Patent ID: 12239943

DETAILED DESCRIPTION OF THE INVENTION

As discussed herein, use of membrane-based API synthesis (as compared to traditional API synthesis) allows for considerable reduction of devices used in the process. For example, traditional solvent extraction can first involve a mixer where one phase is dispersed as drops into another phase, then dispersed in a two phase system before being taken to a settler (often gravity based) to separate the two phases. This can be problematic, besides requiring an additional device. In membrane-based solvent extraction, only one device is needed. In addition, membrane-based synthesis can be used to carry out an equilibrium-limited reaction process and change the equilibrium conversion by removing one of the products through the membrane and achieve a higher conversion and/or selectivity. (See, e.g., J. Whu et al., Modeling of Nanofiltration-assisted Organic Synthesis, J. Membrane Sci., 163(12), 319-331 (1999); see also Park, B. G. et al., Design issues of pervaporation membrane reactors for esterification, Chem. Eng. Sci., 57, 4933 (2002)). Membrane-based synthesis allows for control of the feed introduction rate, mixing of different reactants via a membrane into a membrane reactor, control of the reaction pathways, conversion, and selectivity. Membrane-based synthesis includes membrane devices that do not suffer from phase flow limitations encountered in conventional separation devices (which traditionally suffer from flooding and/or loading). Membrane-based devices can be scaled up or down easily, resulting in easier scale up or down of API manufacturing. Thus, using a membrane-based API synthesis system provides significant advantages over traditional API manufacturing.

FIG.4is a schematic of a multistep membrane-based API synthesis system100(hereinafter “system100”) in accordance with exemplary embodiments of the present disclosure. The system100can include a membrane-based mixer102, a first membrane reactor104, a first heat exchanger106(e.g., a hollow fiber heat exchanger), a first membrane-based solvent separator108, a second membrane reactor110, a second heat exchanger112(e.g., a hollow fiber heat exchanger), a second membrane-based solvent separator114, and a membrane-based crystallizer116. The system100therefore incorporates several membrane-based devices into the sequential steps of the process performed by the system100. The system can incorporate all membrane-based devices to replace traditional non-membrane-based devices for the reaction processes and separation steps, which can reduce the total number of devices used overall.

In some embodiments, the mixer102can be a porous hollow fiber membrane mixer (such as the mixerFIG.3A) instead of an inline mixer to mix neat chloroacetyl chloride (12) with N-methyl-2-pyrrolidone (NMP) and then mix it with 2, 6-xylidine (11) in N-methyl-2-pyrrolidone (NMP). In some embodiments, the membrane-based mixer102using porous membranes can itself be the subsequent membrane reactor104shown inFIG.4, thereby acting as both the mixer102and reactor104. If the synthesis reaction is significantly exothermic and requires cooling during or after the reaction, a non-porous ceramic tubule or a non-porous polymeric hollow fiber based heat exchanger106can be used by the system100to cool the post-reaction solution.

The cooled reaction product-containing solution undergoes membrane separation in the membrane separator108, which can be of one of several types of separators. In some embodiments, if the solvent has to be exchanged with another solvent to prepare for the next synthesis reaction, the system100can use an organic solvent nanofiltration (OSN) with continuous addition of the replacement solvent to the flowing feed solution and removal of the solvents (as shown by the arrows extending out of the separator108inFIG.4) without removing the intermediate product(s) formed in the reactor. Simultaneously, the concentration of the desired solvent increases in the feed solution to the membrane unit. In some embodiments, the system100can use a highly selective organic solvent reverse osmosis (OSRO) membrane in the membrane separator108to remove the undesired solvent through the membrane while retaining the solvent needed in the solvent exchange process. The reaction intermediate product is retained by the membrane.

In some embodiments, the system100can use nondispersive membrane solvent extraction (MSX) in the separator108to remove undesirables/impurities from the reaction product stream through a porous membrane into an extracting immiscible solvent. In some embodiments, the desired intermediate product in the solution exiting the reactor104can be extracted into the extracting solvent through the membrane by MSX and taken to the next synthesis step of the process. Such membrane solvent extraction step combines two steps identified inFIGS.3A and3Bas the packed-bed column and gravity-based separator into a single step/device without any dispersion of one phase into the other.

An example for such a step is provided inFIG.2where preheated aqueous sodium hydroxide (3M) is used to dissolve the reaction product (from the reactor), although the resulting solution contains some impurities. In particular,FIG.2shows the mixer38followed by a gravity-based settler40. Extraction from one phase to the other phase in the mixer38is achieved with high interfacial area via one phase present as dispersed drops in the other phase. Using a gravity-based phase settler40, the lighter phase goes up and the heavier phase goes down to the bottom, thus separating the two phases. Gravity-based phase separation is usually problematic, generally necessitating the use of a separate membrane separator device for phase separation. (See, e.g., M. Peer et al., Biphasic catalytic hydrogen peroxide oxidation of alcohols in flow: Scale-up and extraction, Org. Process Res. Dev., 20, 1677-1685 (2016)). This can be highly problematic in flow chemistry where in biphasic systems, one employs dispersive mode of operation which creates problems during phase coalescence. Instead of two such potentially problematic devices, membrane solvent extraction uses only one device and does not disperse one phase into the other. The phases contact each other at the membrane pore mouth without dispersion. Therefore, no gravity-based separator is needed. Extraction is far more efficient and the device size is an order of magnitude smaller without emulsion problems and consequent API precursor loss. The resulting aqueous solution is next subjected to membrane solvent extraction with hexane, extracting the desired reaction product, which later yields diphenhydramine hydrochloride after treatment with HCl.

As illustrated inFIG.4, the membrane-based mixer102receives a first fluid (fluid1) into the membrane channel, and simultaneously receives a second fluid (fluid2) on both sides of the membrane channel. The mixer102includes a porous membrane (e.g., porous hollow fiber membrane) forming the walls of the membrane channel and defining the membrane channel relative to the surrounding channels for the second fluid. During the process, the second fluid is forced to pass through the pores of the membrane into the first fluid on the other side of the membrane.

Similarly, the reactor104includes a porous/microporous/dense membrane through which the solution passes surrounded by outer channels into which the reactants are introduced, such that the reactants are forced to pass through the pores of the membrane and into the solution. The separator108includes the inner sub-nanoporous membrane channel and solvent is pushed through the pores of the membrane and out of the separator108. A similar process is repeated in the reactor110, the heat exchanger112, and the separator114(and can be repeated in additional reactors, heat exchangers, and separators) before progressing to the membrane crystallizer116. Two or more reactants are needed for a reaction in reactor104. These may come in through the solution. Alternatively, one or more reactants can come with the solution, and additional reactants can be slowly introduced from the outside through the pores in the membrane wall into the reactor104. This enables achieving a controlled rate of reaction. A membrane separator can be of various types. If a solvent from the reaction media is to be removed, pressure can be applied on the solution in the membrane separator and pass the solvent and not the intermediate product through a nanofiltration membrane. Alternatively, if water has been produced in the reaction and is present as an esterification reaction, by pulling a vacuum on the other side of the membrane, water can be removed by a pervaporation process selectively through a nanoporous membrane. This increases the conversion of the process and allows one to obtain a higher yield of the intermediate product. Each of the units is the system100used in continuous pharmaceutical/API manufacturing therefore uses a corresponding membrane-base unit (as compared to non-membrane units in traditional continuous API manufacturing systems). Essentially every step in the continuous pharmaceutical/API synthesis processes discussed herein can be implemented continuously and efficiently using membrane technologies and membrane-based processes.

Membranes used by the system can be of various types depending on the needs of the user and/or end product. A nonporous membrane can be used, but allows small molecules and/or solvents to go through (as in reverse osmosis process and pervaporation process) when pressure is applied to the feed solution and/or vacuum is pulled on the other side. The transport corridors in the nonporous membrane can be slightly increased in nanofiltration membranes to allow larger molecules of molecular weight of up to about 1,100 Dalton to not go through the membrane, while solvents pass through much faster. Membranes having larger transport corridors appropriately termed pores can be used for a variety of separations, such as ultrafiltration. Membranes having these types of somewhat larger pores can be used for mixing, membrane solvent extraction, or the like.

In some embodiments, only one device used in the continuous pharmaceutical/API manufacturing system100is replaced by a corresponding membrane-based unit. In instances where only one or two devices in the system100are replaced by membrane-based units (e.g., not all possible units are membrane-based), the API manufacturing process continues to be improved as compared to traditional synthesis, but may result in less conversion, less recovery, and potentially more operating problems (as compared to a fully membrane-based process). For example, the packed bed and the gravity separator used in conventional continuous pharmaceutical/API manufacturing (e.g.,FIGS.2,3A, and3B) can be replaced by a membrane solvent extraction device. As another example, consider a porous/microporous membrane. If it is hydrophobic, its pores are more likely to be wetted by the organic phase being used in the solvent extraction and flowing on one side of the membrane. If an aqueous phase flows on the other side of the membrane at a pressure equal to or higher than that of the organic phase, then the membrane-wetting organic phase cannot appear on the other side of the membrane where the aqueous phase is flowing. However, the phase interface between the organic and aqueous phase is immobilized at the membrane pore mouth. Then, solvent extraction or back extraction can take place across this aqueous-organic phase interface from the aqueous to the organic, or the organic to the aqueous phase, respectively. As long as the aqueous phase pressure does not exceed that of the organic phase by an amount exceeding a breakthrough pressure, the aqueous-organic phase interface remains immobilized and nondispersive solvent extraction takes place. There is no need for a settler as in gravity-based separator/settler used inFIGS.2,3A and3B.

Alternatively, various other dispersive solvent extraction devices of the system100(such as a mixer and/or a settler) can be replaced by a membrane solvent extraction (MSX) device. In some embodiments, only certain devices used in continuous pharmaceutical/API manufacturing can be replaced by corresponding membrane-based units. In some embodiments, one group of components (e.g., mixer, reactor, heat exchanger and separator) can be membrane-based, while a subsequent group of components can be non-membrane-based. However, at least two steps of the exemplary process and system incorporate a membrane-based device and process.

In some membrane-based devices, referred to as membrane contactors, the membrane contactor device facilitates the conventional reaction/separation step by bringing two immiscible phases into contact without any dispersion of one phase into the other phase. Because dispersion is eliminated, coalescence of the phases is no longer required.

While phase contacting generally requires dispersion of one immiscible phase into another immiscible phase, a porous membrane contactor can eliminate dispersion and yet provides a contacting surface area between the two phases that can be up to 5-20 times what is achieved in a dispersion-based device. Membrane contactor-based devices can also prevent emulsion formation when contacting two immiscible liquid phases. However, if contacting requires creating an emulsion, porous membrane-based devices can achieve such emulsion with a much higher control over the size of the emulsion droplets. In addition, the membrane contactors can bring two miscible phases into intimate contact and achieve mixing, thereby developing a membrane mixer (such as mixer102ofFIG.4).

Catalytic or noncatalytic gas-liquid reactions, such as hydrogenation, aerobic oxidation, carboxylation using CO2, and ozonation, can be carried out in a tubular and hollow fiber membrane contactor, and can easily accommodate scale-up. Catalytic or noncatalytic liquid-liquid reactions requiring mixing of two miscible liquid phases can be carried out with excellent mixing efficiency in a porous hollow fiber membrane-based device mixer, such as a membrane mixer102, or a flat membrane-based device. One of the streams to be mixed can be introduced in a distributed fashion through the membrane pores into the other stream flowing on the other side of the membrane. This allows for an increased level of control.

It will be understood that such membrane-based reaction devices can be short or long to accommodate the needs of the reaction, residence time requirement, combinations thereof, or the like. It will also be understood that several membrane-based reaction devices can be combined in different methods/systems to accommodate the needs of the reaction. For example, short reactors can be followed by solid polymeric hollow fiber membrane-based heat exchangers, dense ceramic tubule-based heat exchangers, or conventional heat exchangers for exothermic reactions. Therefore, in some embodiments, a short reactor can be used followed by a heat exchanger, followed by another short reactor, followed by another heat exchanger, and so on until the desired conversion is attained.

After each synthesis step in a conventional pharmaceutical synthesis, the solvent may need to be exchanged and the catalysts may need to be replaced before the next reaction step. Such work-up involves a significant number of separation steps, including distillation, solvent extraction, and adsorption, which complicates the synthesis process and can have a negative effect on the resulting API. Using the system100, such separation steps can be implemented at near room temperature using porous membrane-based nondispersive membrane solvent extraction (MSX) or dense or relatively dense polymeric membranes through nanofiltration (OSN), reverse osmosis (OSRO), pervaporation, combinations thereof, or the like. If a volatile solvent (including water) must be removed, membrane pervaporation can be implemented to selectively remove the volatile solvent from the feed mixture through the membrane. If the solvent must be removed and the intermediate compound must be concentrated, organic solvent nanofiltration (OSN) can be used. If solvent exchange must be implemented, OSN can be used in the diafiltration mode with the exchange solvent introduced. Alternately, after the exchange solvent is introduced, the system100can use organic solvent reverse osmosis (OSRO) to remove the undesired solvent through a solvent-resistant reverse osmosis membrane at room temperature.

Conventional membrane operations are intrinsically continuous. Membrane devices are scalable, and can be scaled up or down. The membrane devices can carry out the reaction-separation and associated steps in API synthesis in a continuous manner. The steps of an exemplary embodiment of the continuous production of APIs can include (1) membrane solvent extraction; (2) reverse osmosis (RO) and nanofiltration (NF); (3) membrane pervaporation; (4) membrane mixing; (5) membrane reactors; (6) enzymatic synthesis; (7) hollow fiber heat exchangers; (8) membrane adsorption; and (9) membrane crystallization. Membrane fouling is considered after describing these membrane-based steps. Each of the steps is described in greater detail herein.

In some embodiments, a membrane solvent extraction (MSX) device can be used. MSX devices can replace a packed-bed column-based solvent extractor and a gravity settler, which are used in the processes shown inFIGS.2and3A-3B. Hollow fiber (HF) microporous membrane-based devices can be used for non-dispersive solvent extraction (NDSX), which removes the need for a gravity-based separator. (See, e.g., Sirkar, K. K. Membranes, phase interfaces and separations: Novel techniques and membranes—An overview, I&EC Res., 47, 5250-5266 (2008)). MSX devices are significantly smaller than dispersion-based devices, and they do not suffer flooding or loading issues. Additionally, MSX devices can have almost any flow rate ratio between the two immiscible phases flowing on two sides of the membrane. Wider commercialization of such devices has not been achieved due to non-availability of membranes that are resistant to many pharmaceutically relevant solvents. At present, polytetrafluoroethylene (PTFE)-based microporous membranes having smaller pore sizes are in the marketplace and can be used by the system100. (See, e.g., Singh, D. et al., High temperature direct contact membrane distillation-based desalination using PTFE hollow fibers, Chem. Eng. Sci., 116, 824-833 (2014)). Reduction of the membrane pore size via novel strategies would allow extraordinary flexibility in NDSX operation and application.

Following synthesis, solvent exchange is generally needed. Solvent exchange is generally carried out by distillation, either vacuum-based or otherwise. In some embodiments, the exchange can be conducted athermally because pharmaceutical intermediates and APIs are thermally sensitive. In some embodiments, the next solvent can be added to the mix and then the previous solvent is taken out through an appropriate membrane by organic solvent reverse osmosis (OSRO) at about 25° C. Recent results have shown that with a particular perfluoropolymer membrane, pure toluene can be obtained as permeate from its binary mixtures with polar aprotic solvents, such as NMP, DMSO, and DMF, at pressures around 3,500-4,000 kPa. (See, e.g., Chau, J. et al., Reverse osmosis separation of particular organic solvent mixtures by a perfluorodioxole copolymer membrane, J. Membrane Sci., 563, 541-551 (2018)). Pressures used in commercialized RO desalination are often much higher. Research has shown that pure methanol is obtained as permeate from its binary mixtures with polar aprotics, e.g., NMP. See id. Further, recent MD simulations of organic solvent nanofiltration (OSN) membranes have proven to be inadequate, as these membranes have no selectivity for organic solvent mixtures (OSMs). (See, e.g., Liu, J. et al., A molecular simulation protocol for swelling and organic solvent nanofiltration of polymer membranes, J. Membrane Sci., 573, 639-646 (2019)).

Concentration of the APIs in the solvent can be achieved by using organic solvent nanofiltration (OSN) membranes enabling athermal removal of one or more solvents or an exchange with another solvent for APIs during API synthesis. (See, e.g., Marchetti P. et al., Molecular separation with organic solvent nanofiltration: A critical review, Chem. Rev. 114, 10735-10806 (2014); Sheth, J. et al., Nanofiltration-based diafiltration process for solvent exchange in pharmaceutical manufacturing, J. Membrane Sci., 211(2), 251-261 (2003)). Membranes for such steps are demanding for polar aprotic solvents and therefore require significant research. Production of numerous OSMs is ubiquitous in API synthesis. Thus, advanced membranes for pressure-driven OSN and OSRO processes can allow athermal operation and simultaneously achieve significant energy efficiency. OSN membranes that reject Jacobsen catalyst (622 Da), Wilkinson catalyst (925 Da), and Pd-BINAP (849 Da) can be used to remove the intermediate product and the solvent while holding back the larger size catalyst. (See, e.g., Scarpello, J. T. et al., The separation of homogeneous organometallic catalysts using solvent resistant nanofiltration, J. Membrane Sci. 203:71-85 (2002); Wong, H. T. et al., Recovery and reuse of ionic liquids and palladium catalyst for Suzuki reactions using organic solvent nanofiltration. Green Chem., 8, 373-399 (2006); Luthra, S. S. et al., Homogeneous phase transfer catalyst recovery and re-use using solvent resistant membranes. J. Membrane Sci., 201:65-75 (2002)).

Membrane pervaporation can be used by the system100during synthesis to remove unneeded solvents, such as water and volatile solvents, from the solution containing the API or other pharmaceutical intermediate. The pervaporation device can be incorporated into one or both of the membrane-based separator108,114ofFIG.4. The pervaporation membrane allows volatile solvent to be removed through the membrane from the medium obtained after the reaction is completed. A typical volatile solvent removed is water. The pervaporation membrane can also be incorporated into and implemented in the reactor itself. The membrane pervaporation device can include dense membranes and a vacuum. In one embodiment, membrane pervaporation can be conducted at about room temperature. Continuous production of anhydrous tert-butyl hydroperoxide in nonane is one example of this process. (See, e.g., Li, B. et al., Continuous production of anhydrous tert-butyl hydroperoxide in nonane using membrane pervaporation and its application in flow oxidation of a γ-butyrolactam, Org. Process Res. Dev., 22, 707-720 (2018)).

To transition from batch processing in stirred tank reactors to continuous reactions, static mixer-aided tubular metallic reactors as well as microreactors are being studied extensively. (See, e.g., LaPorte, T. L. et al., Process development and case studies of continuous reactor systems for production of API and pharmaceutical intermediates, Chap. 23, pages 437-455, in Am Ende, D. (Ed.), “Chemical Engineering in the Pharmaceutical Industry: R&D to Manufacturing”, John Wiley & Sons, Hoboken, NJ (2011)). Mixing various reactants is an integral step before such liquid-liquid reactions. In some embodiments, thermally and chemically inert porous hollow fiber membranes (HFMs) and ceramic tubular membranes can be used by the system100to achieve extraordinary mixing of two liquid phase reactant streams flowing on two sides of the membrane and can carry out synthesis under controlled conditions. The use of a porous HFM to achieve high mixing efficiency of two liquid streams on one side of the membrane has been shown with miscible aqueous and selected organic phases under room temperature conditions. (See, e.g., Chen, D. et al., Hydrodynamic modeling of porous hollow fiber anti-solvent crystallizer for continuous production of drug crystals, J. Membrane Sci., 556, 185-195 (2018a); Fern, J. C. W. et al., Continuous synthesis of nano-drug particles by antisolvent crystallization using a porous hollow-fiber membrane module, Int. J. Pharmaceut, 543, 139-150 (2018); Zarkadas, D. M. et al., Antisolvent crystallization in porous hollow fiber devices, Chem. Eng. Sci., 61(15), 5030-5048 (2006)).

Membrane emulsification can be used to mix immiscible phases requiring an emulsion-containing feed phase in a membrane reactor. (See, e.g., Joscelyne, S. M. et al., Membrane emulsification: a literature review. J. Membrane Sci. 2000, 169, 107-117). The immiscible phase is forced through the membrane pores into the reaction media on the other side of the membrane. Such membrane emulsification can be incorporated into the mixer102.

The membrane reactor104can be used to/for, e.g., separate products from the reaction mixture, separate a reactant from a mixed stream for introduction into the reactor, control addition of one reactant or two reactants to the stream, nondispersive phase contacting with reaction at the phase interface or in the bulk phases, segregation of a catalyst and cofactor in a reactor, immobilization of a catalyst in or on a membrane, combinations thereof or the like. In some embodiments, the membrane can be the catalyst and/or the reactor. In some embodiments, the mixing device (e.g., mixer102) can be the reactor104itself.

For miscible liquid phase-based reactions and gas-liquid reactions, such as hydrogenation, in pharmaceutical synthesis, porous tubular ceramic and porous HFM-based devices can simultaneously immobilize catalysts, achieve high mixing efficiency and controlled synthesis. Membrane-based ozonation has previously been used for water treatment. (See, e.g., Shanbhag, P. V. et al., Membrane-based ozonation of organic compounds, I&EC Res., 37(11), 4388-4398 (1998)). Membrane reactors are useful for pharmaceutical synthesis using simple hollow fiber, membrane modules of inert polymers, e.g., PTFE and ceramic membranes having hydrophobized surfaces.

Enzymatic catalysis can be used by the system100during enantioselective synthesis in API production. A multiphase/extractive hollow fiber membrane bioreactor has been used for enzymatic resolution of a diltiazem precursor, a poorly aqueous soluble ester, which was hydrolyzed to an alcohol via an immobilized lipase and extracted by MSX into an aqueous stream. (See, e.g., Lopez, J. L. et al., A multi-phase/extractive enzyme membrane reactor for production of diltiazem chiral intermediate, J. Membrane Sci. 1997, 125, 189-211). In a recent study involving synthesis of β-lactams that had undergone site-selective C—H amidation using cytochrome P450 enzymes obtained by directed evolution, it would have been useful to employ a membrane reactor (similar to the reactor of the exemplary system100) retaining the enzyme. (See, e.g., Cho, I. et al., Site-selective enzymatic C—H amidation for synthesis of diverse lactams, Science, 364 (6440), 575-578 (2019)). In a membrane reactor lined with charged nanofiltration (NF) membranes for aqueous solutions, smaller molecule substrates and products flow through the NF membrane, while the enzyme and coenzyme are contained within the enzyme reactor. (See, e.g., Nidetzky, B. et al., Continuous enzymatic production of xylitol with simultaneous coenzyme regeneration in a charged membrane reactor. Biotechnol. Bioeng. 1996, 52, 387-396). Site-directed mutagenesis and membrane pores and surfaces can be used to enhance enzyme life by immobilization.

Hollow fiber heat exchangers used by the system100allow for heating, cooling, and/or quenching of API-containing solutions. In some embodiments, the hollow fiber heat exchanger can be made of inert dense ceramic/polymeric material. However, other suitable materials can be used for the heat exchanger. Polymeric hollow fiber heat exchangers (PHFHEs) demonstrated conductance/volume ratios 3-10 times higher than shell-and-tube devices accompanied by low-pressure drops, reaching as low as 1 kPa/NTU for lower temperature applications. (See, e.g., Zarkadas, D. et al., Polymeric hollow fiber heat exchangers (PHFHEs): An alternative for lower temperature applications, I & EC Res., 43, 8093-8106 (2004a); Song, L. et al., Polymeric hollow fiber heat exchangers for thermal desalination processes, I&EC Res., 49, 11961-11977 (2010)). Thermally stable solvent-impermeable solid hollow fiber membranes, such as PTFE, can provide efficient heat-exchange where fouling-based thermal resistance is of limited effect. Dense ceramic membrane tubules can achieve heat exchange over much higher temperatures.

Membrane-based adsorbers can be used by the system100to exploit convective flow through membrane pores. The membrane-based adsorbers can be incorporated into one or both of the separators108,114ofFIG.4. For example, the adsorbers can be used to remove trace levels of homogeneous catalysts and allow for their recovery and reuse. Membrane-based adsorbers can be used to remove impurities from organic process streams during pharmaceutical synthesis. Membrane-based adsorption processes have been adopted to produce biopharmaceuticals, either for adsorptive purification of monoclonal antibodies (mAbs) or adsorptive removal of impurities from the mAb-containing solution/suspension. The technique is advantageous in its maximum utilization of the available sorption capacity and the rapidity with which it takes place. However, such traditional techniques have not been used with a continuous process and need additional columns for continuous operation.

Membrane crystallization performed by the crystallizer116of the system100is an essential step in API production as the production of dosage form kicks in. Membrane crystallization straddles two branches of pharmaceutical manufacturing. Crystallization can be implemented continuously using HFMs at around room temperature and pressure conditions using anti-solvent crystallization or cooling crystallization. Porous HFMs can be used to continuously crystallize APIs using anti-solvent crystallization, which allows for continuous nanocrystal production (if needed). Polymeric solid HFMs impermeable to the solvents can be used to achieve continuous cooling crystallization as PHFHE. Scale-up to increase the production rate in such membrane devices can be implemented with either an increase in the number of hollow fibers in a larger shell or having a few units in parallel, since membrane devices are modular.

Membrane fouling can occur during API production as the fluid phase can be complex with substances including dispersed particles, precipitates, and emulsions. Membrane fouling and its mitigation in pressure-driven membrane systems is consistently discussed in the industry. Membrane fouling of this type is much less present in membrane contactor-based operations. Reducing membrane fouling in the system100allows for enhanced success of membrane-based approaches for multi-step API synthesis. Recent cross-flow hollow fiber membrane-based desalination studies on concentrating seawater to the level of 18-19% salt was achieved without any flux reduction despite the scaling salt precipitates of CaCO3and CaSO4floating around. (See, e.g., Song, L. et al., Pilot plant studies of novel membranes and devices for direct contact membrane distillation-based desalination, J. Membrane Sci., 323, 257-270 (2008); Li, L. et al., Desalination performances of large hollow fiber-based DCMD devices, I&EC Res., 56, 1594-1603 (2017); Singh, D. et al., Novel cylindrical cross-flow hollow fiber membrane module for direct contact membrane distillation-based desalination, J. Membrane Sci., 545, 312-322 (2018)).

In some embodiments, reactor configurations using a membrane device can be used. For example, the system100can include a 91 m long plug-flow reactor using a 4.57-mm-ID stainless steel tubing to condense a nitrile compound with an excess of hydrazine at 130° C., 500 psig; with the residence time in the reactor of 1 hr. (See, e.g., Cole, K. P. et al., Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions, Science, 356, 6281, 1144-1150 (2017)). Such single-phase reaction can be carried out in a membrane pore operating as if a plug flow reactor is provided with each pore.

In some embodiments, a porous alumina membrane disk can be used for a reactor of the system100. However, it will be understood that other reactors can be used.FIG.5shows a schematic of a dead end flow configuration of a porous ceramic membrane disk-based reactor200operating as a plug flow reactor. The reactor200can be incorporated into the system100as one of the reactors used in the API manufacturing process. The reactor200can include a disk body202with multiple pores204extending through the body202. The body202can itself form a porous membrane capable of permitting passage of liquid through the pores of the body202. The pores204extend from one side to the opposing side of the body202to allow passage of the feed mixture therethrough. The reactor200is referred to herein as a pore flow through reactor (PFTR). In the porous alumina (Al2O3) membrane disk ofFIG.5, each pore204acts as a separate plug flow reactor. The system100can be used to deposit metallic or oxide catalysts on the pore204wall surface for catalytic reactions. The pore L/D ratio in the ceramic disk can be as high as 103-104or even higher to provide the L/D ratio used in the stainless steel/PFA tubing. (See, e.g., Cole, K. P. et al., Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions, Science, 356, 6281, 1144-1150 (2017)). Such a reactor can have an additional advantage in case the feed has suspended material having dimensions larger than the pore204dimensions (discussed in the following paragraph below)

In some embodiments, to accommodate larger flow rates or longer reactor lengths, a ceramic monolith can be used for the reactor. In some embodiments, the reactor of the system100can be in the form of a stack of porous ceramic disks of small length and larger cross-sectional area, allowing the disks to function as a plug flow reactor. In some embodiments, the bulk feed mixture can flow tangentially over the ceramic membrane disk in a recirculation mode as if the membrane were a cross-flow filter for a system containing particulate material, which would be rejected by the small size membrane pores. The reactor can be jacketed in an appropriate environment to maintain the thermal conditions needed in an appropriate pressure environment.

After each reaction, membrane separation steps can be coupled with the membrane reactor output and separations/purifications of the intermediates/API can be carried out by the system100. Having the membrane reactors at each synthesis step can significantly enhance reactions in a multistep API synthesis and production process, with the reactors further supported by membrane separations at each post-reaction processing step. When a membrane reactor improves the selectivity or increases the conversion, the amount of API manufactured is increased. Correspondingly, the load on the separation step(s) downstream of every membrane reactor is decreased as the purification demands are reduced. Thus, use of membrane-based reactors at the synthesis steps provides significant advantages to the final API manufactured in terms of quantity and quality. All of these steps can be carried out continuously to continuously manufacture APIs.

Example of a Membrane-Based Manufacturing of APIs

A dead-end flow configuration of a porous ceramic membrane disk-based reactor operating as a plug flow reactor is shown inFIG.5. This membrane can replace the 91 m long plug-flow reactor (as previously used in Cole, K. P. et al., Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions, Science, 356, 6281, 1144-1150 (2017)) by using a 4.57-mm-ID stainless steel tubing for condensation of a nitrile compound 7 with an excess of hydrazine at 130° C., 500 psig to produce the compound 8 needed during the synthesis of prexasertib monolactate monohydrate. This is shown in greater detail inFIG.6Band discussed below.

FIG.6Bis a schematic illustrating the synthetic route for continuous manufacturing of Stage I synthesis process300capable of being performed by the exemplary system. (See, e.g., Cole, K. P. et al., Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions, Science, 356, 6281, 1144-1150 (2017)). In comparison, the exemplary system provided inFIG.8illustrates the simpler and smaller implementation of membrane-based synthesis. Still with reference toFIG.6B, Stage I begins as input302at step 1 to the condensation PFR section304, which progresses to the counter current extraction section306, and finally enters the rotary evaporator concentration section308. The product is initially cooled down in a dense ceramic tubular membrane heat exchanger or PTFE hollow fiber heat exchanger as it heats up the feed going into the PFR discussed previously. After cooling the product in a PTFE hollow fiber heat exchanger or a dense ceramic tubular membrane heat exchanger, toluene is added to the organic stream containing compound 8 for countercurrent solvent extraction while water is added from the other end of the mixer settler countercurrent extraction cascade (shown inFIG.6B). A single porous hollow fiber membrane solvent extraction device can be used in the system ofFIG.8to carry out continuous countercurrent extraction efficiently (instead of using a 6-device 3-stage extraction implemented traditionally (as shown inFIG.6B), which resulted in additional product losses). See id. The residence time in the reactor is 1 hour. This single-phase reaction can be carried out in a dead-end flow configuration of a porous ceramic membrane disk-based reactor operating as a plug flow reactor (see, e.g., reactor ofFIG.5). Rather than using a gas mixture (See, e.g., Motamedhashemi, Y. et al., Flow-through catalytic membrane reactors for the destruction of a chemical warfare simulant: Dynamic performance aspects, Catalysis Today, 268, 130-141(2016)), a liquid mixture is used.

The solvent extraction process discussed herein includes three stages (shown inFIGS.6B and6C), each with a mixing tank for rapid mass transfer between layers and a static gravity decanter for layer separation, and provide the required purification with minimal product loss. Hydrazine is controlled to <2 parts per million (relative to 8 traditionally), and the deprotected impurity can be removed from as much as 5% traditionally to less than 1% of the total integrated product distribution detected by high-performance liquid chromatography (HPLC area %) after extraction.

Traditionally, DMSO was added to the product in a solution containing toluene, methanol, water and THF after membrane solvent extraction. Next, a rotary evaporator concentration method is used to remove the volatile solvents to yield a solution of 8 in DMSO (as shown inFIG.6B). See id. In some embodiments, this process can be performed continuously using a perfluoropolymer CMS-3 based pervaporation membrane, which is highly selective in removing these solvents by employing a vacuum on the permeate side of the membrane and has very low permeation of DMSO vis-à-vis the other solvents. (See, e.g., J. Tang et al., Permeation and Sorption of Organic Solvents and Separation of their Mixtures through Amorphous Perfluoropolymer Membrane in Pervaporation, J. Membrane Sci., 447, 345-354 (2013); J. Tang et al., Perfluoropolymer Membrane behaves like a Zeolite Membrane in Dehydration of Aprotic Solvents, J. Membrane Sci., 421-422, 211-216 (2012)). This would provide a convenient membrane process where the CMS-3 membrane is completely inert and has extremely low permeation of DMSO. (See, e.g., J. Tang et al., Perfluoropolymer Membrane behaves like a Zeolite Membrane in Dehydration of Aprotic Solvents, J. Membrane Sci., 421-422, 211-216 (2012)).

FIG.6Cshows a schematic of Stage II of the synthesis process300. (See, e.g., Cole, K. P. et al., Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions, Science, 356, 6281, 1144-1150 (2017)). Stage II includes an input310as step 2, an SNAr PFR section312, an antisolvent crystallization MSMPR section314, a filtration/dissolution section316, and a deprotection reaction section318. In Stage II, a solution of 8 in DMSO is mixed efficiently with a solution of pyrazine type compound 9 (N-ethyl morpholine) in DMSO in a porous hollow fiber membrane mixer before introduction into a ceramic membrane reactor of the type shown inFIG.5and maintained at 85° C. This allows a long residence time needed for the S N Ar type reaction between 8 and 9 to yield the pyrazole type compound 10. To remove residual9, the pyrazole-arylated regioisomers, low levels of other process impurities, NEM-HCl, and DMSO, an anti-solvent crystallization (FIG.6B) can be implemented easily with methanol using the technique of porous hollow fiber anti-solvent crystallization (instead of using a mixed suspension mixed product removal (MSMPR) crystallizer as shown inFIG.6C). (See, e.g., Chen, D. et al., Continuous synthesis of polymer-coated drug particles by a porous hollow fiber membrane-based antisolvent crystallization, Langmuir, 31, 432-441 (2015)). Membrane-based devices can replace every single conventional device used in synthesis of organic compounds to produce APIs in pharmaceutical industry. The process shown inFIGS.6B-6Ccan therefore incorporate membrane-based devices for each of the devices used, leading to the compound 1 inFIG.6C.

Next filtration and dissolution of 10 in formic acid (obtained after filtration and dissolution) and deprotection reaction is carried out in a reactor shown inFIG.5to end up with product 1 in formic acid. The reactor used is similar to that inFIG.5, with the flow rate controlled to a very low rate to provide the needed liquid residence time of around 4 hours and an appropriate length of the membrane reactor. However, it can be useful to have a vertically upward configuration of the reactor such that any gasses evolving can naturally travel out through the top.

FIG.6Dis a schematic of Stage III synthesis process300of the system. (See, e.g., Cole, K. P. et al., Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions, Science, 356, 6281, 1144-1150 (2017)). Stage III includes an input320at step 4, a rotary evaporator concentration section322, a crystallization section324, and a filtration section326.

FIGS.6B-6Dillustrate how a traditional continuous manufacturing process of specific APIs can be modified such that API synthesis is performed using membrane-based devices and processes to replace conventional non-membrane devices and processes for synthesis of a particular API. In some embodiments, in Stage III illustrated inFIG.6D, first the four solutions (i.e., 1 in formic acid, lactic acid, water and THF/water) may be mixed together in a porous hollow fiber membrane mixer and then introduced into a membrane evaporator-concentrator (a pervaporation membrane device) containing a perfluorocopolymer membrane to remove THF, water and formic acid with lactic acid remaining. The lactic acid salt is then crystallized using THF as an anti-solvent in a porous hollow fiber antisolvent crystallizer mentioned earlier. Here, replacement of a filtration device (last device inFIG.6D) by a membrane device is not necessary since a filter is a membrane device.

Another example of manufacturing a specific API using the exemplary system is the continuous manufacturing-based synthesis of fluoxetine hydrochloride (PROZAC®). (See, e.g., Adamo, A. et al., On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system, Science, 352, 6281, 61-67 (2016), the entire contents of which are hereby incorporated herein by reference).FIG.7is a schematic of synthesis of the system400for continuous manufacturing of fluoxetine hydrochloride (PROZAC®). The system400includes an upstream section402and a downstream section404. The upstream section402includes reactors406,408,410,412, membrane-based separators414,416,418, back pressure regulators420,422,424,426, gravity based separator428, heater430, and MS cartridge432.FIG.7therefore shows a flowchart detailing the upstream and downstream synthesis of fluoxetine hydrochloride.

In some embodiments, the first reactor406can be a membrane-based reactor, which is used to carry out diisobutylaluminum hydride (DIBAL) reduction of 3-Chloropropiophenone in toluene using a PFTR. In further embodiments, the membrane-based reactor may be the reactor ofFIG.5.

In some embodiments, the second reactor408may be a membrane-based reactor, e.g., a liquid-liquid (L-L) nondispersive membrane reactor (MR). A solution of 4M HCl can be added into a membrane reactor408, e.g., a liquid-liquid (L-L) nondispersive membrane reactor (MR). The exiting stream from reactor406is introduced into the other side of the MR removing the need for a membrane separator. The aqueous stream goes to waste at the end of this reactor. Here, the L-L membrane reactor acts as a nondispersive membrane solvent extraction (MSX) device, which is used for solvent extraction in the membrane-based operations of the present disclosure, replacing traditional chemical engineering devices. The organic stream passes into an MSX device where 4M HCl stream is introduced into the aqueous side. The aqueous stream is withdrawn to waste at the end of this device as shown inFIG.7.

In some embodiments, the third reactor410may be a membrane-based reactor, e.g., a L-L nondispersive extractor/reactor. When two immiscible liquid phases exist in an L-L reactor, there will be extraction occurring from one phase to the other phase. To the organic stream containing the intermediate alcohol entering the reactor410(Reactor III operating at 135° C.) which is a L-L nondispersive extractor/reactor, an aqueous methylamine solution is introduced to the aqueous side.

In some embodiments, the system400may include an additional membrane-based device, e.g., a L-L nondispersive membrane solvent extraction (MSX) device. The two immiscible product streams exiting reactor410can enter the additional membrane-based device, e.g., L-L nondispersive membrane solvent extraction (MSX) device, into which two streams are added: an aqueous 20% NaCl solution, and pure THF. The system400allows amino alcohol to go into a suitable organic solvent (THF) for further reaction downstream in Reactor IV (reactor412). Before that reaction in reactor412, the aqueous phase is taken out from the aqueous stream at the end of the MSX device and sent to waste. The water left in the organic phase stream is removed by passing the organic stream through a membrane pervaporation device using perfluoropolymer membrane discussed herein instead of sending it through a bed of zeolites (FIG.7) (which is not a continuous process). (See, e.g., J. Tang et al., Perfluoropolymer membrane behaves like a zeolite membrane in dehydration of aprotic solvents, J. Membrane Sci., 421-422, 211-216 (2012); see also J. Tang et al., Permeation and sorption of organic solvents and separation of their mixtures through amorphous perfluoropolymer membrane in pervaporation, J. Membrane Sci., 447, 345-354 (2013)).

The dried organic stream is mixed with two DMSO solutions and enters reactor412. In some embodiments, the reactor412may be a membrane-based reactor, e.g., the PFTR ofFIG.5. To the organic solution exiting reactor412, successive streams of water and tert-butyl methyl ether (TBME) are added to the corresponding phase in a L-L MSX device to dispense with the subsequent gravity-based phase separator. The organic phase has the product as a crude solution of fluoxetine in TBME. Thus, virtually all of the steps implemented by traditional devices used in the system400ofFIG.7can be performed in an improved manner with improved results using membrane-based devices, and such membrane-based devices can reduce the overall number of devices used by the system400.

FIG.8is a schematic of membrane-facilitated continuous manufacturing operation or process500for Prexasertib Monolactate Monohydrate. InFIG.8, F&D represents filtration and dissolution, HEX represents heat exchanger, L-L represents liquid-liquid, MEC represents membrane evaporator-concentrator, MM represents membrane mixer, MR represents membrane reactor, MSX represents membrane solvent extraction, PHFAC represents polymeric hollow fiber antisolvent crystallizer, and PV represents pervaporation.FIG.8illustrates the concept that many continuous API manufacturing processes based on traditional nonmembrane-based equipment/processes can be efficiently and effectively replaced by membrane-based equipment. Further, the number of equipment needed and (sometimes) the number of steps can be significantly reduced by using membrane-based equipment.FIG.8essentially shows the processes depicted inFIGS.6B,6C and6Dcan be carried out by the membrane-based devices illustrated inFIG.8.

FIG.9is a schematic of continuous membrane-facilitated synthesis process600of fluoxetine hydrochloride (PROZAC®), andFIG.10is a schematic of a continuous membrane-facilitated synthetic route for synthesis of fluoxetine hydrochloride. InFIG.9, DMSO represents dimethyl sulfoxide, HEX represents heat exchanger, L-L represents liquid-liquid, MeNH2represents methylamine, MR represents membrane reactor, PFTR represents pore flow through reactor, MSX represents membrane solvent extraction, PV represents pervaporation, and TBME represents tert-butyl methyl ether.FIG.9reinforces the idea proposed herein, i.e., that many continuous API manufacturing processes based on traditional nonmembrane-based equipment/processes can be efficiently and effectively replaced by membrane-based equipment. The continuous manufacturing example of PROZAC™ shown inFIG.7using traditional manufacturing devices can be replaced conveniently by membrane-based devices and processes. Further, the number of equipment needed and (sometimes) the number of steps can be significantly reduced by use of membrane-based equipment.

Thus, the exemplary synthesis systems discussed herein incorporate a membrane device into every or virtually every unit used in API manufacturing process. All units in the system are connected in a serial fashion and operate continuously such that continuous membrane-based production of APIs is achieved. There is no batch processing in the system. In general, the heart of any API production system consists of the reactors for synthesis of intermediates and finally the API. Typically, quite a few reaction steps are involved in traditional API synthesis anywhere from 2, 3, 4 to around 20 reaction steps (or more). The systems discussed herein ensure that each reaction step can be carried out in a membrane reactor in a continuous fashion. Steps related to any reaction carried out before introduction to the reactor (such as mixing reactants, heating the feed) or after the reaction (such as quenching or cooling) can be carried out using membrane-based devices. In some embodiments, the membrane reactor itself can carry out such functions. After each reaction, membrane separation steps can be coupled with the membrane reactor output and separations/purifications of the intermediates/API can be carried out. Use of such system can provide for extraordinary enhancements in reactions in a multistep API synthesis and production process employing membrane reactors at every synthesis step which are then supported by membrane separations at each post-reaction processing step. All of these steps can be carried out continuously to continuously manufacture APIs.

Thus, a membrane-based production process is provided to produce active pharmaceutical ingredients (APIs). Virtually every step in a continuous multi-step synthesis-based process to produce an API in the pharmaceutical industry can be carried out with a membrane unit instead of a conventional non-membrane unit. Membrane reactors can achieve a synthesis level not achievable by conventional tubular reactors. Membrane solvent extraction can allow nondispersive solvent extraction with great efficiency. Membrane pervaporation can be used to selectively remove volatile solvents from a mixture. Organic solvent nanofiltration and organic solvent reverse osmosis can remove solvents and hold back reaction intermediates or the API at room temperature. Membrane crystallizers, membrane mixers, solid hollow fiber, and ceramic tubular exchangers can now carry out the processes of crystallization, mixing and heat exchange respectively much more efficiently than conventional non-membrane based devices. For continuous multistep manufacturing of active pharmaceutical ingredients (APIs) in the molecular weight range of ˜150-1000 Da, incorporation of such membrane devices at every step of the API manufacturing process can overcome many deficiencies of batch manufacturing of pharmaceuticals as well as those of continuous processes using non-membrane devices and processes.

While exemplary embodiments have been described herein, it is expressly noted that these embodiments should not be construed as limiting, but rather that additions and modifications to what is expressly described herein also are included within the scope of the invention. Moreover, it is to be understood that the features of the various embodiments described herein are not mutually exclusive and can exist in various combinations and permutations, even if such combinations or permutations are not made express herein, without departing from the spirit and scope of the invention.