high crystal perfection pharmaceuticals. Chem. Eng. Res. Dev., 85(7), 937-944 (2007).
7. Lindenberg, C., Krattli, M., Cornel, J., Mazzotti, M. Design and Optimization of a Combined Cooling/Antisolvent Crystallization Process. Cryst. Growth Des. 9(2), 1124–1136 (2009).
8. Global Burden of Disease Collaborative Network. Global Burden of Disease Study 2016 Results. Seattle, United States: Institute for Health Metrics and Evaluation (IHME) (2017).

Publication no.: IPDOIPM-00657