Reactive Crystallization Method

Abstract

A method of preparing solid particles of a material is described, the method comprising the steps of: controlling the supply of a first liquid phase, the first liquid phase comprising a solution of a first material through a membrane, the membrane defining a plurality of pores; controlling the supply of a second liquid phase, the second liquid phase comprising a solution of a second material; reacting the first and second materials to produce a third liquid phase comprising a solution of a third material; and supersaturating the third liquid phase to form solid particles of the third material.

Description

[Technical field]

[0001] The present invention relates to a novel method for preparing particulate materials using a mixing reactor and a novel apparatus, for example, in reactive crystallization.

[0002] More specifically, the present invention relates to a mixing reactor and the use of such a reactor in the production of particles, such as micro / nanoparticles or metal organic frameworks, or inorganic materials. [Background technology]

[0003] Reactive crystallization occurs when a chemical reaction results in supersaturation of the crystallizing compound.

[0004] These types of crystallization reactions give rise to high local supersaturation, resulting in high nucleation rates and small crystal sizes in the submicron to several micron range.

[0005] The chemical manufacturing process industry is investing heavily in the production of small sized crystals to improve properties such as chemical reactivity, dissolution rate, bioavailability, and to avoid additional downstream operations such as milling to reduce particle size.

[0006] Reactive crystallization combines both the synthesis of a material and a controlled crystallization step that affects the crystal size, crystal size distribution (CSD), and purity of the material.

[0007] There is great interest in the chemical manufacturing industry to combine chemical reactions and controlled crystallization in a single hybrid process.

[0008] Traditional chemical manufacturing plants use a separate recrystallization process after the chemical reaction, but with reactive crystallization, the final chemical reaction to the desired product and the controlled crystallization to the desired size and morphology occur simultaneously.

[0009] Chemical reaction processes in industry tend to involve multi-step reactions where reagents are mixed to obtain a desired product. These reactions need to be carried out under specific conditions such as temperature, pH range, and pressure. After the reaction step, further processes are carried out for separation and purification of the product, either through by-products or residual solvents. For solid materials, one such type of process is crystallization.

[0010] Industrial crystallization process design aims to control the size, shape, purity and polymorphic form of crystals. To directly produce crystals with small average size, isolation techniques and equipment configurations are required to produce uniformly high supersaturation, i.e., high nucleation rates.

[0011] Having both processes occur simultaneously eliminates the need for separate reaction and recrystallization steps, which not only add time and cost but also require additional reagents and energy.

[0012] The production of small crystals in the manufacturing process of a compound is important for improving and obtaining desired properties. For pharmaceutical compounds, for example, to improve properties such as drug dissolution rate, bioavailability, and tableting, as well as to avoid additional downstream operations such as milling to reduce particle size. In addition, many new pharmaceuticals have low water solubility. It is estimated that about half of the new active pharmaceutical ingredients (APIs) being identified are insoluble or poorly soluble in water. Therefore, solving the bioavailability problem is a major challenge for the pharmaceutical industry.

[0013] Studies with poorly water-soluble drugs have demonstrated that particle size reduction to the submicron range can lead to increased dissolution rates and improved bioavailability. Additionally, reactive crystallization can lead to the formation of exclusive metastable polymorphs of pharmaceutical APIs.

[0014] Metal, metal oxide, and metal salt particles having dimensions on the micrometer to nanometer scale are used in a wide variety of applications, including (but not limited to) catalysts, pigments, brighteners, UV absorbers, and ceramics.

[0015] Such particles are formed by chemical reactions of aqueous solutions of metal salts under conditions such as heat, pressure, or supercritical water.

[0016] This method for reaction of metal salts in aqueous solution offers distinct advantages in terms of cost and feasibility over other methods for micro / nanoparticle fabrication, such as (but not limited to) jet milling, since the reaction method and crystallization can be carried out as a continuous process.

[0017] However, current methods make it difficult to carry out this type of reaction process on a commercial scale because existing reactor configurations cannot effectively control the precipitation reaction, leading to frequent reactor blockages and poor control of particle size, shape, and product purity.

[0018] Thus, for example, the design of the reactor that mixes the water and salt solutions can be crucial to the size and properties of the nanoparticles produced.

[0019] Inorganic materials that are generally not considered to be carbon-based, for example, can also be crystallized using reactive crystallization techniques.

[0020] US Patent No. 5,999,943 (University of Nottingham / Promethean Particles) describes a countercurrent mixing reactor for forming solid nanoparticles. The reactor comprises a body with an internal passage, a first inlet, a second inlet, and an outlet, the internal passage being connected to the first inlet. The body also has an external passage extending from the second inlet, where the external passage enters the internal passage at a 90 degree angle, such that in use, the mixing reactor introduces a second fluid perpendicular to the flow of the first fluid. The reactor utilizes turbulent mixing and does not utilize a membrane. [Prior art documents] [Patent documents]

[0021] [Patent Document 1] European Patent Application Publication No. 3071320 [Patent Document 2] International Publication No. 2012 / 094595 Summary of the Invention [Problem to be solved by the invention]

[0022] There is a need for improved reaction crystallization methods, i.e., chemical reactions in which crystallization is controlled, and improved apparatus for reaction crystallization. The methods should be capable of being scaled up, if desired, and may optionally be continuous processes. [Means for solving the problem]

[0023] Thus, the present invention allows for the scale-up and / or continuous production of small, non-agglomerated solid particles by conventional reaction techniques, such as precipitation of salts towards the desired substance. Reagents and solvents for use in chemical reactions to induce supersaturation towards the controlled crystallization of materials will be understood by those skilled in the art.

[0024] The present inventors have surprisingly discovered that a membrane emulsifier can be used to generate laminar mixing of liquid reactants to create a reactive mixing environment.

[0025] Furthermore, it has been surprisingly found that a cross-flow membrane emulsifier (AXF) utilizing a tubular membrane can be suitably used for the reaction production of solid particles.

[0026] According to a first aspect of the present invention there is provided a method of preparing solid particles of a material comprising the steps of controlling the supply of a first liquid phase, the first liquid phase comprising a solution of a first material through a membrane, the membrane defining a plurality of pores; controlling the supply of a second liquid phase, the second liquid phase comprising a solution of the second material; reacting the first and second materials to produce a third liquid phase comprising a solution of the third material; and supersaturating the third liquid phase to form solid particles of the third material.

[0027] It will be appreciated that a reaction between a first material and a second material occurs when a solution of the first material passes through the membrane and comes into contact with a solution of the second material.

[0028] According to a further aspect of the invention there is provided a method of preparing solid particles of a material comprising the steps of controlling the supply of a first liquid phase, the first liquid phase comprising a solution of a first material, in a first flow direction into a membrane, the membrane defining a plurality of pores; controlling the supply of a second liquid phase, the second liquid phase comprising a solution of a second material, the introduction of the second liquid phase being substantially perpendicular to the introduction of the first liquid phase; reacting the first and second materials to produce a third liquid phase comprising a solution of the third material; and supersaturating the third liquid phase to form solid particles of the third material.

[0029] The process of the invention may involve the reactive preparation of solid particles of material that are in crystalline or amorphous form, or a combination thereof.

[0030] In one aspect of the invention, the method comprises the reactive preparation of solid crystalline particles of the material. In another aspect of the invention, the method comprises the reactive preparation of solid amorphous particles of the material.

[0031] According to a further aspect of the invention there is provided a method for the reactive preparation of solid particles of a third material, the method comprising the steps of reacting a first liquid phase with a second liquid phase by dispersing the first liquid phase in the second liquid phase, the first liquid phase comprises a solution of a first solution material, and the second liquid phase comprises a solution of a second solution material; The method includes the steps of controlling a supply of a first liquid phase in a first flow direction to a membrane, the membrane defining a plurality of pores, and controlling a supply of a second liquid phase to the membrane in cross-flow (AXF) in the first flow direction through the plurality of pores to reactively form a solution of a third material; Optionally, supersaturating the solution of the third material to produce particles of the third material.

[0032] Those skilled in the art will appreciate that the term "cross-flow" as used herein means substantially perpendicular, i.e., at an angle of 90 degrees, plus or minus 45 degrees, to the flow direction of the first liquid phase. Thus, according to this aspect of the invention, there is provided a method as described herein, wherein the "cross-flow" of the second liquid phase is at an angle of 90 degrees, plus or minus 45 degrees, to the flow direction of the first liquid phase.

[0033] According to a further aspect of the invention there is provided a method of reactively preparing solid particles of a material, the method comprising dispersing a first liquid phase comprising a solution of a first material in a second liquid phase comprising a solution of a second material, The method uses a cross-flow reactive mixer, the cross-flow reactive mixer comprising: an outer tubular sleeve provided with a first inlet at a first end, a material outlet, and a second inlet distal to and angled relative to the first inlet; a tubular membrane having a plurality of holes and configured to be disposed inside the tubular sleeve; Optionally, an insert configured to be positioned inside the tubular membrane, the insert having an inlet end and an outlet end, each of the inlet end and the outlet end being provided with a chamfered area, the chamfered area being provided with a plurality of openings and a bifurcation plate; and A method is provided that includes controlling the supply of a first liquid phase to a tubular membrane and controlling the supply of a second liquid phase to the tubular membrane through a plurality of holes to reactively form a solution of a third material.

[0034] It will be appreciated that the methods of the invention may involve preparing solid particles of more than one material comprising two or more components, for example as co-crystals, which may form unique crystal structures with unique properties.

[0035] The prepared reacted solution (i.e., after reaction) will contain one or more dissolved materials. A variety of dissolved materials may be used in the method of the present invention. Typically, the dissolved materials may be one or more organic compounds, such as unreacted reagents, pharma- ceutical active compounds, bioactive agents, nutraceuticals, polymers, etc., metal-organic frameworks, or inorganic materials.

[0036] According to one aspect of the invention, the prepared reacted solution (ie, after reaction) will contain dissolved material, which is an organic compound.

[0037] According to another aspect of the invention, the reacted solution prepared (i.e., after the reaction) will contain a dissolved material, which is an inorganic material.

[0038] The method of the invention may involve the reactive preparation of solid particles of a material that is in crystalline or amorphous form, or a combination thereof. In one aspect of the invention, the method involves the reactive preparation of solid crystalline particles of a material. In another aspect of the invention, the method involves the reactive preparation of solid amorphous particles of a material.

[0039] In certain embodiments of the present invention, the dissolved preparation material (i.e., after reaction) comprises a material that is poorly soluble. The term "poorly soluble" should be interpreted as meaning a material that is poorly water-soluble and therefore has poor bioavailability. Nearly 90% of active pharmaceutical ingredients under development are poorly water-soluble and therefore generally have poor bioavailability.

[0040] In one aspect of the invention, the term "soluble" is intended to mean that 10-30 parts of solvent are required to dissolve one part of solute. The term "poorly soluble" is intended to mean that 100-10,000 parts of solvent are required to dissolve one part of solute. The term "slightly soluble" is intended to mean that 100-1,000 parts of solvent are required to dissolve one part of solute. The term "insoluble" is intended to mean that more than 10,000 parts of solvent are required to dissolve one part of solute. These terms are generally defined in the United States Pharmacopeia.

[0041] Reactive crystallization uses miscible solvents in which the reagents and by-products are all soluble. The term "solvent" is used herein to describe a solvent or mixture of solvents in which the material of interest is at least slightly soluble, as defined in the United States Pharmacopoeia. However, the desired product is insoluble as it is formed and crystallized. This also provides a means to aid in the separation process. The type of solvent to use for reactive crystallization of a material will be understood by one of ordinary skill in the art.

[0042] The ratios and amounts of these materials may be adjusted according to the materials, solvents, and physicochemical properties such as solubility, melting point, and the like.

[0043] The addition of surfactants can affect reactive crystallization; surfactants may contribute to the nucleation and growth rate, and may change the size distribution of crystalline and amorphous particles. The addition of surfactants may also change the crystal polymorphism and particle morphology. The solution solvent may additionally contain one or more surfactants or co-surfactants.

[0044] The surfactant may be selected from one or more of nonionic surfactants, anionic surfactants, cationic surfactants, and zwitterionic surfactants, and combinations thereof.

[0045] Nonionic surfactants for use in the present invention include polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), Pluronic P123 (PEO-PPO-PEO), ethoxylates including fatty alcohol ethoxylates, such as octaethylene glycol monodecyl ether, pentaethylene glycol monodecyl ether, and hexoxyethylene glycol mono-n-dodecyl ether, alkylphenol ethoxylates, such as Triton The surfactant may be selected from, but is not limited to, X-100, fatty acid esters such as glycerol monostearate and glycerol monolaurate, fatty acid esters of sorbitol such as sorbitan monolaurate, sorbitan monostearate, and sorbitan tristearate, fatty acid amides such as cocamide monoethanolamine and cocamide diethanolamine, and Tweens such as Tween 20, Tween 40, Tween 60, and Tween 80, which are non-ionic detergents widely used in biochemical applications, and fatty alcohol ethoxylates such as ethoxylates including octaethylene glycol.

[0046] The anionic surfactant may be selected from, but is not limited to, sodium dodecyl sulfate (SDS), sodium dodecylbenzenesulfonate (SDBS), ammonium lauryl sulfate, and sodium bis(2-ethylhexyl)sulfosuccinate.

[0047] The cationic surfactant may be selected from ammonium salts such as, but not limited to, cetyltrimethylammonium bromide (CTAB), cetylpyridinium chloride (CPC), benzalkonium chloride (BAC), benzethonium chloride (BZT), dimethyldioctadecylammonium chloride, dioctadecyldimethylammonium bromide (DODAB), and dodecyldimethylammonium bromide (DDAB).

[0048] The zwitterionic surfactant may be selected from phospholipids, such as, but not limited to, phosphatidylserine, phosphatidylcholine (PC), and phosphatidylethanolamine (PE).

[0049] The amount of surfactant needed to obtain good particle size and shape can vary, but can be about 0.005-2.0 w / w% of the total solution.

[0050] Surfactants and co-surfactants include, but are not limited to, Tween, a non-ionic detergent widely used in biochemical applications, also known as PEG(20) sorbitan monolaurate. Other emulsifiers include poloxomers of hydrophilic non-ionic surfactants, which are non-ionic triblock copolymers, Tween 80, and lecithin.

[0051] In the present process, cross-flow membrane reactive crystallization utilizes the flow of the second phase to detach droplets from the membrane and sweep the flow of the first phase through the membrane pores to uniformly mix them, in contrast to the use of turbulent flow (e.g., by stirring) to generate solid particles.

[0052] The location of the particle outlet may vary depending on the flow direction of the first liquid phase, i.e., from inside to outside of the membrane or from outside to inside of the membrane. If the flow of the first liquid phase is from outside to inside of the membrane, the particle outlet is generally at the second end of the tubular sleeve. If the flow of the first liquid phase is from inside to outside of the membrane, the particle outlet may be at a side branch or at the end.

[0053] In one embodiment of the invention, the cross-flow device comprises an insert as described herein, wherein the first inlet is a first inlet for a first liquid phase and the second inlet is an inlet for a second liquid phase, such that the first liquid phase moves from the outside to the inside of the tubular membrane.

[0054] In another embodiment of the invention, the cross-flow device does not include an insert, and the first inlet is for the inlet of a first liquid phase and the second inlet is for the inlet of a second liquid phase, such that the first liquid phase moves from the inside to the outside of the tubular membrane.

[0055] When an insert is present and the tubular membrane is disposed inside the outer sleeve, the spacing between the insert and the tubular membrane may vary depending on the desired laminar flow conditions, etc. Typically, the insert is centrally located within the tubular membrane such that the spacing between the insert and the membrane has a circular ring of equal or substantially equal dimensions at any point around the circumference of the insert. Thus, for example, the spacing may be about 0.05 to about 10 mm (the distance between the outer wall of the insert and the inner wall of the membrane), about 0.1 to about 10 mm, about 0.25 to about 10 mm, or about 0.5 to about 8 mm, or about 0.5 to about 6 mm, or about 0.5 to about 5 mm, or about 0.5 to about 4 mm, or about 0.5 to about 3 mm, or about 0.5 to about 2 mm, or about 0.5 to about 1 mm.

[0056] When the tubular membrane is placed inside the outer sleeve, the spacing between the tubular membrane and the outer sleeve may vary depending on the desired droplet size, etc. In general, the tubular membrane is centrally located within the outer sleeve, and the spacing between the membrane and the sleeve is such that the membrane has a circular ring of equal or substantially equal dimensions at any point around the circumference of the tubular membrane. Thus, for example, the spacing can be about 0.5 to about 10 mm (the distance between the outer wall of the membrane and the inner wall of the sleeve), or about 0.5 to about 8 mm, or about 0.5 to about 6 mm, or about 0.5 to about 5 mm, or about 0.5 to about 4 mm, or about 0.5 to about 3 mm, or about 0.5 to about 2 mm, or about 0.5 to about 1 mm.

[0057] In an alternative embodiment of the present invention, the insert is tapered so that the spacing between the insert and the tubular membrane can diverge along the length of the membrane. The spacing and amount of divergence will vary depending on the slope of the tapered insert, the desired laminar flow conditions / flow rate, particle size distribution, etc. Those skilled in the art will understand that the spacing between the insert and the tubular membrane can diverge or taper along the length of the membrane depending on the direction of the taper. The use of tapered inserts can be advantageous in that a suitable taper can allow laminar flow to remain constant for a particular formulation and set of flow conditions. Thus, tapered inserts can be used to control the variation in droplet size due to changes in fluid properties such as viscosity as the concentration of material in a solvent increases through a path along the length of the membrane.

[0058] In an alternative embodiment of the invention, the cross-flow device may comprise more than one tubular membrane, i.e., multiple tubular membranes, located inside the outer tubular sleeve. When multiple tubular membranes are provided, each membrane may optionally have an insert located therein, as described herein. Multiple membranes may be grouped as a cluster of membranes located next to each other. Desirably, the membranes are not in direct contact with each other. It will be appreciated that the number of membranes may vary depending, among other things, on the nature of the droplets to be generated. Thus, by way of example only, when multiple tubular membranes are present, the number of membranes may be between 2 and 100.

[0059] The inclined second inlet on the outer tubular sleeve generally comprises a bifurcation of the tubular sleeve and may be perpendicular to the longitudinal axis of the tubular sleeve. The location of the bifurcation or second inlet may vary and may depend on the plane of the membrane. In one embodiment, the location of the bifurcation or second inlet is substantially equidistant from the inlet and outlet, but one skilled in the art will understand that the location of the second inlet may vary. It is also within the scope of the present invention to provide more than one bifurcation inlet. For example, the use of two bifurcations may advantageously allow for the flow of the second phase during priming, or flushing for cleaning, or draining / venting for sterilization.

[0060] The inlet and outlet ends of the outer sleeve are generally provided with a seal assembly. The seal assemblies of the inlet and outlet ends of the outer sleeve may be the same or different, but preferably, they are the same. Typical O-ring seals have O-rings of various shapes that are compressed between the two surfaces where a seal is required. Commercially available O-ring seals have a variety of groove options with standard dimensions. Each seal assembly comprises a tubular ferrule with a flange at each end. The first flange, located at the end adjacent to the outer sleeve (when mated), may have a circumferential inner recess that serves as a seat for the O-ring seal. When the O-ring seal is in place, it sits around the end of the insert (if present) and in the recess of the outer sleeve, and is configured to seal against leakage of fluid from within any of the elements of the cross-flow device. However, the O-ring seal used in the present invention is designed to allow a clearance fit, with the membrane sliding within the O-ring. This arrangement is advantageous in that it avoids two potential problems when installing the membrane tube: (1) The thin membrane tubes may collapse during installation; and (2) The thin membrane tube may cut the curved surface of the O-ring.

[0061] The O-ring seals used in the present invention require careful dimensional design and tolerances because when the end ferrules are clamped onto the outer sleeve, the sides of the O-ring are crushed and deformed, compressing the outer surface of the tubular membrane and the inner surface of the sleeve to form a seal.

[0062] However, those skilled in the art will appreciate that other means of forming a seal may be suitably used, such as, for example, using threaded joints tightened to a specific torque (which eliminates the need for close tolerances) or clamping the parts to a specific force followed by welding (which may be particularly suitable when using plastic cross-flow equipment).

[0063] The inner diameter of the tubular membrane may vary. In particular, the inner diameter of the tubular membrane may vary depending on whether an insert is present or not. Generally, the inner diameter of the tubular membrane will be quite small. In the absence of an insert, the inner diameter of the tubular membrane may be about 1 mm to about 10 mm, or about 2 mm to about 8 mm, or about 4 mm to about 6 mm. If an insert is intended to be used in conjunction with the tubular membrane, the inner diameter of the tubular membrane may be about 5 mm to about 50 mm, or about 10 mm to about 50 mm, or about 20 mm to about 40 mm, or about 25 mm to about 35 mm. The larger the inner diameter of the tubular membrane, the lower the injection pressure it may be able to handle. Since the cylinder must be able to withstand the injection pressure from the outside, the upper limit of the inner diameter of the tubular membrane may depend, among other things, on the thickness of the membrane tube and whether it is possible to drill a uniform hole through the thickness. The inner chamber of the cylindrical membrane usually contains the second liquid phase.

[0064] In contrast to membrane emulsification using a vibrating membrane, in the present invention the membrane, sleeve and insert are generally stationary.

[0065] As described herein, prior art membranes, such as those described in US Pat. No. 5,999,336, have conical or concave holes in the membrane. As an example, holes can be laser drilled in the membrane. Laser drilled membrane holes or through holes are substantially more uniform in hole size, hole shape, and hole depth. The hole geometry can be important, for example, it is preferable for the hole to have a clear and well-defined edge around the hole outlet. It can be desirable to avoid complex paths (such as those resulting from sintered membranes) to minimize blockages, reduce feed pressure (referring to mechanical strength), and maintain equal flow rates from each hole. However, as discussed herein, it is within the scope of the present invention to use holes whose internal lumens are non-circular (e.g., rectangular holes) or complex shapes (e.g., tapered or stepped diameters to minimize pressure drop).

[0066] In the membrane, the holes may be uniformly spaced or have a variable pitch, or the membrane holes may have a uniform pitch in a row or circumference but a different pitch in another direction.

[0067] The pores of the membrane may vary. By way of example only, the pores of the membrane may have a pore size of about 1 μm to about 100 μm, or about 10 μm to about 100 μm, or about 20 μm to about 100 μm, or about 30 μm to about 100 μm, or about 40 μm to about 100 μm, or about 50 μm to about 100 μm, or about 60 μm to about 100 μm, or about 70 μm to about 100 μm, or about 80 μm to about 100 μm, or about 90 μm to about 100 μm. In further embodiments of the invention, the pores of the membrane may have a pore size of about 1 μm to about 40 μm, for example about 3 μm, or about 5 μm to about 20 μm, or about 5 μm to about 15 μm.

[0068] In the membrane, the pores may be substantially tubular in shape. However, it is within the scope of the present invention to provide the membrane with uniformly tapered pores. Such uniformly tapered pores may be advantageous in that their use may reduce the pressure drop across the membrane and increase throughput / flux. It is also within the scope of the present invention to provide membranes with pores that have essentially constant diameters but have non-circular (e.g. rectangular holes) or complex shapes (e.g. tapered or stepped diameters to minimize pressure drop) and high aspect ratios.

[0069] The distance or pitch between the holes may vary depending on, inter alia, the pore size and can be from about 1 μm to about 5,000 μm, or from about 1 μm to about 1,000 μm, or from about 2 μm to about 800 μm, or from about 5 μm to about 600 μm, or from about 10 μm to about 500 μm, or from about 20 μm to about 400 μm, or from about 30 μm to about 300 μm, or from about 40 μm to about 200 μm, or from about 50 μm to about 100 μm, for example about 75 μm.

[0070] The surface porosity of the membrane may depend on the pore size and may be from about 0.001% to about 20%, or from about 0.01% to about 20%, or from about 0.1% to about 20%, or from about 1% to about 20%, or from about 2% to about 20%, or from about 3% to about 20%, or from about 4% to about 20%, or from about 5% to about 20%, or from about 5% to about 10% of the surface area of ​​the membrane.

[0071] The arrangement of the holes can vary depending on, among other things, the hole size, the throughput, etc. In general, the holes can be in a patterned arrangement, and can be in a square, triangular, linear, circular, rectangular, etc. In one embodiment, the holes are in a square arrangement.

[0072] It will be appreciated that the reactive mixing device and, in particular, the membrane of the present invention may comprise known materials such as glass, ceramic, metal, e.g., stainless steel or nickel, polymer / plastic, such as fluoropolymer, or silicon. The use of metals, such as stainless steel or nickel, or polymer / plastic, such as fluoropolymer, is advantageous, among other things, in that the device and / or membrane may be sterilized, if desired, using conventional sterilization techniques known in the art, such as gamma irradiation. The use of polymer / plastic materials, such as fluoropolymer, is advantageous, among other things, in that the device and / or membrane may be manufactured using injection molding techniques known in the art.

[0073] Thus, according to a further aspect of the present invention there is provided a reactive crystallizer for reactively dispersing a first phase in a second phase, comprising: a membrane defining a plurality of apertures connecting a first liquid phase to a second liquid phase, the first liquid phase being on a first side of the membrane and comprising a solution of a first material, and the second liquid phase being on a second, different side of the membrane and comprising a solution of a second material; The apparatus is configured to generate a reactive mixture by discharging a first liquid phase into a second liquid phase through a plurality of apertures; The apparatus also includes a reaction chamber positioned to receive the first and second liquid phases and / or the reactive mixture from the membrane. A reactive crystallizer is provided.

[0074] As described herein, an insert may be included in the membrane to promote uniform flow distribution. However, the absence of an insert is within the scope of the cross-flow device of the present invention. If an insert is present, the bifurcation plate may be configured to split the flow of the second or first phase into multiple branches. Whether the bifurcation plate splits the second or first phase depends on the flow direction of the second phase, i.e., whether the second phase flows through the first inlet or the second inlet. The number of bifurcation plates may vary, but the number selected should be suitable to provide uniform flow distribution and should not have excessive shear forces (at the particle outlet end). Preferably, if an insert is present, the bifurcation plate is a bifurcation plate or a trifurcation plate to provide uniform flow of the second phase in the annular region between the insert and the membrane. Most preferably, the bifurcation plate is a trifurcation plate.

[0075] The number of openings provided in the insert may vary depending on the injection speed, etc. Generally, the number of openings may be 2 to 6. Preferably, the number of openings is 3.

[0076] The chamfered area on the insert is advantageous in that it allows the insert to be centered when it is placed in place inside the membrane. The outer circumference of the end of the insert has a minimum tolerance to the inner diameter of the tubular membrane. This allows the insert to be accurately centered, resulting in a consistent annulus and consistent laminar flow. Generally, the chamfered area includes a shallow chamfer, which is advantageous in that it evens out the flow distribution and allows the use of openings in the insert with a larger cross-sectional area than would be possible if the flow were to enter directly through openings parallel to the axis of the insert. This keeps the flow velocity low, thereby minimizing undesirable pressure losses and shear forces at the outlet. The distance between the beginning of the openings and the beginning of the perforated area on the tubular membrane allows for the establishment of an even velocity distribution. The radial dimension of the insert is selected to provide a depth of the annulus that produces a particular laminar flow that produces a selected flow rate. The axial dimension is generally designed to provide a combined opening area that is larger than both the annular area and the inlet / outlet tube area.

[0077] The use of membrane emulsification techniques in the reactive preparation of solid materials described herein may involve the use of turbulent flow, for example by stirring or liquid flow, or the use of laminar flow. In certain aspects of the invention, the reactive membrane emulsification techniques involve the use of laminar flow, i.e., while at the same time generally avoiding or minimizing turbulence.

[0078] The use of reactive membrane emulsification technology in preparing solid materials as described herein may include the use of one or more pump systems.It is understood that any pump system known in the art for reactive membrane emulsification may be suitably used.However, in certain aspects of the present invention, pump system may include gear pump or peristaltic pump, and combinations thereof.

[0079] Using the method of the present invention, the chemical conditions and mechanical force distribution can be precisely controlled to be substantially constant over long distances, and therefore the resulting solid material particles have a more uniform particle size and a narrow particle size distribution.

[0080] The process of the present invention may comprise a batch process or a continuous process. Desirably, the process of the present invention comprises a continuous process.

[0081] Reactive membrane emulsifiers can include laboratory dispersion cells (LDCs) that use precisely engineered circular membranes coupled with agitators to generate the shear forces necessary for droplet formation, or cross-flow apparatus (AXFs), which when used in a continuous flow mode are commonly referred to as continuous cross-flow (CXFs).

[0082] The size distribution of solid particles can be measured by various techniques. An exemplary technique is to measure the size distribution of solid particles by laser diffraction, for example using a Malvern Mastersizer 2000 (Worcestershire, UK). The relative volumes Vi of particles of different size classes i, with mean diameters di between 0.01 and 3500 μm, can be used to calculate the volume-weighted mean diameter d[4,3].

[0083]

number

[0084] The size uniformity of the solid particles was estimated using the span of the particle size distribution.

[0085]

number

[0086] where d(v,0.1), d(v,0.5), and d(v,0.9) are the particle sizes at 10%, 50%, and 90% by volume of the cumulative distribution.

[0087] In one embodiment of the invention, a cross-flow reactive mixing / emulsification apparatus includes an insert as described herein, where the first inlet is a first inlet for a second phase, such that the second inlet is an inlet for a first phase, and the first phase travels from the outside to the inside of the tubular membrane.

[0088] In another embodiment of the invention, the cross-flow reactive mixing / emulsification apparatus does not include an insert, and the first inlet is a first inlet for a first phase and the second inlet is an inlet for a second phase, such that the first phase moves from the inside to the outside of the tubular membrane.

[0089] The solid material particles prepared by the methods of the present invention are useful as components of pharmaceutical compositions. These compositions typically contain, in addition to the pharma- ceutically active solid particles, a pharma- ceutically acceptable carrier.

[0090] According to a further aspect of the present invention there is provided the use of a membrane emulsification apparatus as a reactive mixing apparatus.

[0091] In particular, there is provided the use of a cross-flow membrane emulsifier as a reactive mixing device.

[0092] In the use according to this aspect of the invention, the membrane emulsifier is a reactive cross-flow emulsifier.

[0093] There is further provided the use of a reactive cross-flow emulsifier as a reactive mixing device, the cross-flow emulsifier comprising: an outer tubular sleeve provided with a first inlet at a first end, an emulsion outlet, and a second inlet distal to and angled relative to the first inlet; a tubular membrane having a plurality of holes and configured to be disposed inside the tubular sleeve; Optionally, an insert configured to be positioned inside the tubular membrane, the insert having an inlet end and an outlet end, each of the inlet end and the outlet end being provided with a chamfered area, the chamfered area being provided with a plurality of openings and a bifurcation plate; Includes.

[0094] Thus, according to a further aspect of the invention, there is provided a material in solid particulate form prepared by the method described herein. The material in solid particulate form according to this aspect of the invention may be in crystalline or amorphous form, or a combination thereof. In one aspect of the invention, the material in solid particulate form comprises solid crystalline particles. In another aspect of the invention, the material in solid particulate form comprises solid amorphous particles.

[0095] According to this aspect of the invention, the material in solid particulate form, e.g., crystalline or amorphous, may include an active agent.

[0096] By way of example only, active agents that comprise the solid particles of the present invention include, but are not limited to, biologically active agents, such as pharmaceutical active agents, pesticides, etc. Biologically active agents may also include, for example, plant growth regulators. Alternatively, the active agents may be biologically inactive, such as plant nutrients, flavorings, fragrances, etc.

[0097] A pharmacologic active agent refers to a natural, synthetic, or semi-synthetic material (e.g., a compound, ferment, extract, cell structure) capable of exerting one or more physical, chemical, and / or biological effects, directly or indirectly, in vitro and / or in vivo. Such an active agent may be capable of preventing, mitigating, treating, and / or curing an abnormality and / or pathological condition of an organism, for example, by combating a parasite or by substantially altering the physiology of the host or parasite to inhibit the effects of the disease or abnormality. Such an active agent may be capable of maintaining, enhancing, reducing, limiting, or disrupting a physiological body function. An active agent may be capable of diagnosing a physiological condition or state by in vitro and / or in vivo testing. An active agent may be capable of controlling or protecting the environment or organism by attracting, neutralizing, inhibiting, killing, modifying, repelling, and / or inhibiting animals or microorganisms. An active agent may be capable of otherwise treating the body (e.g., deodorizing, protecting, decorating, grooming). Depending on the effect and / or its application, the active agent may be further referred to as a bioactive agent, a pharmaceutical (such as a prophylactic or therapeutic agent), a diagnostic agent, a nutraceutical, and / or a cosmetic, and may include, but is not limited to, a prodrug, an affinity molecule, a synthetic organic molecule, a proteinaceous compound, a peptide, a vitamin, a steroid, a steroid analogue, a nucleic acid, a carbohydrate, precursors thereof, and derivatives thereof. The active agent may be ionic, non-ionic, neutral, positively charged, negatively charged, or zwitterionic, and may be used alone or in combination of two or more thereof. The active agent may be water-insoluble or water-soluble.

[0098] A wide variety of pharma- ceutical active agents may be utilized in the present invention. Thus, the pharma- ceutical active agent may include one or more of polynucleotides, peptides, proteins, small organic active agents, small inorganic active agents, and mixtures thereof.

[0099] In certain aspects of the invention, the solid particles produced comprise a pharma- ceutical active compound. It will be appreciated by those skilled in the art that any suitable poorly soluble pharma- ceutical active compound may be used in the methods of the invention. Such pharma- ceutical active compounds include antifungals such as itraconazole, fluoconazole, terconazole, ketoconazole, and saperconazole, anti-infectives such as griseofulvin and griseoverdine, antibiotics such as amoxicillin, azithromycin, cephalexin, cefixime, cefoperazone, ceftriaxone, ciprofloxacin, clarithromycin, clavulanic acid, clindamycin, doxycycline, erythromycin, gentamicin, erythromy ... carbamazepine, levofloxacin, meropenem, metronidazole, neomycin, norfloxacin, ofloxacin, ornidazole, oxytctracycline, piperacillin, rifampicin, streptomycin, sulbactam, sulfadiazine, tazobactam, tetracycline, and tinidazole, antimalarials such as atovaquone and artesunate, protein kinase inhibitors such as afatinib, axitinib, bosutinib, cetuximab, crizotinib, Dasatinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, zemurasenib, lapatinib, lenvatinib, mubritinib, and nilotinib, immune system modulating drugs such as cyclosporine, cardiovascular drugs such as digoxin and spironolactone, sterols or steroids such as betamethasone, ACE inhibitors such as captopril, enalapril, ramipril, quinapril, perindopril, lisinopril, and fosinopril, adenohypophyseal hormones, adrenergic antagonists such as fulvopril, Entolamine, Phenoxybenzamine, Tamsulosin, Propranolol, Atenolol, Metoprolol, Timolol, and Acebutolol, Corticosteroids, Inhibitors of the Biosynthesis of Corticosteroids, alpha adrenergic agonists such as methoxamine, phenylephrine, methyldopa, norepinephrine, alpha adrenergic antagonists such as phentolamine and phenoxybenzamine, Analgesics such as Aspirin and Paracetamol, Antipyretics and Anti-inflammatory Agents such as Diclofenac, Ibuprofen, Naproxen,and ketoprofen, androgens, local anesthetics such as lidocaine, anti-addiction drugs, antiandrogens, antiarrhythmic drugs such as verapamil and diltiazem, antiasthmatics such as beclomethasone, budesonide, fluticasone, reproterol, salbutamol, and salmeterol, anticholinergics such as ipratropium and oxybutynin, anticholinesterase drugs such as donepezil, anticoagulants such as dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban, antidiabetic drugs such as metformin, antidiarrheals, antidiuretics, antiemetics and gastrointestinal motility enhancers, antiepileptics, e.g. carbamazepine, gabapentin, oxcarbazepine, antiestrogens, antifungals, antihypertensives, e.g. losartan, olmesartan, telmisartan, and valsartan, antibacterials, antimigraine drugs, e.g. zolmitriptan, antimuscarinics, antineoplastics, antiparasitic drugs, antiparkinsonian drugs, e.g. carbidopa and levodopa, antiplatelet agents, antiprogestins, antithyroid drugs, antitussives, antivirals, antidepressants, azaspirodecanediones, barbiturates, benzodiazepines, benzothiadiazides, beta adrenergic agonists kinetic drugs, beta-adrenergic antagonists, selective adrenergic antagonists, selective agonists, bile salts, butyrophenones, calcium channel blockers, catecholamines and sympathomimetics, cholinergic agonists, cholinesterase reactivators, nootropics such as piracetam, dermatological drugs, diphenylbutylpiperidine, diuretics, ergot alkaloids, estrogens, ganglionic blockers, ganglionic stimulants, glucocorticoid steroids such as dexamethasone and prednisolone, gastric acidity regulators and anti-ulcer drugs, hematopoietic agents, histamine, antihistamines, HMG-CoA reductase inhibitors, such as statins, such as atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, 5-hydroxytryptamine antagonists, hypnotics and sedatives, immunosuppressants, laxatives, methylxanthines, monoamine oxidase inhibitors, neuromuscular blocking agents, nutrients or dietary supplements, such as vitamin B1, vitamin B6, and retinol, organic nitrates, opioid sedatives and antagonists, pancreatic enzymes, phenothiazines, progestins, prostaglandins, psychiatric medications, retinoids, sodium channel blockers,Thrombolytic agents, thyroid agents, tricyclic antidepressants, tyrosine kinase inhibitors such as axitinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, and vemurafenib, as well as danazol, acyclovir, dapsone, indinavir, lopinavir, nifedipine, nitrofurantoin, phentytoin, ritonavir, saquinavir, sulfamethoxazole, valproic acid, trimethoprim, Examples of pharmacokinetic and pharmacokinetic agents include, but are not limited to, acetazolamide, azathioprine, iopanoic acid, nalidixic acid, nevirapine, praziquantel, rifampicin, albendazole, amitriptyline, artemether, lumefantrine, chlorpromazine, clofazimine, efavirenz, iopinavir, folic acid, glibenclamide, haloperidol, ivermectin, mebendazole, niclosamide, pyrantel, pyrimethamine, sulfadiazine, sulfasalazine, triclabendazole, and cinnarizine, and combinations thereof. Such pharmacokinetic and pharmacokinetic agents may be in free or salt form. Effect of the Invention

[0100] The particles obtained by the method of the present invention can be formulated into pharmaceutical compositions.Examples of pharmaceutical forms for administering the solid particles prepared by the method described herein can include solid dosage forms, such as tablets, capsules, granules, pellets, or powders.The resulting compositions can have enhanced performance, including but not limited to supersaturation, improved dissolution rate, improved bioavailability, improved or controlled release, etc.

[0101] The particles obtained by the method of the present invention can be formulated into pharmaceutical formulations in the form of excipients. Excipients are substances that are formulated with a pharmaceutical active ingredient and are included for the purpose of long-term stabilization, bulking up a solid formulation, or therapeutically enhancing the active ingredient in the final dosage form. Excipients can be useful in other areas, such as facilitating drug absorption, reducing viscosity, improving solubility, etc.

[0102] The invention will now be described, by way of example only, with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0103] [Figure 1(a)] Particle size of CaSO4·2H2O obtained by batch crystallization is shown. [Figure 1(b)] The particle size of CaSO4·2H2O obtained by reactive crystallization using the AXF mini is shown. [Figure 1(c)] A microscopic image (100x) of reactively crystallized CaSO4·2H2O is shown. [Figure 1(d)] The FTIR spectrum of reactively crystallized CaSO4·2H2O(*) is shown. The vibration peaks in the spectrum match those of the reference CaSO4·2H2O(Δ) obtained from NIST. [Figure 1(e)] S-1) X-ray diffraction patterns of batch reactive crystallization of CaSO4·2H2O and S-2) X-ray diffraction patterns of AXF-mini reactive crystallization of CaSO4·2H2O are shown. [Diagram 2] Particle size of CaHPO4·2H2 crystallized using batch reactive crystallization. [Figure 3(a)] Particle size of CaHPO4·2H2O crystallized using AXF-mini stoichiometric reaction crystallization at CP:DP of 5:1 mL / min. [Figure 3(b)] A microscopic image (100x) of reactively crystallized CaHPO4·2H2O is shown. [Figure 3(c)] The FTIR spectrum of reactively crystallized CaHPO4 2H2O(*) is shown. The vibration peaks in the spectrum match those of the reference CaHPO4 2H2O(Δ) obtained from NIST. [Figure 4(a)] Particle size of CaHPO4·2H2O crystallized using AXF-mini by non-stoichiometric reaction crystallization with CP:DP of 10:0.5mL / min. [Figure 4(b)]Microscope images (100x) of CaHPO4·2H2O crystals using AXF-mini via non-stoichiometric reaction crystallization with CP:DP at 10:0.5mL / min. The initial image shows that stirring the amorphous CaHPO4·2H2O crystals results in the formation of crystalline CaHPO4·2H2O crystals. [Figure 4(c)] FTIR spectra of amorphous and crystalline CaHPO4·2H2O obtained by reactive crystallization using AXF mini (non-stoichiometric reaction concentration). [Figure 5(a)] Particle size of CaHPO4·2H2O crystallized using AXF-mini by stoichiometric reaction crystallization with CP:DP at 10:0.5mL / min. [Figure 5(b)] Microscope images (100x) of CaHPO4·2H2O crystals using AXF-mini via stoichiometric reaction crystallization with CP:DP at 10:0.5mL / min. The initial image shows that stirring the amorphous CaHPO4·2H2O crystals results in the formation of crystalline CaHPO4·2H2O crystals. [Figure 5(c)] Particle size of CaHPO4·2H2O crystallized using AXF-mini by stoichiometric reaction crystallization with CP:DP at 10:0.5mL / min. [Figure 5(d)] Shown is a microscope image (100x) of amorphous CaHPO4·2H2O obtained from stoichiometric reaction crystallization using the AXF mini. [Figure 5(e)] The following X-ray diffraction patterns are shown: P-1) batch reactive crystallization of CaHPO4·2H2O, P-2) LDC-1 reactive crystallization of CaHPO4·2H2O, P-3) AXF-mini reactive crystallization of amorphous non-stoichiometric Ca5(PO4)3OH, P-4) AXF-mini reactive crystallization of crystalline non-stoichiometric CaHPO4·2H2O, P-5) AXF-mini reactive crystallization of amorphous stoichiometric CaHPO4·2H2O, P-6) AXF-mini reactive crystallization of crystalline stoichiometric CaHPO4·2H2O. [Figure 6(a)] 1 shows particle size of CaCO3 from batch reactive crystallization. [Figure 6(b)] The particle size of CaCO3 using AXF-mini reactive crystallization is shown. [Figure 6(c)] A microscopic image (400x) of reactively crystallized CaCO3 is shown. [Figure 6(d)] The FTIR spectrum of reactively crystallized CaCO3(*) is shown. The vibration peaks in the spectrum match those of the reference CaCO3(Δ) obtained from NIST. [Figure 6(e)] Particle size of CaCO3 obtained by reactive crystallization using AXF-1, flow rate 250:50mL / min, 10x200μm membrane and 9.5, 9.7 and 9.8mm inserts. [Figure 6(f)] The following X-ray diffraction patterns are shown: C-1) Batch reactive crystallization of a mixture of CaCO3 calcite and vaterite, C-2) AXF-mini reactive crystallization of CaCO3 calcite and vaterite, C-3) AXF-1 reactive crystallization of CaCO3 calcite and vaterite using a 9.5mm insert, C-4) AXF-1 reactive crystallization of CaCO3 calcite using a 9.7mm insert, and C-5) AXF-1 reactive crystallization of CaCO3 calcite using a 9.8mm insert. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0104] As case studies, the formation of CaSO4·2H2O, CaHPO4·2H2O and CaCO3 was carried out.

[0105] CaSO4·2H2O, CaHPO4·2H2O and CaCO3 are all readily used as excipients (inactive ingredients) in the pharmaceutical industry. Good size and CSD control improves overall particle handling processes as well as blending and mixing with active pharmaceutical ingredients (API).

[0106] Other uses for these materials include, but are not limited to: CaSO4·2H2O - Construction materials, fertilizers, dental fillers, CaHPO4·2H2O - Treatment of wastewater and contaminated soils, source of calcium and phosphorus, premium nutrient, and CaCO3-filler in adhesives and sealants, plastics, paper, paints and inks, catalysts and gas filters.

[0107] Inorganic reactive crystallization studies were carried out using the following reaction: CaCl2+Na2SO4→CaSO4·2H2O+2NaCl CaCl2+NaH2PO4·2H2O→CaHPO4·2H2O+NaCl+HCl+2H2O CaCl2+Na2CO3→CaCO3+2NaCl

[0108] All reactions were performed in aqueous conditions and based on solubility. For example, CaCl2, Na2SO4, NaH2PO4·2H2O, Na2CO3, NaCl, and HCl are all water-soluble. CaSO4·2H2O, CaHPO4·2H2O, and CaCO3 are all sparingly soluble in water. EXAMPLES

[0109] CaSO4·2H2O crystallization Reactive crystallization was carried out in a mini cross-flow membrane emulsifier (AXF mini) after a standard batch process. The device has a continuous phase (CP) and a dispersed phase (DP) containing the reagents that undergo reactive crystallization toward CaSO4·2H2O. This was compared with the batch reactive crystallization process to observe the benefits of the cross-flow membrane method.

[0110] 1.1 Batch Operations 14V agitator, 10mL / min speed ·DP CaCl2 / DI water 0.100g / mL, 10mL added ·CP Na2SO4 / DI water 0.0256g / mL, total 50mL Flux 1842.2mL / min / cm2, shear 24.577Pa 1.2 AXF-mini operation ·5×100μm membrane, 9.8mm ·Flow rate - CP 5mL / min, DP 1mL / min ·Pore Velocity (m / s)=0.0270, Annulus Velocity (m / s)=0.0268 Momentum flux ratio = 1.02, Re(annulus) = 5.36

[0111] The results are shown in Figures 1(a) to 1(e).

[0112] FTIR spectroscopy and X-ray diffraction analysis indicate that reactive crystallization of CaSO4·2H2O was successful in both batch and continuous AXF-mini operation. Particle size analysis indicates that the AXF-mini equipment reduced the size of the crystals. EXAMPLES

[0113] CaHPO4·2H2O crystallization Reactive crystallization was carried out in a mini cross-flow membrane emulsifier (AXF mini) after a standard batch process. The device has a continuous phase (CP) and a dispersed phase (DP) containing the reagents that undergo reactive crystallization toward CaHPO4·2H2O. This was compared with the batch reactive crystallization process to observe the benefits of the cross-flow membrane method.

[0114] 2.1 Batch Processing ·DP CaCl2 / DI water 0.100g / mL, 10mL added ·CP NaH2PO4 ·2H2O / DI water 0.0281g / mL, total 50mL Flux 1842.2mL / min / cm2, shear 24.577Pa Note- The CP solution was raised to pH=6.51 with 4M NaOH because CaHPO4·2H2O cannot precipitate under acidic conditions. 14V stirring, 10mL / min speed

[0115] The results are shown in Figure 2.

[0116] 2.2 AXF mini operation DP CaCl2 / DI water 0.100g / mL, ·CP NaH2PO4·2H2O / DI water 0.0281g / mL, 10×200μm membrane, 9.8mm membrane Note- The CP solution was brought to pH=6.51 with 4M NaOH.

[0117] Both stoichiometric and non-stoichiometric reactions were performed. Stoichiometric (5:1) reaction Based on flow rate and concentration, 5 parts NaH2PO4·2H2O solution was reacted with 1 part CaCl2 solution. Hole velocity (m / s) = 0.0270, Annular velocity (m / s) = 0.0268 Momentum flux ratio = 1.02, Re(annulus) = 5.36 Non-stoichiometric (10:0.5) reaction Based on flow rate and concentration, 20 parts of NaH2PO4·2H2O solution was reacted with 1 part of CaCl2 solution. Hole velocity (m / s) = 0.0135, Annular velocity (m / s) = 0.0536 Momentum flux ratio = 0.0636, Re(annulus) = 10.72

[0118] The results are shown in Figures 3(a) to 4(c).

[0119] 2.3 AXF mini operation ·DP CaCl2 / DI water 0.200g / mL, 0.5mL / min ·CP NaH2PO4 ·2H2O / DI water 0.01425g / mL, 10mL / min 10×200μm membrane, 9.8mm membrane Note- The CP solution was brought to pH=6.51 with 4M NaOH.

[0120] Stoichiometric (5:1) reaction CP:DP flow rate 10:0.5mL / min Based on flow rate and concentration, 5 parts NaH2PO4·2H2O solution was reacted with 1 part CaCl2 solution. Hole velocity (m / s) = 0.0135, Annular velocity (m / s) = 0.0536 Momentum flux ratio = 0.0636, Re(annulus) = 10.72

[0121] The results are shown in Figures 5(a) to 5(e).

[0122] FTIR spectroscopy and X-ray diffraction analysis indicate that reactive crystallization of CaSO4·2H2O was successful in both batch and continuous AXF-mini operation towards crystalline material. The continuous AXF-mini setup initially produced amorphous crystals that arranged in a long range regular crystalline morphology under stirring. Different crystal morphologies were also identified using FTIR spectroscopy and X-ray diffraction analysis. XRPD analysis indicates that the amorphous non-stoichiometric material is Ca5(PO4)3OH, while the amorphous stoichiometric material is a mixture of CaHPO4·2H2O and Ca5(PO4)3OH.

[0123] Particle size analysis shows that the AXF-mini instrument reduced the size of the crystals and improved the CSD compared to batch. This improvement was possible by changing the concentration and flow rate for stoichiometric reactions. Alternatively, non-stoichiometric reactions can be obtained by simply changing the flow rate. EXAMPLES

[0124] CaCO3 crystallization Reactive crystallization was carried out in a mini cross-flow membrane emulsifier (AXF mini) and a cross-flow membrane emulsifier (AXF). The apparatus has a continuous phase (CP) and a dispersed phase (DP) containing various reagents that undergo reactive crystallization towards CaCO3. Scale-up of the apparatus and reactive crystallization was shown to be successful with reproducible particle size and purity levels.

[0125] 3.1 Batch Processing ·DP CaCl2 / DI water 0.100g / mL, 10mL added ·CP NaCO3 / DI water 0.0212g / mL, total 50mL Flux 1842.2mL / min / cm2, shear 24.577Pa

[0126] The results are shown in Figure 6(a).

[0127] 3.2 AXF mini operation ·DP CaCl2 / DI water 0.111g / mL, ·CP Na2CO3 / DI water 0.0212g / mL, 10×200μm membrane, 9.8mm Flow rate - CP 5mL / min, DP 1mL / min Hole velocity (m / s) = 0.0270, Annular velocity (m / s) = 0.0268 Momentum flux ratio = 1.02, Re(annulus) = 5.36

[0128] The results are shown in Figures 6(b) to 4(d).

[0129] 3.3 AXF-1 operation ·DP CaCl2 / DI water 0.111g / mL, ·CP Na2CO3 / DI water 0.0212g / mL, 10 x 200μm membrane, 9.8, 9.7 and 9.5mm inserts Flow rate - CP=250mL / min, DP=50mL / min

[0130] 9.5mm insert Hole velocity (m / s) = 0.135, Annular velocity (m / s) = 0.544 Momentum flux ratio = 0.0616, Re(annulus) = 272.06 9.7mm insert Hole velocity (m / s) = 0.135, Annular velocity (m / s) = 0.898 Momentum flux ratio = 0.0226, Re(annulus) = 269.30 9.8mm insert Hole velocity (m / s) = 0.135, Annular velocity (m / s) = 1.340 Momentum flux ratio = 1.02, Re(annulus) = 267.94

[0131] The results are shown in Figures 6(e) to 6(f).

[0132] FTIR spectroscopy and X-ray diffraction analysis showed that reactive crystallization of precipitated CaCO3 was successful in AXF-mini operation with a mixture of calcite and vaterite polymorphs. Scale-up of crystallization with AXF-1 was investigated and shown to be successful with reproducible crystal sizes in AXF-mini results. This was possible by investigating different insert sizes and their effect on crystal size and the overall reactive crystallization process. Inserts with diameters of 9.7 and 9.8 mm were found to form pure calcite but eventually block the flow of CaCO3 crystals. However, when a 9.5 mm insert was used, no blockages were identified during operation, but XRPD results showed a mixture of vaterite and calcite.

Claims

1. 1. A method for preparing solid particles of a material, the method comprising: controlling the supply of a first liquid phase, the first liquid phase comprising a solution of a first material through a membrane, the membrane defining a plurality of pores; controlling the supply of a second liquid phase, the second liquid phase comprising a solution of a second material; reacting the first and second materials to produce a third liquid phase comprising a solution of a third material; and supersaturating the third liquid phase to form solid particles of the third material.

2. 1. A method for preparing solid particles of a material, the method comprising the steps of controlling the supply of a first liquid phase, the first liquid phase comprising a solution of a first material, in a first flow direction to a membrane, the membrane defining a plurality of pores; controlling the supply of a second liquid phase, the second liquid phase comprising a solution of a second material, and the introduction of the second liquid phase being substantially perpendicular to the introduction of the first liquid phase; reacting the first material with a second material to produce a third liquid phase comprising a solution of a third material; supersaturating the third liquid phase to form solid particles of the third material; A method comprising:

3. 3. The method of claim 1 or 2, characterized in that the method comprises the reactive preparation of solid particles of material in crystalline or amorphous form, or a combination thereof.

4. 1. A method for reactive preparation of solid particles of a third material, said method comprising the steps of reacting a first liquid phase with a second liquid phase by dispersing said first liquid phase in said second liquid phase; the first liquid phase comprises a solution of a first solution material, and the second liquid phase comprises a solution of a second solution material; The method includes the steps of controlling the supply of the first liquid phase to a membrane in a first flow direction, the membrane defining a plurality of pores; and controlling the supply of the second liquid phase to the membrane through the plurality of pores in cross-flow (AXF) in the first flow direction to reactively form a solution of a third material. optionally supersaturating said solution with said third material to produce particles of said third material; A method comprising:

5. 5. The method of claim 4, wherein the "cross-flow" of the second liquid phase is at an angle of 90 degrees, plus or minus 45 degrees, relative to the flow direction of the first liquid phase.

6. 1. A method for reactively preparing solid particles of a material, the method comprising dispersing a first liquid phase comprising a solution of a first material in a second liquid phase comprising a solution of a second material; The method uses a cross-flow reactive mixer, the cross-flow reactive mixer comprising: an outer tubular sleeve having a first inlet at a first end, a material outlet, and a second inlet distal to and angled relative to the first inlet; a tubular membrane having a plurality of holes and configured to be disposed inside the tubular sleeve; optionally, an insert configured to be positioned inside the tubular membrane, the insert having an inlet end and an outlet end, the inlet end and the outlet end each provided with a chamfered area, the chamfered area provided with a plurality of openings and a bifurcation plate; and controlling the supply of the first liquid phase to the tubular membrane; and controlling the supply of the second liquid phase to the tubular membrane through the plurality of holes to reactively form a solution of a third material; A method comprising:

7. 7. A method according to any one of claims 1 to 6, characterised in that the method comprises preparing solid particles of more than one material, for example as a eutectic comprising two or more components.

8. The method of claim 1, 2, 4, or 6, wherein the prepared reacted solution (i.e., after reaction) comprises one or more dissolved materials, the dissolved materials comprising one or more organic compounds, which may include, for example, pharmaceutically active compounds, bioactive agents, dietary supplements, polymers, metal organic frameworks, or inorganic materials.

9. 10. The method of claim 1, wherein the method comprises the reactive preparation of solid amorphous particles of the material.

10. The method of claim 1, 2, 4, or 6, wherein the dissolved preparation material (i.e., after reaction) comprises a material with low solubility.

11. The method of claim 1, 2, 4, or 6, wherein the prepared reacted solution (i.e., after reaction) comprises dissolved material, the material comprising one or more organic compounds, the one or more organic compounds comprising pharmaceutically active compounds or drugs, bioactive agents, dietary supplements, polymers, etc.

12. 10. The method of claim 1, 2, 4, or 6, wherein the prepared reacted solution (i.e., after reaction) comprises dissolved material, the material comprising a pharmaceutically active compound having low bioavailability.

13. The method of claim 1, 2, 4, or 6, wherein the prepared reacted solution (i.e., after reaction) contains a dissolved material, the material being an inorganic material.

14. 10. The method of claim 1, 2, 4, or 6, wherein the device includes an insert.

15. 7. The method of claim 6, wherein the cross-flow device comprises a plurality of tubular membranes.

16. 1. A reactive crystallizer for reactively dispersing a first phase in a second phase, comprising: a membrane defining a plurality of apertures connecting a first liquid phase to a second liquid phase, the first liquid phase being on a first side of the membrane and comprising a solution of a first material, and the second liquid phase being on a second, different side of the membrane and comprising a solution of a second material; the apparatus is configured to generate a reactive mixture by discharging the first liquid phase into the second liquid phase through the plurality of apertures; The apparatus also includes a reaction chamber positioned to receive the first and second liquid phases and / or the reactive mixture from the membrane. A reactive crystallizer characterized by:

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