(173b) Process Intensification and Integration of the Continuous Manufacturing of Atorvastatin Calcium Using Spherical Agglomeration

In recent years, the pharmaceutical industry has shown growing interest in continuous manufacturing, where all process operations are integrated and run under one roof, end-to-end.¹ This approach offers numerous benefits such as increased manufacturing flexibility, reduced plant footprint, and the ability to handle large production volumes for high demand drug molecules. End-to-end continuous manufacturing also significantly reduces production time by eliminating inter-process hold-up times and enhancing process agility.^1–4

Traditionally, Atorvastatin calcium (ASC) - like most active pharmaceutical ingredients (APIs) - has been produced in batch. However, some recent work has been done on continuous crystallization of ASC, which offers several advantages, such as lower cost and higher yield.^5,6 One of the important critical quality attributes of the API controlled by the crystallization unit operation is crystal size distribution (CSD), which has a significant impact on downstream processes such as filtration and drying unit operations. Another key factor in the effectiveness of the final drug product is the polymorphic form, which significantly affects the physiochemical properties of the drug, such as solubility, dissolution rate, and melting point. These properties, in turn, influence the bioavailability of the drug.^6,7

In our recent work, it was observed that the ASC crystallization process is a strongly nucleation dominated process that typically yields very small size crystals (D₅₀ < 10 μm), making the filtration step inefficient. To overcome this challenge, spherical agglomeration of ASC is proposed.

Process intensification via spherical agglomeration, not only enhances the quality of the final product in terms of crystal size and morphology, but also minimizes the amount of waste generated during the manufacturing process. One important parameter in this step is the impeller stirring rate, which influences the rate of mixing and mass transfer between the liquid and solid phases. Different impeller stirring rates were tested to determine the most effective operating conditions for creating spherical and similarly sized crystals. Another key factor is the volume of bridging solvent used, which is expressed as the Bridging Solvent Ratio (BSR).^8–10 BSR is defined as the volume of bridging solvent required to achieve a given degree of agglomeration, divided by the volume of solid particles. BSR is a critical factor in determining the polymorphic nature of the final product. To optimize the continuous crystallization–spherical agglomeration process, various impeller stirring rates and BSR values were studied. The aim was to identify the most effective operating conditions for producing spherical and similarly sized crystals.

This design of experiment approach allows for control over size and shape, making downstream steps easier and more efficient. This integrated two-stage anti-solvent crystallization–spherical agglomeration setup is followed by the addition of a continuous intensified filtration-washing-drying unit, and it is also integrated with an upstream continuous reactor to complete the end-to-end continuous ASC manufacturing system.

References

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