A continuous manufacturing system for the production of active pharmaceutical ingredients including albuterol sulfate

Abstract

Continuous flow methods for producing Active Pharmaceutical Ingredients (APIs), such as albuterol are provided. The methods yield large amounts of high purity APIs quickly and efficiently. Continuous flow systems for carrying out the methods are also provided.

Description

[0001]A CONTINUOUS MANUFACTURING SYSTEM FOR THE PRODUCTION OF ACTIVE PHARMACEUTICAL INGREDIENTS INCLUDING ALBUTEROL SULFATE CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benefit of United States Provisional Patent Application 63 / 556,160 filed February 21, 2024. STATEMENT OF FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT This invention was made with government support under Grant Number BAA75F40122C00122 awarded by Federal Drug Administration. The United States government has certain rights in the invention. BACKGROUND OF THE INVENTION Technical Field The invention generally relates to improved methods of producing Active Pharmaceutical Ingredients (APIs). In particular, the invention provides improved continuous flow methods of producing albuterol sulfate. Description of Related Art APIs are traditionally manufactured in large-scale batch chemical processes which require iterative batch chemical processing steps, each of which is followed by a subsequent purification process and manually validated on a batch-to-batch basis against stringent regulatory impurity standards. The traditional manufacturing approach requires hands-on labor, numerous batch manufacturing reports, extensive chain of custody documentation, and complex logistical supply chain networks which span across continents. There is a need in the art for improved synthetic processes for the continuous manufacturing (CM) of APIs, including albuterol sulfate, via CM and process monitoring in flow. SUMMARY OF THE INVENTION Other features and advantages of the present invention will be set forth in the description of invention that follows, and in part will be apparent from the description or may be learned by practice of the invention. The invention will be realized and attained by the compositions and methods particularly pointed out in the written description and claims hereof. The present disclosure describes novel synthetic processes and devices, and control systems which can be configured for the continuous manufacturing of various APIs. This disclosure enables the continuous manufacturing (CM) of APIs, including the exemplary albuterol sulfate, via CM and process monitoring in flow. The disclosure encompasses (1) a new chemical synthetic pathway for the production of albuterol sulfate, (2) a continuous API manufacturing system with inline chemical and process monitoring, and (3) a digital control system with user interfaces that enable set point selection of CPPs to ensure product quality and ease of regulatory assessment. These features differ from the current state-of-the-art (i.e., batch API manufacturing) by providing more efficient drug manufacturing from Regulatory Starting Material (RSM) to API all within a single streamlined manufacturing system which is equipped with integrated process analytical technologies (PATs) to enable data recording of process conditions and impurities to meet FDA standards. It is an object of this invention to provide a method of preparing albuterol sulfate, comprising i) aminating 2-bromo-1-(4-hydroxy-3-(hydroxymethyl)phenyl)ethan-1-one by reaction with tert-butylamine to de-brominate a bromine moiety to provide an intermediate which retains a carbonyl moiety; ii) hydrogenating the carbonyl moiety on the intermediate to produce albuterol; and iii) forming a sulfate salt of (sulfating) the albuterol to produce albuterol sulfate. In some aspects, at least the steps of aminating, hydrogenating, and sulfate salt formation are performed in a continuous flow process, wherein the intermediate in the aminating step is produced using a tubular reactor, wherein effluent from the tubular reactor containing the intermediate is passed through a catalytic packed bed reactor to produce an effluent containing the albuterol, and wherein the effluent containing albuterol is passed into a continuous stirred tank reactor for sulfate salt formation. In some aspects, the method further comprises: filtering the effluent from the tubular reactor before passing the effluent through the catalytic bed reactor. In further aspects, the method further comprises removal of excess reactants from the filtered effluent via distilling. In yet other aspects, the method further comprises filtering a product containing the albuterol sulfate to separate waste from the albuterol sulfate; and drying the albuterol sulfate. In additional aspects, the method further comprises the step of producing the 2-bromo-1-(4-hydroxy-3-(hydroxymethyl)phenyl)ethan-1-one by hydrogenating a first carbonyl moiety of salicaldehyde to produce a second intermediate; and reacting the second intermediate with bromoacetyl chloride to provide the 2-bromo-1-(4-hydroxy-3-(hydroxymethyl)phenyl)ethan-1-one. In alternative aspects, of the method, at least a plurality of the steps are performed in a continuous flow process. The disclosure also provides a continuous active pharmaceutical ingredient (API) manufacturing system, comprising i) a tubular reactor configured to receive reactants and solvents from one or more pumps; ii) a first microfiltration filter configured to receive an output of the tubular reactor; iii) a distillation column to receive the output of the microfiltration filter, iv) a catalytic packed bed reactor configured to receive an output of the distillation column; v) a continuous stirred-tank reactor configured to receive an output of the catalytic packed bed reactor; vi) at least one additional microfiltration filter configured to receive an output of the continuous stirred-tank reactor; and vii) a filter dryer configured to receive an output of the second microfiltration filter and isolate the API. In some aspects, the continuous API manufacturing system further comprises one or more in-line process analytical technologies (PAT) selected from a group consisting of a temperature sensor, a thermostat, a pressure sensor, a weight sensor, ultraviolet / visible spectroscopy, and nuclear magnetic resonance spectroscopy, wherein the one or more in-line process analytical technologies are configured to assess process conditions and impurities. In additional aspects, the continuous API manufacturing system further comprises a digital control system with a user interface configured to enable selection of process parameters. In yet further aspects, the reactants include salicylaldehyde and the API is albuterol sulfate. The present disclosure also provides a method for synthesizing albuterol, comprising i) hydrogenating form starting material (RSM) salicylaldehyde to form halogenated compound 1’, wherein x = a halogen; iii) aminating halogenated compound 1’ to form compound 2’ iv) hydrogenating the carbonyl group of compound 2’ to form compound 3’ In some x = In some aspects, the method further comprises forming a salt of compound 3’. In alternative aspects, the salt of compound 3’ is compound 4’ . BRIEF DESCRIPTION OF THE DRAWINGS Figure 1A and B. Process chemistry routes for the synthesis of albuterol sulfate including (A) Babad's 1988 literature route (See Molecules: RSM, 1, 2, 3, 4) and (B) the new processing route for continuous manufacturing of albuterol sulfate in flow (See Molecules: RSM, 0, 1', 2', 3', 4'). Figure 2. A process flow diagram detailing major components of the continuous API manufacturing system. This is a small-scale version (throughput: 1.0 mL / min Basis) of the continuous manufacturing system for the production of a representative API (e.g., albuterol sulfate). In this figure, IPA = isopropyl alcohol. DETAILED DESCRIPTION This disclosure describes a novel, continuous, automated drug manufacturing system used to produce active pharmaceutical ingredients (APIs) including albuterol sulfate (CAS# 51022-70-9, i.e., salbutamol) via new synthetic chemical pathways in flow with integrated process monitoring and control. This disclosure encompasses at least two (2) primary areas: (1) A new synthetic pathway for the production of albuterol sulfate starting from salicaldehyde (CAS# 90-02-8), a regulatory starting material (RSM) registered with the Food and Drug Administration (FDA); and (2) A modular, automated, continuous manufacturing (CM) system consisting of a series of vessels, reactors, pumps, valves, fittings, instruments, and purification systems which are connected in series with tubing to continuously synthesize and purify APIs while simultaneously monitoring critical process parameters (CPPs) and critical quality attributes (CQAs) via integrated process analytical technologies (PATs) for quality control, data logging, and regulatory assessment. DEFINITIONS As used herein, "RSM" stands for "Regulatory Starting Material," which refers to the specific point in the drug substance synthesis process where strict quality controls under Good Manufacturing Practices (cGMP) begin, essentially marking the starting material that significantly contributes to the structure of the final Active Pharmaceutical Ingredient (API) and is subject to stringent regulatory oversight. Provided herein is a continuous active pharmaceutical ingredient (API) manufacturing system. The system is used to manufacture a variety of APIs efficiently in a cost-effective manner. Herein, production of an exemplary API, albuterol, is described in detail (see Figure 1). With reference to Figure 2, the manufacturing system generally comprises or consists of at least the following components which are in fluid communication with each other: one or more pumps for transferring (moving) liquids e.g. from a reservoir. The reservoirs are not shown in Figure 2. The liquids are, for example liquid solvents with reactants dissolved therein, liquid solvents with no dissolved reactants, solvents or media for priming, washing and / or flushing the system, etc. The liquids are generally transferred from a suitable reservoir to a tubular reactor by one or more pumps, i.e. they are placed at or near the beginning (“upstream”) in the flow system as shown in Figure 2, although it is noted that inline pumps located downstream of the tubular reactor may be included in the system as needed. The tubular reactor is configured to receive reactants and solvents from one or more pumps, e.g. via inlet and / or outlet ports which may also comprise valves and / or gauges for controlling the flow rate of the liquids. Such inlet and / or outlet ports and valves and / or gauges are known in the art. A tubular reactor comprises a cylindrical pipe and is normally operated at steady state. In the tubular reactor, the reactants are continually consumed as they flow down the length of the reactor. Using albuterol sulfate as an exemplary API, a new synthetic pathway is provided for the production of albuterol sulfate starting from salicaldehyde (CAS# 90-02-8), a regulatory starting material (RSM) registered with the Food and Drug Administration (FDA). The initial reaction of the synthesis method is the conversion (hydrogenation) of salicylaldehyde form the alcohol and recognized starting material (RSM) salicyl alcohol . Solvents used in this step of the reaction include but are not limited to: methanol, ethanol and isopropanol, and mixtures of these. The temperature for this initial reaction is in the range of from about 30oC to about 90oC, such as about 30, 35, 40, 45, 50, 66, 60, 65, 70, 75, 80, 85 or 90oC, and is preferably about 60oC; and this reaction takes place within the tubular reactor, with reference to the system depicted in Figure 2. Salicyl alcohol is then reacted with a halogenating agent such as (a halogen acetyl chloride) to form a halogenated material , where X = a halogen including but not limited to chlorine, bromine, etc. Suitable halogenating agents include but are not limited to chloro acetyl chloride (x=Cl); bromo acetyl chloride (x=Br); and the like. In some aspects, X = Br and the compound 1’ is 2-bromo-1-(4-hydroxy-3-(hydroxymethyl) phenyl)ethan-1-one. As shown in Figure 1, in some aspects, this halogenation reaction occurs “in line” during the mixing of two streams of reactants, and it is the halogenated product that is then transferred to the tubular reactor of the system. Solvents used in this step of the reaction include but are not limited to: methanol, ethanol, isopropanol, and mixtures of these. The temperature for this initial reaction is in the range of from about 30oC to about 90oC, such as about 30, 35, 40, 45, 50, 66, 60, 65, 70, 75, 80, 85 or 90oC, and is preferably about 60oC and this reaction takes place in a packed bed reactor with reference to the system depicted in Figure 2 Alternatively, a commercial source of the salicylaldehyde, salicyl alcohol, and / or the halogenated salicylaldehyde may be identified and used instead For the exemplary albuterol synthesis, amination of the halogenated starting material occurs within the tubular reactor, where e.g. 2-bromo-1-(4-hydroxy-3-(hydroxymethyl)phenyl) ethan-1-one is mixed with and reacts with an amination agent (e.g. tert-butylamine), to de-brominate a halogen moiety, thereby forming an intermediate which retains a carbonyl moiety. Solvents used in this step of the reaction include but are not limited to: methanol, ethanol, isopropanol, and mixtures thereof. The temperature for this initial reaction is in the range of from about 30oC to about 90oC, such as about 30, 35, 40, 45, 50, 66, 60, 65, 70, 75, 80, 85 or 90oC, and is preferably about 60oC. The residence time in a PFR can vary from e.g., about 5 to 90 minutes, such as about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 minutes or more. In some aspects, such as for albuterol synthesis, the residence time may be about 40 minutes. Typically, the flow rate into and through a tubular reactor (e.g. into and out of) is about 1 ml / minute, e.g. about 0.5, 0.1 or 1.5 ml / minute or more, e.g. up top about 5 or 10 ml per minute, depending on the drug that is synthesized. Those of skill in the art will recognize that the reaction conditions described herein that pertain to the manufacture of albuterol may differ somewhat and still be within the scope of the present method. Further, for the manufacture of other APIs, the conditions may vary according to each particular drug. However, the temperature, pressure and flow rate ranges and the types of solvents may be similar. As depicted in Figure 2, the system also comprises a first microfiltration filter downstream (e.g., usually immediately downstream) of the tubular reactor. The microfiltration filter is configured to receive an output of the tubular reactor (e.g. for albuterol, the intermediate which retains a carbonyl moiety). The filter removes unreacted solids, unwanted solid by products, solid impurities, etc. In some aspects, the microfiltration filter is a tangential flow filter (TFF), i.e. a filter for separating and purifying substances by passing a liquid over and parallel to the filter. Tangential flow filtration (TFF) systems include microfiltration, ultrafiltration, hollow fiber filters, and single-pass TFF. In all cases, TFF is a filtration method that uses membranes to separate and purify substances. Microfiltration TFF uses membranes with pore sizes to remove microorganisms or particulates; ultrafiltration TFF uses smaller membranes to reject microorganisms and / or particulates; hollow fiber filters TFFs are made of many small, porous fibers bundled together in a casing; and single-pass TFFs use capsules and cassettes to concentrate process streams without recirculating. Generally, the TFFs of the present systems are micro- or ultrafiltration TFFs and may be multiuse or single pass. A TFF allows solids to remain in suspension while minimizing filter cake build-up that can foul other membranes. TFFs are gentler on shear-sensitive products and are less likely to clog than normal flow filtration (NFF). A dead-end filter can also be used but it fouls more quickly and needs to be cycled under continuous operation The flow rate through a TFF is typically from about 1-10 ml / min, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 ml / min. In some aspects, the flow rate is 5 ml / min. . In some instances, when TFF membrane areas are between 0.001 and 0.01 m^2, flowrates can be between 0.1 and 5 mL / min. Waste is removed from the filter at similar flow rates. For the production of some drugs such as albuterol, liquid comprising the first intermediate that was generated in the tubular reactor is transferred, after filtering e.g. via a TFF filter, to a continuous multistage distillation column. In the case of albuterol, the column is used to remove excess volatile components from the intermediate stream before the intermediate is passed along. Either the output of the TFF or the distillation column is transferred to a catalytic packed bed reactor configured to receive output from the microfiltration filter, and also from other sources. A packed bed reactor is a type of chemical reactor where a vessel is filled with a fixed bed of solid catalyst particles immobilized thereon, creating a "packed bed," essentially, a container filled with catalyst pellets to facilitate chemical reactions. Reactions of components dissolved in a flowing fluid, or reactions of the fluid itself, or reactions of a gas that is also received by and flows into the reactor, are catalyzed via contact with the catalysts during flow. The flow of fluid / gas through the packed bed of catalyst particles, (generally in a plug flow manner) allows for efficient contact and reaction between reactants and the catalyst immobilized on the surfaces of the pellets. These reactors typically exhibit high conversion rates per unit mass of catalyst, relatively low operating costs, and permit continuous operation. A wide variety of catalysts can be immobilized on the pellets of a packed bed reactor, examples of which include but are not limited to: metal catalysts like platinum, palladium, nickel, and rhodium, enzyme catalysts (like lipases and proteases), heterogeneous catalysts supported on porous materials like silica, alumina, or zeolites, and even whole microbial cells depending on the desired chemical reaction and desired level of stability and reusability; the key is that the catalyst particles should be small enough to fit within the packed bed and have suitable properties for immobilization on the support materials. In some aspects, more than one type of catalyst is immobilized on the pellets and / or more than one type of pellet with a catalyst immobilized thereon is present in the packed bed. In the example of synthesizing albuterol, a Pd catalyst is typically used, for example, palladium (0.1-20 wt% Pd) on carbon (Pd / carbon), Pearlman’s catalyst, more generally referred to as Pd(OH)2 / C, etc. Also, for the production of some drugs such as albuterol, an inlet for transferring a gas into the packed bed reactor is present. In the case of albuterol, the gas is hydrogen gas and the reaction that occurs within the backed bed reactor is hydrogenation of the carbonyl moiety of the first intermediate to produce albuterol. At this stage, the albuterol is not in the form of a salt. Alternative hydrogen sources include hydrogen donors in cases of transfer hydrogenation, ex. formic acid (a liquid). Alternatively, for the production of some drugs, no gas is required. Solvents used in this step of the reaction include but are not limited to: methanol, ethanol, isopropanol and mixtures of these solvents. The temperature for this initial reaction is in the range of from about 30oC to about 90oC, such as about 30, 35, 40, 45, 50, 66, 60, 65, 70, 75, 80, 85 or 90oC, and is preferably about 60oC. The flow rate through a TFF is typically from about 1-10 ml / min, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ml / min. In some aspects, the flow rate is 5 ml / min. In some aspects, the pressure within the catalytic packed bed reactor is in the range of from about 1-20 bar, such as about 1, 5, 10, 15 or 20 bar, and is preferably about 10 bar. The system typically includes a continuous stirred-tank reactor (CSTR) configured or positioned to receive an output of the catalytic packed bed reactor. A CSTR is a type of chemical reactor where reactants are continuously fed in, mixed thoroughly through constant stirring, and the reaction products are continuously removed, allowing for a steady-state reaction with uniform composition throughout the vessel; it's commonly used in industrial processes to produce chemicals and pharmaceuticals due to its precise control over reaction conditions and high conversion rates. In addition to receiving input from the packed bed reactor, the CSTR may be configured to receive liquid or gas input from another source, e.g. a source of other reactants, acids, bases, and the like. Alternate acids are used to make other salts. For example, HCl is used to make an HCl salt and H2SO4, is used to make a sulfate salt. In the exemplary synthesis of albuterol, the CSTR receives input from the packed bed reactor (albuterol that is not in the form of a salt) and also an agent such as H2SO4, which may be H2SO4in water. In this exemplary synthesis, the albuterol is transformed into a salt, in particular, albuterol sulfate. For this reaction, the H2SO4 is typically about 1.5 equivalents, such as from about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0 equivalents. In some aspects, 3M H2SO4is used. Solvents used in this step of the reaction include but are not limited to methanol, ethanol, isopropanol and mixtures of these. The temperature for this initial reaction is in the range of from about 30oC to about 90oC, such as about 30, 35, 40, 45, 50, 66, 60, 65, 70, 75, 80, 85 or 90oC, and is preferably about 60oC. The present system also generally comprises a at least one additional (e.g. a “second, third, etc.” microfiltration filter or set of filters configured to receive an output of the CSTR. Thes additional filters may be the same or different from the first microfiltration filter discussed above but generally possesses the same features and properties. The present system generally comprises a filter dryer configured to i) receive the output of the at least one additional (e.g. “second”) microfiltration filter(s) and ii) isolate and dry the desired product in a pure form. A filter dryer is a piece of equipment used to separate solids from liquids and dry the solids during pharmaceutical manufacturing. Essentially, a liquid , such as a liquid slurry, is transferred into the filter dryer (e.g. from the CSTR via the second microfiltration filter). Within the filter dryer, the liquid is mechanically agitated, pressurized, and heated; the solids are separated from the liquid; the solids are washed to remove impurities and solvent traces; waste is removed via an outlet; and the solids are dried. In the present system the dried solids that remain are the API salt, such as albuterol sulfate. The continuous API manufacturing system disclosed herein may further comprise one or more in-line process analytical technologies that are configured or positioned with the flow system to assess process conditions and impurities, especially when the system is in use but also prior to start-up and between uses, e.g. when manufacturing is switching from one product to another. Exemplary in-line technologies include but are not limited to: One or more technologies related to detecting (measuring) and / or maintaining a desired temperature, and / or pH. Examples include but are not limited to temperature sensors, thermometers, thermostats, pH probes, pH meters, etc. For the present systems, it is generally desired to maintain a temperature of from about 25oC to about 100oC for the various reaction steps. Different parts of the system may require or operate optimally at different temperatures. In other words, the temperatures of the catalytic packed bed reactor, continuous stirred-tank reactor and the tubular reactor, and even reservoirs, lines for carrying or transferring liquids between parts of the systems, the housing for the system, etc., may be the same or different and thus multiple temperature measuring and controlling technologies may be included at different positions in the system. Generally, a pH of from about 1 to about 4 is utilized, e.g. a pH of about 1, 1.5, 2.0, 2.5, 3.0, 3.5 or 4.0. The system may also comprise one or more pressure sensors and / or gauges. A pressure sensor is an electronic device that detects or monitors either gas or liquid pressure (force) and converts that information into an electrical signal that can be used to monitor or regulate the force being measured. The way pressure sensors work depends on the type of technology used, examples of which include but are not limited to: piezoresistive pressure sensors (strain gauge), piezoelectric pressure sensors, capacitive pressure sensors, differential pressure sensors, absolute pressure sensors, and Micro-Electro-Mechanical Systems (MEMS) pressure sensors. The type of sensor that is selected can depend on the required accuracy, response time, and operating conditions. The term pressure gauge usually refers to a self-contained indicator that converts the detected process pressure into the mechanical motion of a pointer. The system may also comprise one or more weight sensors. Examples of weight sensors include but are not limited to load cells. A load cell is essentially a force transducer or force sensor that is used principally to measure weight. The one or more in-line process analytical technologies may also include, for example, spectroscopy capabilities such as ultraviolet / visible (UVvis) spectroscopy, Raman spectroscopy, infrared (IR) spectroscopy, nuclear magnetic resonance spectroscopy. Instruments for carrying out measurements using these technologies are known in the art. The overall goal of the present technology is to provide a system capable of generating from about 120-1200 doses / hour of a drug of interest, such as albuterol. As is described in the Examples section below, the present system generated at least about 200 doses per hour of albuterol. In some aspects, with some modifications to the equipment, the system is configured produce between 100 - 10,000 doses per hour. In further aspects, the underlaying processes design are scaled to much larger equipment and produce much larger (e.g. 1,000,0000) doses per hour. In some aspects, the continuous API manufacturing system further comprises a digital control system with a user interface configured to enable selection of process parameters, e.g. time, flow rate, pressure, residence time in a particular spot within the system, temperature, etc. Digital and / or visual output may also be provided, permitting the user to monitor e.g. time, flow rate, pressure, residence time in a particular spot within the system, temperature, purity of an intermediate or product (e.g. by US-vis or NMR), etc. The output may be displayed as graphs, lists, etc. Also encompassed are APIs made by the methods disclosed herein, such as the API albuterol sulfate as well as pharmaceutical compositions comprising at least one of the APIs. Methods of using the APIs are also encompassed, e.g. methods of treating a disease or condition in a patient or subject in need thereof by administering a therapeutically effective dose of the API. A therapeutically effective dose eliminates or at least lessens at least one symptom of the disease or condition. As an example, if the API is albuterol sulfate, its uses include but are not limited to prevention and treatment of wheezing, difficulty breathing, chest tightness, and coughing caused by lung diseases such as asthma and chronic obstructive pulmonary disease (COPD; a group of diseases that affect the lungs and airways). Albuterol made by the present methods is in a class of medications called bronchodilators and can be formulated, e.g. for administration to the nasal passages and / or airways via, e.g. a delivery device such as an inhaler. All such delivery devices comprising an API made by the methods disclosed herein, e.g. albuterol sulfate, are encompassed. It is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Representative illustrative methods and materials are herein described; methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention. All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual dates of public availability and may need to be independently confirmed. It is noted that, as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as support for the recitation in the claims of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitations, such as "wherein [a particular feature or element] is absent", or "except for [a particular feature or element]", or "wherein [a particular feature or element] is not present (included, etc.)...". As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible. The invention is further described by the following non-limiting examples which further illustrate the invention, and are not intended, nor should they be interpreted to, limit the scope of the invention. EXAMPLE SYNTHESIS OF ALBUTEROL An exemplary synthesis of albuterol is depicted in Figure 1. For this synthesis: When the startup command was received, 1’ in IPA, at a concentration of 100 mg / ml and heated to 45°C, was pumped to the Tubular Reactor at 0.5 ml / min. A 4:1 molar ratio of t-butylamine was simultaneously pumped to the tubular reactor at a flow rate of 0.5ml / min. The tubular reactor has a residence time of 40 mins and was held at 60°C. The mix from the Tubular Reactor was sent through a Single-Pass Tangential Flow Filter (SPTFF). There are 2 SPTFFs but only one was in operation at one time. The second SPTFF is a backup. The ratio of permeate to filtrate was determined by two separate back-pressure controllers – one for the waste set to 15 PSIG and one for the product to process set at 0 PSIG. The desired product (filtrate) passed through the filter membrane to the distillation column downstream. The undesired product (retentate) passed through to waste tanks. The distillation column utilized to separate excess t-butylamine operated at a reflux ratio of 1.40. The heat flow into the reboiler was controlled by the pressure drop across the column and IPA was added back to the bottoms stream at the same rate that it was removed from the distillate stream. There can be multiple Packed Bed Reactors (PBR) in parallel that hydrogenate the intermediate from the distillation column though, alternatively one reactor can be sized appropriately. Flow from the distillation column is mixed with hydrogen at a volumetric flow rate ratio of 1.2:20 mL / min and flown through the PBRs. The reactors operate with an added back pressure of 10 bar and 60°C. In some cases, conditions including a rate of 0.3 – 2.4 mL / min with 0 – 30 bar added back pressure and a temperature of up to 80°C are used. The method is scalable to use e.g. as much as 75 mg / mL. The hydrogenated product formed albuterol in solution with IPA that was diverted to the salt formation and precipitation tank. The albuterol solution at a concentration of ~20 mg / mL was combined with sulfuric acid in a 0.5:1 molar ratio to form a slurry of albuterol sulfate in IPA. This reaction occured in a CSTR with a residence time of 20 minutes. The slurry was pumped from the bottom of the reactor to a series of tangential flow filters. Once the feed from the salt formation tank was flowing to the tangential flow filters, backpressure controllers throttled the flow through the retentate to a holding tank. As the retentate left each filter unit, IPA was injected into each of the three lines with separate flow controls to ratio in an equal flow of IPA to the flow from the permeate of each filter. The IPA feed to each filter needs to replace the amount sent to waste. The flow from the permeate of the filters went to a waste tank. The slurry from the holding tank was pumped to the Filter Dryer, the slurry was cooled to 0°C and mixed. Liquid waste (mostly IPA) was removed from the filter dryer via pressure from the top and vacuum from the bottom retaining the solid salt as a filter cake. Optionally, additional washing steps can be repeated by adding back fresh IPA as required to wash the precipitate. The filter cake was dried via heating at 100°C under vacuum. When ready to transfer the API, water for injection (WFI) is pumped to the Filter Dryer. The unit was mixed and heated to dissolve the API into solution. Once the API was dissolved, the solution was transferred to the final product holding tank. While the invention has been described in terms of its several exemplary embodiments, those skilled in the art will recognize that the invention can be practiced with modification within the spirit and scope of the appended claims. Accordingly, the present invention should not be limited to the embodiments as described above, but should further include all modifications and equivalents thereof within the spirit and scope of the description provided herein.

Claims

CLAIMS We claim:

1. A method of preparing albuterol sulfate, comprising aminating 2-bromo-1-(4-hydroxy-3-(hydroxymethyl)phenyl)ethan-1-one by reaction with tert-butylamine to de-brominate a bromine moiety to provide an intermediate which retains a carbonyl moiety; hydrogenating the carbonyl moiety on the intermediate to produce albuterol; and sulfating the albuterol to produce albuterol sulfate.

2. The method of claim 1 wherein at least the steps of aminating, hydrogenating, and sulfating are performed in a continuous flow process wherein the intermediate in the aminating step is produced using a tubular reactor, wherein effluent from the tubular reactor containing the intermediate is passed through a catalytic packed bed reactor to produce an effluent containing the albuterol, and wherein the effluent containing albuterol is passed into stirred tank reactor for sulfation of the albuterol.

3. The method of claim 2 further comprising filtering the effluent from the tubular reactor before passing the effluent through the catalytic bed reactor; and filtering the effluent from the catalytic bed reactor passing the effluent into the stirred tank reactor.

4. The method of claim 3 further comprising filtering a product containing the albuterol sulfate to separate waste from the albuterol sulfate; and drying the albuterol sulfate.

5. The method of claim 1 further comprising the step of producing the 2-bromo-1-(4-hydroxy-3-(hydroxymethyl)phenyl)ethan-1-one byhydrogenating a first aldehyde moiety of salicylaldehyde to produce a second intermediate; and reacting the second intermediate with bromoacetyl chloride to provide the 2-bromo-1-(4-hydroxy-3-(hydroxymethyl)phenyl)ethan-1-one.

6. The method of claim 5 wherein at least a plurality of the steps are performed in a continuous flow process.

7. A continuous active pharmaceutical ingredient (API) manufacturing system, comprising a tubular reactor configured to receive reactants and solvents from one or more pumps; a first microfiltration filter configured to receive an output of the tubular reactor; an optional distillation column configured to receive the filtrate of the first microfiltration filter; a catalytic packed bed reactor configured to receive an output of either the microfiltration filter or the distillation column; a continuous stirred-tank reactor configured to receive an output of the catalytic packed bed reactor; at least one additional microfiltration filter configured to receive an output of the continuous stirred-tank reactor; and a filter dryer configured to receive an output of the at least one additional microfiltration filter and isolate the API.

8. The continuous API manufacturing system of claim 7, further comprising one or more in-line process analytical technologies selected from a group consisting of a temperature sensor, a thermostat, a pressure sensor, a weight sensor, ultraviolet / visible spectroscopy, and nuclear magnetic resonance spectroscopy, wherein the one or more in-line process analytical technologies are configured to assess process conditions and impurities.

9. The continuous API manufacturing system of claim 7, further comprising a digital control system with a user interface configured to enable selection of process parameters.

10. The continuous API manufacturing system of claim 7, wherein the reactants includesalicaldehyde and the API is albuterol sulfate.

11. A method for synthesizing albuterol, comprising i) converting salicylaldehyderecognized starting material (RSM) salicyl alcohol ;ii) reacting the salicyl alcoholto form halogenated compound 1’,wherein X = a halogen; iii) aminating halogenated compound 1’ to form compound 2’and iv) hydrogenating the carbonyl group of compound 2’ to form compound 3’.

12. The method of claim 11, wherein x = Br and compound 1’ is.

13. The method of claim 11, further comprising forming a salt of compound 3’.

14. The method of claim 13, wherein the salt of compound 3’ is compound 4’.

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