Continuous production of active pharmaceutical ingredients
Inventors
Assignees
New Jersey Institute of Technology
Publication Number
US-12239943-B2
Publication Date
2025-03-04
Expiration Date
2041-12-09
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Abstract
The present invention is directed to a method of producing active pharmaceutical ingredients (APIs). The method includes subjecting a reaction mixture with an API precursor to solvent extraction to produce a reactant stream with the API precursor. The method includes concentrating the API precursor in the reactant stream using at least one membrane. The method includes carrying out a reaction in a membrane reactor. The method includes separating the API precursor from the reaction stream using a separator. The method includes crystallizing the API precursor using a crystallizer to produce APIs.
Core Innovation
The invention concerns a method for producing active pharmaceutical ingredients (APIs) by using membrane-based devices at one or more steps in a continuous manufacturing process. This method improves upon conventional systems by integrating membrane devices—such as membrane reactors, membrane separators, membrane crystallizers, and membrane mixers—throughout the API manufacturing sequence to perform reactions, separations, solvent exchanges, mixing, heat exchange, and crystallization in a more compact, modular, and scalable form.
The background explains that traditional batch or continuous chemical synthesis of APIs involves multiple reaction and work-up steps using a variety of non-membrane-based devices, resulting in inefficiency, operational complications, reduced process control, and potential product loss. There has been a need to address these drawbacks by improving continuous API production methods, especially in terms of device count, efficiency, and process control.
The membrane-based method consists of several steps: solvent extraction of a reaction mixture containing the API precursor, concentration of the precursor stream using at least one membrane, conducting reactions in a membrane reactor, separating substances using a membrane separator, and crystallizing the API precursor in a membrane crystallizer to yield the final API. Membrane operations, such as solvent extraction, nanofiltration, reverse osmosis, pervaporation, mixing, and heat exchange, are specifically enabled as intrinsic, scalable, and continuous steps using various types of membranes suited to each unit’s function.
Claims Coverage
There are two independent claims, covering the method for continuous manufacturing of prexasertib monolactate monohydrate and the system for such manufacturing with at least one membrane-based unit.
Continuous manufacturing method using at least one membrane-based unit
The method comprises: 1. Combining compound 7 with hydrazine in the presence of acetic acid in methanol and THF at about 130°C to produce compound 8. 2. Combining compound 8 with compound 9 in the presence of N-ethylmorpholine in DMSO at about 85°C to produce compound 10. 3. Deprotecting compound 10 by combining with formic acid at about 25° to produce compound 1. 4. Subjecting compound 1 to lactic acid distillation in THF/water to produce compound 12. Each of these steps is carried out in a series of units connected to support continuous flow, with at least one unit as a membrane-based unit.
System for continuous API manufacturing with membrane-based units
A system comprising a series of units connected to support continuous flow for the manufacture of prexasertib monolactate monohydrate, wherein at least one unit in the system is a membrane-based unit.
The inventive features define methods and systems for continuous API production that incorporate at least one membrane-based unit in the manufacturing series, enabling continuous flow and improved process integration.
Stated Advantages
Reduction in the number of devices required for API synthesis compared to traditional methods.
Membrane-based synthesis enables higher conversion and/or selectivity in equilibrium-limited reactions by removing one of the products through the membrane.
Improved control of feed introduction rate, mixing, reaction pathways, conversion, and selectivity during synthesis.
Membrane devices do not suffer from phase flow limitations like flooding or loading that are present in conventional separation devices.
Easy scalability of membrane-based devices allows for straightforward scale-up or scale-down of API manufacturing.
Membrane solvent extraction combines multiple traditional steps into a single operation, reducing device size and eliminating emulsion problems and product loss.
Membrane reactors can achieve synthesis levels not possible with tubular reactors and enable continuous, efficient processing.
Membrane crystallizers and related membrane-based devices allow for efficient and continuous crystallization, mixing, and heat exchange.
Membrane-based methods allow for athermal solvent exchange and concentration processes at near room temperature, benefiting thermally sensitive pharmaceuticals.
Documented Applications
Continuous manufacturing of prexasertib monolactate monohydrate using a series of units with at least one membrane-based unit.
Continuous manufacturing of fluoxetine hydrochloride employing membrane-based reactors, separators, mixers, and crystallizers.
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