Continuous production of active pharmaceutical ingredients
Inventors
Assignees
New Jersey Institute of Technology
Publication Number
US-11779859-B2
Publication Date
2023-10-10
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 provides a method for continuously producing active pharmaceutical ingredients (APIs) using membrane-based devices. The process comprises several steps: subjecting a reaction mixture containing an API precursor to solvent extraction to yield a reactant stream, concentrating the API precursor through at least one membrane, conducting a reaction in a membrane reactor, separating the API precursor from the reaction mixture using a separator, and crystallizing the API precursor to form APIs. The method allows for membrane-based devices to be incorporated in one or more steps, including reactors, separators, crystallizers, and heat exchangers.
Traditional batch and continuous processes for API synthesis can involve many steps, large batch volumes, long hold times between steps, and increased product loss if the product quality is compromised. Conventional continuous systems often require a variety of devices—such as reactors, packed-bed extractors, gravity-based separators, and filters—and face challenges including operational inefficiency and limited control over production. The described invention addresses these issues by enabling most or all unit operations—including mixing, reaction, separation, heat exchange, and crystallization—to be performed by membrane-based devices, which are compact, modular, and allow for continuous operation.
The method supports a wide range of API molecular weights and can be applied to multi-step syntheses, with each reaction and subsequent processing steps implemented via membrane-based units. Membrane-based approaches offer improved efficiency in mixing, reaction control, separations (including solvent exchange, nanofiltration, pervaporation, and adsorption), and crystallization. This results in a continuous, modular production process that can reduce the number of devices needed, streamline production steps, and improve operational efficiency in the manufacturing of APIs.
Claims Coverage
The patent includes one independent claim, outlining several inventive features relating to the continuous production of APIs using membrane-based devices.
Continuous API production using membrane-based devices
A method of producing APIs comprises: 1. Subjecting a reaction mixture with an API precursor to solvent extraction to produce a reactant stream containing the API precursor. 2. Concentrating the API precursor in the reactant stream using at least one membrane. 3. Carrying out a reaction in a membrane reactor. 4. Separating the API precursor from the reaction stream using a separator. 5. Crystallizing the API precursor using a crystallizer to produce APIs. At least one of the reactor performing solvent extraction, the separator, or the crystallizer is a membrane-based device.
The claims cover the continuous production of APIs where membrane-based devices perform at least one of the critical synthesis operations (reaction, separation, or crystallization), incorporating solvent extraction, membrane concentration, membrane-operated reaction, and membrane-enabled separation and crystallization.
Stated Advantages
Use of membrane-based devices allows reduction in the number of process devices, enabling more efficient production by replacing multiple traditional units (such as mixers and gravity-based separators) with a single membrane-based device.
Membrane technologies are compact, modular, scalable, and highly energy efficient, supporting continuous operation and easier scale-up or down of API manufacturing.
Membrane-based synthesis enables a higher level of control over reaction conditions, pathways, conversion, and selectivity, improving final product quality and yield.
Membrane solvents extraction, separation, and crystallization eliminate issues such as flooding, loading, emulsion formation, and phase coalescence often seen in conventional separation devices.
Membrane operations, including pervaporation and nanofiltration, allow for athermal separations at near room temperature, protecting thermally sensitive pharmaceutical intermediates and APIs.
Continuous membrane-based manufacturing results in high operational efficiency and can lead to significant energy savings compared to traditional batch or conventional continuous processes.
Documented Applications
Continuous manufacturing of APIs, specifically including prexasertib monolactate monohydrate and fluoxetine hydrochloride (PROZAC®), using membrane-based units for each processing step.
Membrane-based methods for solvent exchange, nanofiltration, reverse osmosis, and pervaporation in chemical synthesis processes.
Continuous, multi-step pharmaceutical synthesis where membrane reactors, mixers, heat exchangers, solvent extractors, and crystallizers replace conventional, non-membrane equipment.
Enzyme catalysis using membrane reactors for immobilizing catalysts and facilitating enzyme reactions in API production.
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