Process Development for Continuous Manufacturing of Baloxavir Marboxil. Part 1: Step 1 Synthesis

Most industries, such as automobiles, electronics, food, and petrochemicals, utilize automated and continuous processing. Conversely, small-molecule pharmaceutical synthesis remains one of the last industrial processes to use “batch.” Some key disadvantages of “batch” manufacturing of small-molecule pharmaceuticals include: (1) large physical footprint; (2) long lead time because pharmaceutical companies generally have separate plants to manufacture the active pharmaceutical ingredient (API) and the final drug product; (3) time inefficiency due to the equipment cleaning and changeover between batches to avoid cross-contamination and ensure product quality; (4) scale-up challenges for factors such as heat transfer, mixing, and reaction kinetics; (5) limited real-time process monitoring; (6) variability between batches due to the inherent batch-to-batch variability; (7) high cost of goods; and (8) environmental impact due to the higher water/solvent and energy consumption.

These disadvantages have led to an increased interest in the continuous manufacturing of small-molecule APIs and drug products in the pharmaceutical industry. Continuous manufacturing of small-molecule pharmaceuticals generally includes the following unit operations: dissolution, reaction, crystallization or reactive crystallization, filtration, drying, hot melt extrusion (HME), tablet compression, or granulation. Other unit operations such as clarification, neutralization, thin-film evaporation, membrane separation, and solvent recovery may also be required. In the reactive crystallization process, reactants undergo a reaction, resulting in the formation of a solute that crystallizes into a solid product from the solvent.

The primary processes involved include simultaneous reaction, mass transfer, rapid nucleation, and growth. Additionally, there may be secondary processes such as aging, ripening, agglomeration, and breakage. The driving force behind crystallization is the generation of supersaturation through the reaction. Crystallization processes are necessary to purify and separate the API, as well as control the shape, particle size distribution (PSD), and polymorphic form. A filtration process usually follows crystallization, where solid particles are physically retained by a filter medium, and byproducts, catalysts, or other unwanted materials generated during the reaction are removed.

In a continuous manufacturing process, continuous filtration is usually integrated with the preceding crystallization process, allowing for a steady and uninterrupted flow of the material through the filter. Baloxavir marboxil (S-033188, marketed as Xofluza) is an antiviral medication and is approved by the Food and Drug Administration (FDA) for the treatment of influenza A and influenza B in patients 12 years and older who have had flu-like symptoms (e.g., fever, stuffy nose, headache, cough, and joint or muscle pain) for not more than 48 h. Baloxavir acid, also called baloxavir, is the active metabolite of the prodrug baloxavir marboxil and functions as a protein inhibitor targeting the cap-dependent endonuclease within the polymerase acidic protein (PA) subunit of influenza A and B viruses. Its mechanism involves the inhibition of mRNA synthesis initiation, thereby impeding the replication of influenza viruses. Xofluza is given as a single oral dose.

The current batch process route to produce baloxavir marboxil from tricyclic benzyl ether S199AL consists of four chemical reaction steps (Scheme 1a). The process begins by replacing the benzyloxy group of S199AL with an n-hexyloxy group to produce S199BK. In the second step, the tricyclic hexyl ether S199BK is coupled with the tricyclic benzylic alcohol S199AR to produce S199BH. This coupling is mediated by a propylphosphonic anhydride (T3P, S199AY) and the acidic catalyst methanesulfonic acid (MsOH), in a solvent mixture of ethyl acetate and cyclohexane. In the third step, the n-hexyl group in S199BH is removed to produce S-033447. In the last step, S-033447 is converted to the prodrug S-033188 by treatment with chloromethyl methyl carbonate under Finkelstein conditions (using potassium carbonate and catalytic potassium iodide) in a solvent mixture of THF, N,N-dimethylacetamide (DMA), and water. From the chemistry described in a Shionogi patent, wherein the conditions for the condensative coupling between S199AL and S199AR produce S-033188 directly, the synthesis has been reduced to a 2-step process (Scheme 1b).

Part 1 of this 2-part series summarizes all the unit operations in the Step 1 synthesis (from S199AL to S-033447, Scheme 1b), which includes the reactive crystallization to form S-033447·CSA (camphorsulfonic acid), continuous rotary filtration of S-033447·CSA, neutralization and purification of S-033447·CSA to S-033447, and continuous rotary filtration of S-033447. All of these unit operations were run continuously but separately. The next step will be their seamless integration.

Read Part 2 here