System for crystalizing chemical compounds and methodologies for utilizing the same

A system including a fluid receiver defined by a crystallization chamber, three or more fluid input conduits, wherein each fluid input conduit is configured to direct a fluid into the crystallization chamber such that the fluids from the fluid input conduits converge on a single spatial coordinate (X—Y—Z) within the crystallization chamber, and a fluid outlet body portion. A process for crystallization of the chemical compound is also disclosed. Polymorphs of paracetamol, carbamazapine, ketoprofen, atorvastatin, and itraconazole also are disclosed.

TECHNICAL FIELD

The disclosure relates to a system for crystalizing chemical compounds and methodologies for utilizing the same.

BACKGROUND

Crystallizing devices are known in the art. Even though known crystallizing devices may be suitable for their intended purpose, improvements are continuously being sought in order to advance the arts.

SUMMARY

One aspect of the disclosure provides a system that includes a fluid receiver defined by a crystallization chamber, three or more fluid input conduits, wherein each fluid input conduit is configured to direct a fluid into the crystallization chamber such that the fluids from the fluid input conduits converge on a single spatial coordinate (X—Y—Z) within the crystallization chamber, and a fluid outlet body portion.

The fluid receiver may also include a first fluid inlet port, a second fluid inlet port, a third fluid inlet port, and a fourth fluid inlet port, wherein the first fluid inlet port and the second fluid inlet port are respectively formed in opposing side surfaces of the fluid receiver, wherein the third fluid inlet port and the fourth fluid inlet port are formed in a side surface connecting the opposing side surfaces. Also, a first axis may extend through the first fluid inlet port, a second axis may extend through the second fluid inlet port, a third axis may extend through the third fluid inlet port, a fourth axis may extend through the fourth fluid inlet port, the first axis may be offset from the second axis at a first angle, the third axis may be offset from the fourth axis at a second angle, both of the first angle and the second angle may not be equal to 90°, and both of the first angle and the second angle may not be equal to 180°. In some examples, the first angle may range between about 120° and about 175° or, more specifically, the first angle may be approximately equal to 150°. In other examples, the second angle may range between about 30° and about 85° degrees or, more specifically, the second angle may be approximately equal to 60°.

In another aspect of the disclosure, the system also may include a processed fluid reservoir that is fluidly-connected to a distal end of the fluid output conduit. In another aspect of the system, each of the three or more fluid input conduits may include a proximal end that is respectively fluidly-connected to a fluid source of a plurality of fluid sources to permit the proximal end of each of the three or more fluid input conduits to respectively draw a fluid from each fluid source of the plurality of fluid sources, and a distal end that is respectively fluidly-connected to the crystallization chamber.

In a further aspect of the invention, the system also may include one or more pumps that are arranged downstream of each fluid input conduit of the three or more fluid input conduits. In another feature of the invention, each fluid input conduit of the three or more fluid input conduits may include a check valve that is arranged downstream of the pump and upstream of the distal end of each fluid conduit of the three or more fluid input conduits.

In another aspect, the invention may include a computing resource that is communicatively-coupled to each pump and that controls an operating speed of each pump to therefore control a flow rate of each fluid that is drawn from each fluid source of the plurality of fluid sources.

In some examples, of the system, each fluid input conduit of the three or more fluid input conduits may include a distal end portion having a substantially cylindrically-shaped body that defines a proximal end and a distal end, wherein the distal end of the substantially cylindrically-shaped body forms a portion of the distal end of each fluid input conduit of the three or more fluid input conduits. Further, the substantially cylindrically-shaped body of the distal end portion may form a passage that extends through an entire length of the substantially cylindrically-shaped body, wherein access to the passage may be permitted by a proximal opening formed in the proximal end of the substantially cylindrically-shaped body and a distal opening formed in the distal end of the substantially cylindrically-shaped body.

In another aspect of the invention, the proximal opening and a first substantially cylindrical inner surface of the substantially cylindrically-shaped body may define the passage to include a first diameter that extends through a majority of the length of the substantially cylindrically-shaped body, the distal opening and a second substantially cylindrical inner surface of the substantially cylindrically-shaped body may define the passage to include a second diameter that extends through a minority of the length of the substantially cylindrically-shaped body, a radial shoulder surface further may define the passage and connect the first substantially cylindrical inner surface to the second substantially cylindrical inner surface, the second diameter may be greater than the first diameter, the second substantially cylindrical inner surface and the radial shoulder surface may define the passage to include a counter bore formed in the distal end of the substantially cylindrically-shaped body

In other examples, the system also may include a nozzle removably-disposed within a counter bore for removably-connecting the nozzle to the distal end of the distal end portion. And in further examples, the nozzle may include a body having a proximal end and a distal end wherein the distal end of the body of the nozzle and the distal end of the substantially cylindrically-shaped body of the distal end portion forms the distal end of each fluid input conduit of the three or more fluid input conduits. In further examples of the system, the body of the nozzle may form a passage that extends through an entire length of the body wherein access to the passage is permitted by a proximal opening formed in the proximal end of the body of the nozzle and a distal opening formed in the distal end the body of the nozzle, the passage may be formed by a substantially conical inner surface defining a diameter that decreases along the length of the body of the nozzle such that the proximal opening defines the passage to include a first, larger diameter and the distal opening defines a second, smaller diameter. In some aspects of the invention, the second, smaller diameter formed by the distal opening of the nozzle may range between about 0.001″ to about 0.1″.

In other examples, the system may include a fluid receiver defined by a crystallization chamber, a first fluid inlet port and a second fluid inlet port, wherein a first axis may extend through the first fluid inlet port, wherein a second axis may extend through the second fluid inlet port, wherein the first axis may be offset from the second axis at a first angle, wherein the first angle may not be equal to 90° and the first angle may not be equal to 180°; two or more fluid input conduits, wherein each fluid input conduit may be configured to direct a fluid into the crystallization chamber such that the fluids from the fluid input conduits converge on a single spatial coordinate (X—Y—Z) within the crystallization chamber, and a fluid outlet body portion.

Yet another aspect of the disclosure provides a process for crystallization of a chemical compound by using the above-described system, and that chemical compound may be a pharmaceutical compound. In some examples of the process, a first fluid of three or more fluids carried by a first fluid input conduit of the three or more fluid input conduits is a feed solution, and a second fluid, a third fluid, and a fourth fluid of the three or more fluids carried, respectively, by a second fluid input conduit, a third fluid input conduit, a fourth fluid input conduit of the three or more fluid input conduits are one or more anti-solvents. In some aspects, the feed solution may be a compound to be crystallized and one or more solvents, and the compound may be at a concentration in the solvent from about 1% to about 30% or, more specifically, the compound may be at a concentration from about 5% to about 25% or, more specifically, the compound may be at a concentration from about 10% to about 20% or, more specifically, the compound may be at a concentration from about 7% to about 8%.

In other examples, the feed solution and anti-solvents may be independently at a temperature in a range from about 0° C. to about 80° C. or, more specifically, the feed solution and anti-solvents may be independently at a temperature in a range from about 25° C. to about 60° C. Further, the feed solution or anti-solvent independently may include one or more surfactants, and those surfactants may be gelatin, casein, lecithin, gum acacia, cholesterol, steric acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, sorbitan esters, polyoxyethylene alkyl esters, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearate, sodium dodecylsulfate, hydroxyl propylcellulose, polyvinylpyrrolidone and polyvinyl alcohols, emulsifying surfactants, or soy lecithin. Additionally, in some instances, the feed solution and anti-solvents may independently run at a flow rate in a range from about 50 ml/min to about 15 l/min.

Other aspects of the disclosure include any of a polymorph of paracetamol that may have a median particle size less than about 1.3 microns, a polymorph of Carbamazapine that may have a median particle size less than about 1.5 microns, a polymorph of ketoprofen that may have a median particle size less than about 3.1 microns, a polymorph of atorvastatin that may have a median particle size less than about 126 nanometers, and a polymorph of itraconazole that may have a median particle size less than about 36 nanometers. And in some aspects the polymorph of paracetamol may have a span less than about 0.901, the polymorph of Carbamazapine may have a span less than about 0.916, the polymorph of ketoprofen may have a span less than about 1.078, the polymorph of atorvastatin may have a span less than about 0.99, or the polymorph of itraconazole may have a span less than about 0.34.

DETAILED DESCRIPTION

Referring toFIG. 1, a system for crystalizing chemical compounds is shown generally at10. The system10draws a plurality of fluids, F, from a plurality of fluid sources, S, in order to produce a product, P, that is derived from two, three, or more fluids, F1-Fn, of the plurality of fluids, F. In some instances, the plurality of fluid sources, S, containing the plurality of fluids, F, are not considered to be components of the system10, but, rather, implements or workpieces that interface with the system10.

As will be explained in the following disclosure, structural components of the system10are arranged and sized for manipulating the two, three, or more fluids, F1-Fn, of the plurality of fluids, F, such that the more than the two fluids, F1-Fn, of the plurality of fluids, F, undergo a ‘crystallization process;’ in some instances, the crystallization process performed by the system10may be exploited by one or more industries including, for example: the pharmaceutical industry, the fine chemical industry or the like. When utilized by the pharmaceutical industry, the system10may produce, for example: pharmaceutical products, P, having smaller particles that provide a higher bioavailability and shorter dissolution time; further, pharmaceutical products, P, produced by the system10may be defined as having, for example, improved: pharmaceutical stability, pharmaceutical purity, and pharmaceutical shelf life.

The structural components of the system10may include, but is not limited to: a plurality of fluid input conduits12that are fluidly-connected to a fluid receiver14. The structural components of the system10may be made from any desirable material (e.g., stainless steel) that may be, for example, non-corrosive and durable in nature.

The plurality of fluid input conduits12of the exemplary system10includes two, three, or more fluid input conduits12n(i.e., the plurality of fluid input conduits12may include “n” fluid conduits so long as “n” is greater than or equal to two). As seen in the following disclosure atFIGS. 2A-2B, 3A-3B, 7 and 8A-8B, the exemplary system10may include four fluid conduits, such as, for example: a first fluid input conduit121, a second fluid input conduit122, a third fluid input conduit123and a fourth fluid input conduit124that are fluidly-connected to the fluid receiver14.

Referring toFIG. 1, each fluid input conduit121-12nof the plurality of fluid input conduits12includes a proximal end16. The proximal end16of each fluid input conduit121-12nof the plurality of fluid input conduits12is respectively fluidly-connected to a fluid source, S1-Sn, of the plurality of fluid sources, S (e.g., the proximal end16of the first fluid input conduit121is fluidly-connected to a first fluid source, S1, and, the proximal end16of the second fluid input conduit122is fluidly-connected to a second fluid source, S2, and, the proximal end16of the third fluid input conduit123is fluidly-connected to a third fluid source, S3, and, the proximal end16of the “nth” fluid input conduit12nis fluidly-connected to an “nth” fluid source, Sn), in order to permit the proximal end16of each fluid input conduit121-12nof the plurality of fluid input conduits12to respectively draw each fluid, F1-Fn, of the plurality of fluids, F, from each fluid source, S1-Sn, of the plurality of fluid sources, S (e.g., the proximal end16of the first fluid input conduit121draws a first fluid, F1, from the first fluid source S1, and, the proximal end16of the second fluid input conduit122draws a second fluid, F2, from the second fluid source S2, and, the proximal end16of the third fluid input conduit123draws a third fluid, F3, from the third fluid source S3, and, the proximal end16of the “nth” fluid input conduit12ndraws an “nth” fluid, Fn, from the “nth” fluid source Sn).

With continued reference toFIG. 1, each fluid input conduit121-12nof the plurality of fluid input conduits12includes a distal end18. In some instances, any component (such as, e.g., structure identified at references numerals241,242,243,24n,261,26,263,26n,361,362,363,36n,581,582,583,58n) located between the proximal end16and the distal end18may constitute a portion of each fluid input conduit121-12n. The distal end18of each fluid input conduit121-12nof the plurality of fluid input conduits12is disposed within and respectively fluidly-connected to a fluid inlet port201-20nof a plurality of fluid inlet ports20formed by the fluid receiver14. The plurality of fluid inlet ports20of the exemplary fluid receiver14includes two, three, or more fluid inlet ports20n(i.e., the plurality of fluid inlet ports20may include “n” fluid inlet ports so long as “n” is greater than or equal to three). As seen in the following disclosure atFIGS. 2, 2A-2B, 3A-3B, 7 and 8A-8B, the exemplary fluid receiver14may include four fluid inlet ports, such as, for example: a first fluid inlet port201, a second fluid inlet port202, a third fluid inlet port203and a fourth fluid inlet port204that respectively receive the distal end18of the first fluid input conduit121, the second fluid input conduit122, the third fluid input conduit123and the fourth fluid input conduit124.

As seen inFIG. 1, the plurality of fluid inlet ports20formed by the fluid receiver14permits the plurality of fluid input conduits12to fluidly connect each fluid source, S1-Sn, of the plurality of fluid sources, S, with the fluid receiver14such that each fluid, F1-Fn, of the plurality of fluids, F, may be transported from each fluid source, S1-Sn, of the plurality of fluid sources, S, to a fluid mixing and crystallization chamber22formed by the fluid receiver14. The fluid mixing and crystallization chamber22is fluidly connected to each fluid inlet port201-20nof the plurality of fluid inlet ports20formed by the fluid receiver14. Therefore, upon interfacing the distal end18of each fluid input conduit121-12nof the plurality of fluid input conduits12with each fluid inlet port201-20nof the plurality of fluid inlet ports20formed by the fluid receiver14, the fluid mixing and crystallization chamber22is fluidly-connected to each fluid source, S1-Sn, of the plurality of fluid sources, S, such that each fluid, F1-Fn, of the plurality of fluids, F, may be transported from each fluid source, S1-Sn, of the plurality of fluid sources, S, to the fluid mixing and crystallization chamber22.

Referring toFIG. 1, a plurality of pumps is shown generally at24. Each fluid input conduit121-12nof the plurality of fluid input conduits12may include a pump241-24nof the plurality of pumps24. Each pump241-24nmay be arranged downstream of each fluid source, S1-Sn, associated with each fluid input conduit121-12n.

With continued reference toFIG. 1, a plurality of check valves are shown generally at26. Each fluid input conduit121-12nof the plurality of fluid input conduits12may include a check valve261-26nof the plurality of check valves26. Each check valve261-26nmay be arranged downstream of each pump,241-24n, and upstream of each distal end18of each fluid input conduit121-12n.

As seen inFIG. 1, a computing resource is shown generally at28. The computing resource28may include, but is not limited to: one or more processors or central processing units (CPUs) in communication with one or more storage resources (e.g., memory, flash memory, dynamic random access memory (DRAM), phase change memory (PCM), and/or disks having spindles)). The computing resource28may be communicatively-coupled (e.g., wirelessly or hardwired) to each pump241-24nof the plurality of pumps24in order to, for example, control the speed of each pump241-24nof the plurality of pumps24, and, therefore, a flow rate/amount of each fluid, F1-Fn, of the plurality of fluids, F, that is transported from each fluid source, S1-Sn, of the plurality of fluid sources, S, to the fluid mixing and crystallization chamber22formed by the fluid receiver14.

The ‘crystallization process’ may take place upon arrival of the two, three, or more fluids, F1-Fn, of the plurality of fluids, F, within the fluid mixing and crystallization chamber22. In some instances, the crystallization process takes place upon the two, three, or more fluids, F1-Fn, of the plurality of fluids, F, being directed toward and converging upon a single spatial coordinate (i.e., an X—Y—Z spatial coordinate) within the fluid mixing and crystallization chamber22.

After the two, three, or more fluids, F1-Fn, of the plurality of fluids, F, have been directed into the fluid mixing and crystallization chamber22and converged upon the single spatial coordinate, X—Y—Z, the processed fluid, P, of the two, three, or more fluids, F1-Fn, is then evacuated from the fluid mixing and crystallization chamber22at a fluid outlet port30formed by the fluid receiver14. A fluid output conduit32is fluidly-connected to the fluid outlet port30for transporting the processed fluid, P, from the fluid outlet port30to a processed fluid reservoir34that received the processed fluid, P, from the fluid receiver14.

Referring toFIGS. 4-5, an exemplary distal end portion of each fluid input conduit121-12nof the plurality of fluid input conduits12is shown generally at36. The distal end portion36may include a substantially cylindrically-shaped body38having a proximal end40and a distal end42; the distal end42of the substantially cylindrically-shaped body38may also define a portion of the distal end18of each fluid input conduit121-12nof the plurality of fluid input conduits12.

The distal end portion36forms a passage44that extends through an entire length, L44(see, e.g.,FIG. 5), of the substantially cylindrically-shaped body38from the proximal end40of the substantially cylindrically-shaped body38to the distal end42of the substantially cylindrically-shaped body38. Access to the passage44is permitted by a proximal opening46(see, e.g.,FIG. 5) formed in the proximal end40of the substantially cylindrically-shaped body38and a distal opening48formed in the distal end42of the substantially cylindrically-shaped body38.

The proximal opening46and a first substantially cylindrical inner surface50of the substantially cylindrically-shaped body38generally defines the passage44to include a first diameter, D44-1(see, e.g.,FIG. 5), that extends through a majority, L44-1(see, e.g.,FIG. 5), of the length, L44, of the substantially cylindrically-shaped body38. The distal opening48and a second substantially cylindrical inner surface52of the substantially cylindrically-shaped body38generally defines the passage44to include a second diameter, D44-2, that extends through a minority, L44-2, of the length, L44, of the substantially cylindrically-shaped body38. A radial shoulder surface54further defines the passage44and connects the first substantially cylindrical inner surface50to the second substantially cylindrical inner surface52. In some examples, the second diameter, D44-2, that extends through a minority, L44-2, of the length, L44, of the substantially cylindrically-shaped body38is greater than the first diameter, D44-1, that extends through a majority, L44-1, of the length, L44, of the substantially cylindrically-shaped body38.

The second substantially cylindrical inner surface52and the radial shoulder surface54generally defines the passage44to include a substantially cylindrically-shaped counter bore56formed in the distal end42of the substantially cylindrically-shaped body38. A nozzle581,582,583,58n(see, e.g.,FIG. 6) may be removably-disposed within the substantially cylindrically-shaped counter bore56in order to permit the nozzle581,582,583,58nto be removably-connected to the distal end42of the distal end portion36of each fluid input conduit121-12nof the plurality of fluid input conduits12.

Referring toFIG. 6, a plurality of exemplary nozzles is shown generally at58. Each nozzle581,582,583,58nof the plurality of exemplary nozzles58may include a substantially cylindrically-shaped body60having a proximal end62and a distal end64; the distal end64of the substantially cylindrically-shaped body60may also define a portion of the distal end18of each fluid input conduit121-12nof the plurality of fluid input conduits12. Each nozzle581,582,583,58nforms a passage66that extends through an entire length, L60, of the substantially cylindrically-shaped body60from the proximal end62of the substantially cylindrically-shaped body60to the distal end64of the substantially cylindrically-shaped body60. Access to the passage66is permitted by a proximal opening68formed in the proximal end62of the substantially cylindrically-shaped body60and a distal opening701,702,703,70nformed in the distal end64of the substantially cylindrically-shaped body60.

The passage66of each nozzle581,582,583,58nmay be formed by an inner surface72, e.g., the inner surface72is conical. The passage66includes a diameter, D66, that may decrease along the length, L60, as each nozzle581,582,583,58nextends from the proximal end62of the substantially cylindrically-shaped body60toward the distal end64of the substantially cylindrically-shaped body60.

Because the diameter, D66, may decrease along the length, L60, as each nozzle581,582,583,58nextends from the proximal end62to the distal end64, the proximal opening68generally defines the passage66to include a first, larger diameter, D66-L, and, the distal opening701,702,703,70ngenerally defines the passage66to include a second, smaller diameter, D66-S. In some instances, the first, larger diameter, D66-L, formed by the proximal opening68of the nozzle581,582,583,58nmay be substantially similar to the first diameter, D44-1, formed by the passage44of the substantially cylindrically-shaped body38of the distal end portion36.

As seen inFIG. 6, comparatively, the second, smaller diameter, D66-S, of each nozzle581,582,583,58nhas a unique size. For example, the diameter, D66-S, of formed by the distal opening701of the nozzle581is larger than the diameter, D66-S, of formed by the distal opening702of the nozzle582, and, the diameter, D66-S, of formed by the distal opening702of the nozzle582is larger than the diameter, D66-S, of formed by the distal opening703of the nozzle583, and, the diameter, D66-S, of formed by the distal opening703of the nozzle583is larger than the diameter, D66-S, of formed by the distal opening70nof the nozzle58n.

Each diameter, D66-S, formed by the distal opening701,702,703,70nof each nozzle581,582,583,58nyields a different flow rate of the fluid, F1-Fn, that is directed into the fluid mixing and crystallization chamber22formed by the fluid receiver14. Therefore, upon determining a desired flow rate provided by a particle nozzle581,582,583,58n, a user of the system10may be permitted to select and subsequently removably-deposit the selected nozzle581,582,583,58nof the plurality of nozzles58within the substantially cylindrically-shaped counter bore56formed in the distal end42of the substantially cylindrically-shaped body38of the distal end portion36of each fluid input conduit121-12nof the plurality of fluid input conduits12.

In some instances, each diameter, D66-S, formed by the distal opening701,702,703,70nof each nozzle581,582,583,58nmay be independently sized to range between about 0.001″ to about 0.1″. In other instances, each diameter, D66-S, formed by the distal opening701,702,703,70nof each nozzle581,582,583,58nmay be independently sized to range between about 0.002″ to about 0.2″. In other embodiments, each diameter, D66-S, formed by the distal opening701,702,703,70nof each nozzle581,582,583,58nmay be independently sized to range between about 0.004″ to about 0.008″.

Referring toFIG. 5, upon disposing a selected nozzle581,582,583,58nof the plurality of nozzles58within the cylindrically-shaped counter bore56, the selected nozzle581,582,583,58nand the distal end portion36may form a subassembly751,752,753,75n. The subassembly751,752,753,75nmay be referred to as a “controlled flow cavitation device.” Collectively, the distal ends42,64of the distal end portion36and the selected nozzle581,582,583,58ndefine the distal end18of each fluid input conduit121-12nof the plurality of fluid input conduits12.

Referring toFIGS. 2 and 7, an exemplary fluid receiver14of an exemplary system10is shown. Although the fluid receiver14shown and described atFIGS. 2 and 7as including a plurality of components, the receiver14is not limited to the plurality of components or a particular shape, size or geometry. In some instances, the exemplary fluid receiver14shown atFIGS. 2 and 7may include a body100. The body100may include a fluid inlet body portion100a(see also, e.g.,FIGS. 2A-2B and 3A-3B) and a fluid outlet body portion100b. The fluid inlet body portion100amay form the plurality of fluid inlet ports20, and, the fluid outlet body portion100bmay form the fluid outlet port30. The plurality of fluid inlet ports20may include a first fluid inlet port201, a second fluid inlet port202, a third fluid inlet port203and a fourth fluid inlet port204.

As seen inFIGS. 2 and 2A-2B and 3A-3B, an exemplary fluid inlet body portion100aincludes a substantially cube shape having four side surfaces102a-102da lower surface104and an upper surface106. The four side surfaces102a-102dinclude a first side surface102a, a second side surface102b, a third side surface102cand a fourth side surface102d. The first side surface102ais directly opposite the second side surface102b, and, the third side surface102cis directly opposite the fourth side surface102d. The lower surface104is directly opposite the upper surface106.

Referring toFIGS. 2A and 3A, the first fluid inlet port201of the plurality of fluid inlet ports20is formed by and recessed in the first side surface102a. As seen inFIGS. 2B and 3A, the second fluid inlet port202of the plurality of fluid inlet ports20is formed by and recessed in the second side surface102b. Referring toFIGS. 2A-2B and 3B, both of the third fluid inlet port203of the plurality of fluid inlet ports20and the fourth fluid inlet port204of the plurality of fluid inlet ports20are formed by and recessed in the lower surface104.

As seen inFIGS. 3A and 3B, each of the first, second, third and fourth fluid inlet ports201,202,203,204of the plurality of fluid inlet ports20are, respectively, defined by a first, second, third and fourth substantially stepped counter bore1081,1082,1083,1084. Each substantially stepped counter bore1081,1082,1083,1084is in fluid communication with the fluid mixing and crystallization chamber22.

Each of the first, second, third and fourth stepped counter bore1081,1082,1083,1084is defined by a stepped surface110. As will be shown and described in the following disclosure atFIGS. 8A-8B, an outer surface portion74of the distal end portion36of the controlled flow cavitation device751,752,753,754may be disposed adjacent an axial distal portion110Aof the stepped surface110, and, the distal end42,64of each the controlled flow cavitation devices751,752,753,754is disposed adjacent a radial distal portion1108of the stepped surface110.

Referring toFIG. 3A, a first axis, A1-A1, extends through the first fluid inlet port201that is formed by and recessed in the first side surface102a. A second axis, A2-A2, extends through the second fluid inlet port202that is formed by and recessed in the second side surface102b. As will be explained in the following disclosure atFIG. 8A: upon insertion of the first controlled flow cavitation device751within the first fluid inlet port201, the first controlled flow cavitation device751is removably-fixed within the first fluid inlet port201along the first axis, A1-A1, and, upon insertion of the second controlled flow cavitation device752within the second fluid inlet port202, the second controlled flow cavitation device752is removably-fixed within the second fluid inlet port202along the second axis, A2-A2.

The first axis, A1-A1, is non-orthogonal to the second axis, A2-A2. As used herein, the term “non-orthogonal” means not at a right angle (90°), such that, as will be described in the following disclosure atFIGS. 7 and 8A-8B, a stream of a first fluid, F1, supplied to the fluid mixing and crystallization chamber22by the first controlled flow cavitation device751(that is disposed within the first fluid inlet port201) does not intersect at a right angle at the single spatial coordinate, X—Y—Z, with a second fluid, F2, supplied to the fluid mixing and crystallization chamber22by the second controlled flow cavitation device752(that is disposed within the second fluid inlet port202). Further, the first axis, A1-A1, is not arranged relative to the second axis, A2-A2, at an angle (see, e.g., the first angle θ1) equal to 180° such that, as will be described in the following disclosure atFIGS. 7 and 8A-8B, a stream of a first fluid, F1, supplied to the fluid mixing and crystallization chamber22by the first controlled flow cavitation device751(that is disposed within the first fluid inlet port201) does not directly oppositely impact at the single spatial coordinate, X—Y—Z, with a second fluid, F2, supplied to the fluid mixing and crystallization chamber22by the second controlled flow cavitation device752(that is disposed within the second fluid inlet port202).

The arrangement of the first axis, A1-A1, and the second axis, A2-A2, may be defined by a first angle, θ1. In some instances, the first angle, θ1, may range between, for example, about 120° and about 175° degrees. In other instances, the first angle, θ1, may range between about 140° and about 160°. In some implementations, the first angle, θ1, may be equal to about 150°.

Referring toFIG. 3B, a third axis, A3-A3, extends through the third fluid inlet port203that is formed by and recessed in the lower surface104. A fourth axis, A4-A4, extends through the fourth fluid inlet port204that is formed by and recessed in the lower surface104. As will be explained in the following disclosure atFIG. 8B: upon insertion of the third controlled flow cavitation device753within the third fluid inlet port203, the third controlled flow cavitation device753is removably-fixed within the third fluid inlet port203along the third axis, A3-A3, and, upon insertion of the fourth controlled flow cavitation device754within the fourth fluid inlet port204, the fourth controlled flow cavitation device754is removably-fixed within the fourth fluid inlet port204along the fourth axis, A4-A4.

The third axis, A3-A3, is non-orthogonal to the fourth axis, A4-A4. As used herein, the term “non-orthogonal” means not at a right angle (90°), such that, as will be described in the following disclosure atFIGS. 7 and 8A-8B, a stream of a third fluid, F3, supplied to the fluid mixing and crystallization chamber22by the third controlled flow cavitation device753(that is disposed within the third fluid inlet port203) does not intersect at the single spatial coordinate, X—Y—Z, at a right angle with a fourth fluid, F4, supplied to the fluid mixing and crystallization chamber22by the fourth controlled flow cavitation device754(that is disposed within the fourth fluid inlet port204). Further, the third axis, A3-A3, is not arranged relative to the fourth axis, A4-A4, at an angle (see, e.g., the second angle θ2) equal to 180° such that, as will be described in the following disclosure atFIGS. 7 and 8A-8B, a stream of a third fluid, F3, supplied to the fluid mixing and crystallization chamber22by the third controlled flow cavitation device753(that is disposed within the third fluid inlet port203) does not directly oppositely impact at the single spatial coordinate, X—Y—Z, with a fourth fluid, F4, supplied to the fluid mixing and crystallization chamber22by the fourth controlled flow cavitation device754(that is disposed within the fourth fluid inlet port204).

The arrangement of the third axis, A3-A3, and the fourth axis, A4-A4, may be defined by a second angle, θ2. In some instances, the second angle, θ2, may range between, for example, about 30° and about 85° degrees. In other instances, the second angle, θ2, may preferably range between about 50° and about 70°. In some implementations, the second angle, θ2, may more preferably be equal to about 60°.

In some instances, the fluid mixing and crystallization chamber22may include a generally tubular shape. However, the fluid mixing and crystallization chamber22can be configured to include any desirable shape as long as the fluid mixing and crystallization chamber22allows all of the first, second, third and fourth controlled flow cavitation devices751,752,753,754to be angularly positioned at, for example, the first angle, θ1, and the second angle, θ2, such that all of the fluid streams, F1-F4, provided by the first, second, third and fourth controlled flow cavitation devices751,752,753,754converge at the single spatial coordinate, X—Y—Z, at a non-orthogonal and not directly opposite manner.

Referring toFIGS. 2 and 8A-8B, some implementations of the fluid outlet body portion100bof the body100may include a plurality of members112-118. Although the fluid outlet body portion100bof the body100is shown atFIGS. 2 and 8A-8Bas including a plurality of members112-118, the fluid outlet body portion100bof the body100is not limited to the plurality of members112-118or a particular shape, size or geometry. The plurality of members112-118may be defined by a first member112, a second member114, a third member116and a fourth member118. As seen inFIGS. 8A-8B, each member112-118of the fluid outlet body portion100binclude at least one passage that permits the fluid mixing and crystallization chamber22to be in fluid communication with the fluid output conduit32. Further, the at least one passage in members112-118of the fluid outlet body portion100bcan be used to restrict the flow of fluid out of the crystallization chamber22. Similar to the diameter D66-Sformed by the distal openings701,702,703,70nof each nozzle581,582,583,58n, the at least one passage in members112-118of the fluid outlet body portion100bhas a diameter than can be sized to range from about 0.001″ and 0.1″. By using a different diameter size for the at least one passage in members112-118, the flow of processed fluid, P, out of the crystallization chamber22can be restricted, thereby creating a condition of controlled hydraulic cavitation. For example, the passage through member112can be changed to control the flow of fluid out of the crystallization chamber22thus providing back pressure in the crystallization chamber22. This back pressure focuses mixing of fluids F1-F4away from the interior walls of the crystallization chamber22and into a mixing zone about the single spatial coordinate, X—Y—Z. As such, changing the size of the passage through member112will change the size of the mixing zone. Various structures can be used to form members112-118and the passage through members112-118. For example, member112may be formed similar to any of nozzles581,582,583,58n, having a fixed-size proximal opening and a distal opening of any of a variety of sizes. Referring toFIG. 2, the third member116and the fluid inlet body portion100amay include a plurality of axially-aligned passages116pand100ap. The axially-aligned passages116pand100apreceive a plurality of fasteners120that removably-attaches the fluid outlet body portion100bto the fluid inlet body portion100a.

Referring toFIGS. 8A-8B, upon attachment of the fluid outlet body portion100bto the fluid inlet body portion100awith the plurality of fasteners120, the first member112and the second member114are contained by the fluid inlet body portion100aand the third member116. In some instances, the fluid inlet body portion100amay define a recessed portion100aR, and, the third member116may define a first recessed portion,11681that collectively defines a lower cavity122that contains the first member112. In some examples, the first member112may define a recessed portion1128, and, the third member116may define a second recessed portion,116R2that collectively defines an intermediate cavity124that contains second member114. In some examples, the third member116may define a third recessed portion,11683that defines an upper cavity126that contains fourth member118and a proximal end portion of the fluid output conduit32.

Referring toFIG. 2, one or more leg portions128may be connected to the fluid inlet body portion100afor supporting the fluid inlet body portion100aupon an underlying ground surface, G. Each leg portion of the one or more leg portions128may include one or more fastener passages130that are aligned with one or more corresponding fastener passages132(see also, e.g.,FIGS. 2A-2B and 7) formed in, for example, the third side surface102cand the fourth side surface102din order to permit, for example, one or more fasteners134to connect the one or more leg portions128to the fluid inlet body portion100a.

Referring toFIGS. 7 and 8A-8B, an exemplary system10may include four controlled flow cavitation devices751,752,753,754. The four controlled flow cavitation devices may be defined by: a first controlled flow cavitation device751, a second controlled flow cavitation device752, a third controlled flow cavitation device753and a fourth controlled flow cavitation device754.

As described above, each diameter, D66-S, formed by the distal opening701,702,703,70nof each nozzle581,582,583,584yields a different flow rate of the fluid, F1-F4, that is directed into the fluid mixing and crystallization chamber22formed by the fluid receiver14; therefore, in some instances, a user may select four unique nozzles581,582,583,584having four unique diameters, D66-S, that may structurally independently control different flow rates of the fluids, F1-F4(e.g., solvents and/or anti-solvents), carried through the four controlled flow cavitation devices751,752,753,754. In an example, the first nozzle581of the first controlled flow cavitation device751may include a diameter, D66-S, equal to approximately about 0.004″, and, the second nozzle582of the second controlled flow cavitation device752may include a diameter, D66-S, equal to approximately about 0.008″, and, the third nozzle583of the third controlled flow cavitation device753may include a diameter, D66-S, equal to approximately about 0.006″, and, the fourth nozzle584of the fourth controlled flow cavitation device754may include a diameter, D66-S, equal to approximately about 0.008″. Within the above described exemplary diameter, D66-S, parameters, each nozzle581,582,583,584can be utilized to crystallize various types of chemical compounds; because each nozzle581,582,583,584is removably-disposed within the substantially cylindrically-shaped counter bore56formed in the distal end42of the substantially cylindrically-shaped body38of each distal end portion36, each nozzle581,582,583,584can be replaced with a nozzle581,582,583,584having a desired diameter, D66-S, for crystalizing a particular chemical compound.

The distal end18(that may be formed by, for example, the distal ends42,64) of each of the four controlled flow cavitation devices751,752,753,75nis disposed within a corresponding fluid inlet port201-204of a plurality of fluid inlet ports20formed by the fluid receiver14; the plurality of fluid inlet ports20are defined by (and as described above atFIGS. 2, 2A-2B and 3A-3B): a first fluid inlet port201, a second fluid inlet port202, a third fluid inlet port203and a fourth fluid inlet port204.

After disposing distal end18of each of the four controlled flow cavitation devices751,752,753,75nwithin the corresponding fluid inlet port201-204of the plurality of fluid inlet ports20formed by the fluid receiver14, the system10may be actuated by, for example, activating the computing processor28. The computing processor28may then send a signal to each pump241-24nof the plurality of pumps24such that the computing processor28may be programmed to selectively control the speed of each pump241-24nin order to regulate an amount of each of the four fluids, F1-F4, being supplied to the fluid mixing and crystallization chamber22by the first fluid input conduit121, the second fluid input conduit122, the third fluid input conduit123and the fourth fluid input conduit124.

When at least three of the four fluids, F1-F4, arrive at the fluid mixing and crystallization chamber22, the at least three of the four fluids, F1-F4, converge upon the single spatial coordinate, X—Y—Z, within the fluid mixing and crystallization chamber22to form the processed fluid, P. By permitting the four fluids, F1-F4, to converge and impinge upon one another at the single spatial coordinate, X—Y—Z, the processed fluid, P, is formed at a very high level of super-saturation; as a result, crystallization of the processed fluid, P, occurs rapidly within a small mixing zone at the single spatial coordinate, X—Y—Z, of the four streams formed by each of the first fluid, F1, the second fluid, F2, the third fluid, F3, and the fourth fluid, F4.

The speed of each pump241-24nof the plurality of pumps24is sufficient to create a downstream fluid force behind the four fluids, F1-F4, within the fluid mixing and crystallization chamber22in order to urge the processed fluid, P, out of the fluid mixing and crystallization chamber22and into the outlet port30formed by the fluid receiver14. The downstream fluid force may further urge the processed fluid, P, out of the outlet port30and into the fluid output conduit32that is fluidly-connected to the fluid outlet port30, via the fluid outlet body portion100b, for transporting the processed fluid, P, from the fluid outlet port30and to the processed fluid reservoir34that received the processed fluid, P, from the fluid receiver14.

In some instances, the computing resource28may operate the plurality of pumps24for continuous processing in a batch-wise fashion. Continuous processing may afford two advantages: (1) the same amount of fluids, F1-F4, supplied to the fluid receiver14may be crystallized in significantly less volume by continuous processing than would be possible by using a batch method, and (2) continuous processing enhances reproducibility of results because all the fluids, F1-F4, may crystallize under uniform conditions.

Customized crystallization of, for example, pharmaceuticals or fine chemical compounds may be achieved via a process using the system10. Referring toFIG. 9, the system10is capable of producing different particle sizes of a molecule with narrow distributions to provide a desired processed fluid, P. Further, as shown inFIGS. 10-12, the system10may produce more uniform and smaller crystals.

Referring back toFIG. 1, one or more of the fluids, F1-Fn, may be a “feed solution” in which a compound to be crystallized within the fluid mixing and crystallization chamber22is substantially dissolved in a suitable solvent or combination of one or more solvents. Further, one or more of the fluids, F1-Fn, may be one or more anti-solvents; the term “anti-solvent” may be refer to a suitable solvent or combination of one or more solvents that causes processed fluid, P, to crystallize or precipitate. An anti-solvent may be typically miscible with the solvent of a feed solution, whereas a processed fluid, P, to be crystallized is sparingly soluble in it.

With continued reference toFIG. 1, one or more of the fluids, F1-Fn, may be a suitable surfactant. Alternatively, one or more surfactants may be added as part of a premix with one or more of the fluids, F1-Fn. Thus, the feed solution and one or all of anti-solvents may contain a surfactant. In some embodiments, the surfactant may be an emulsifying surfactant which is soluble in the feed solution and insoluble in the anti-solvent. A surfactant and a compound to be crystallized may be dissolved together in the process of the present invention. In a preferred embodiment, soy lecithin may be the surfactant. In some embodiments, a compatible emulsifying surfactant may also be used in the anti-solvent. For example, if tetrahydrofuran is the solvent of a feed solution, and the surfactant in the solvent is sobitan monooleate, then an appropriate surfactant in the anti-solvent (such as water) may be selected from the polysorbate series. Generally, suitable surfactants include, but are not limited to: gelatin, casein, lecithin, gum acacia, cholesterol, steric acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, sorbitan esters, polyoxyethylene alkyl esters, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearate, sodium dodecylsulfate, hydroxyl propylcellulose, polyvinylpyrrolidone and polyvinyl alcohols.

In some embodiments, the computing resource28may operate each pump241-24nof the plurality of pumps24at different speeds; therefore the solvents and anti-solvents may be pumped into the fluid mixing and crystallization chamber22at different rates. In some instances, when the computing resource28operates each pump241-24nof the plurality of pumps24at different speeds, a pressure difference of each fluid, F1-Fn, with their respective fluid input conduit121-12nmay be approximately 1500 psi. The difference in ranges of pressures may be between about 50 psi to 30,000 psi. Higher pressures may be utilized in order to influence the particle size distribution and to affect an increase in production rate of the processed fluid, P. Pressure also can be used to add asymmetry to the system10.

Flow rate of the streams of the fluid, F1-Fn, may be proportional to the square root of the pressure. Flow rates of the streams of the fluid, F1-Fn, may dictate the kinetics of crystallization (i.e., particle size and uniformity). As described above, in some instances, the flow rate of the streams of the fluid, F1-Fn, may also be controlled by the diameter, D66-S, of each selected nozzle581,582,583,58n. In some instances, flow rates of the fluid, F1-Fn, toward the fluid mixing and crystallization chamber22may range from about 50 ml/min to 15 l/min. In some examples, one of the selected nozzles581,582,583,58nmay include a low flow rate and the remainder of the selected nozzles581,582,583,58nmay include a high flow rate; for example, a feed solution, F1, may enter the fluid mixing and crystallization chamber22through a diameter, D66-S, of a selected nozzle581that is equal to approximately 0.004″ and the anti-solvents, F2-Fn, may enter fluid mixing and crystallization chamber22through diameters, D66-S, of selected nozzles582,582,583that are approximately equal to for example, 0.008″, 0.006″ and 0.008″, with one or of the 0.008″ diameters, D66-S, opposing the 0.004″ diameter, D66-S. Such an exemplary configuration may provide asymmetry leading to nucleation of a low energy polymorph (i.e. a very stable polymorph).

In some example, the flow rate may be controlled by the power of the plurality of pumps24. Further, a maximum practical flow rate may be determined by the final concentration of a compound in the anti-solvent. Yet even further, the solvent and anti-solvent may be removed to isolate the particles; as such, if the concentration of a compound in the final liquid, P, is below about 1% then significant amount energy may be utilized to remove the liquid. Conversely, if there is too little liquid (i.e., the concentration of a compound to be crystallized is higher than about 20%), then there may be too much agglomeration.

In some instances, the temperature of the fluids, F1-Fn, may be varied to allow for super-saturation of the compound, P. For example, when a compound, P, is only modestly soluble in a solvent, the temperature of one or more of the fluids, F1-Fn, might be increased (e.g., by, e.g., a heat exchanger, not shown) to allow for higher loading. In some examples, fluid temperatures may range from below room temperature to about 60° C., depending on the compound, P, to be crystallized. If a fluid temperature is too high, the high fluid temperature may break down a compound to be crystallized, whereas, conversely, a too low fluid temperature may limit the concentration of the compound in the solvent. In some embodiments, when the fluid temperature of the solvent is high, the fluid temperature of the anti-solvent is low; for example, when water is used as an anti-solvent, the temperature for the water may be about 1° C. When an organic solvent is used, the organic solvent may be cooled down to as low as the lowest freezing point of the solvent or anti-solvent.

The system10may enable the production of customized particle sizes. For example, the system10may form crystals in a range from about 10 nanometers to 90 microns.

Just as importantly as desirable small particle sizes is uniformity of particle size distributions (i.e., described by “D values”). D values of “D10”, “D50” and “D90” may be used to represent the midpoint and range of particle sizes of a given sample. The D10 particle size is the diameter at which 10% of a sample's mass is comprised of smaller particles. The D50 is the “mass median diameter” as it divides the sample equally by mass. The D90 particle size is the diameter at which 90% of a sample's mass is comprised of smaller particles.

System10of the present invention enables the production of customized particles within a narrow range of particle sizes. A common value used to express the uniformity of particle size distribution is the “span”. The span is a measure of how wide of a spectrum of particle sizes is produced. A system with a low relative span is desirable as it will produce more uniform distribution of particle sizes. Span can be calculated with the equation below:
Span=(D90−D10)/D50.

The following examples are provided for the purpose of illustrating the present invention and should not be construed as being a limitation on the scope or spirit of the present invention. It should be understood that there may be other embodiments which fall within the spirit and scope of the invention as defined by the claims appended hereto.

Example 1 Crystallization of paracetamol (N-(4-hydroxyphenyl)ethanamide)

Two grams of Paracetomol was dissolved in 100 grams of ethanol. Two grams of Soy Lecithin was dissolved in 50 grams of tetrahydrofuran (THF). The two solutions were combined and heated to 60° C. The solution was added to the input hopper of a dual piston pump241. The pump241was fed into fluid input conduit121of the crystallization chamber22through a 0.006″ opening701of a nozzle581. Heptane, at 10° C. was fed into fluid input conduits122,123and124through 0.006″, 0.008″ and 0.008″ openings702,703, and704of nozzles582,583, and584respectively by an identical piston pump242. The pressure on both pumps241and242was adjusted to 1000 psi. The mixed streams exited through fluid output conduit32and into fluid reservoir34containing approximately 100 ml of heptane. Approximately, the first third and last third of the mixture were discarded and only the central third collected in fluid reservoir34. The final solution was sampled and the particle size was measured, in heptane, using a Horiba L950 particle size analyzer. The median particle size was about 1.3 microns. The Span was about 0.901.

Two grams of Carbamazepine was dissolved in 100 grams of ethanol. Two grams of Soy Lecithin was dissolved in 50 grams of THF. The two solutions were combined and heated to 60° C. The solution was added to the input hopper of a dual piston pump241. The pump241was fed into fluid input conduit121of the crystallization chamber22through a 0.004″ opening701of a nozzle581. Heptane, at 10° C. was fed into fluid input conduits122,123and124through 0.006″, 0.007″ and 0.007″ openings702,703, and704of nozzles582,583, and584respectively by an identical piston pump242. The pressure on both pumps241and242was adjusted to 1500 psi. The mixed streams exited through fluid output conduit32and into fluid reservoir34containing approximately 100 ml of heptane. Approximately, the first third and last third of the mixture were discarded and only the central third collected in fluid reservoir34. The final solution was sampled and the particle size was measured, in heptane, using a Horiba L950 particle size analyzer. The median particle size was about 1.5 microns. The Span was about 0.916.

Two grams of Ketoprofen was dissolved in 100 grams of DMSO. Two grams of Sorbitan Monostearate was dissolved in 50 grams of THF. The two solutions were combined and heated to 60° C. The solution was added to the input hopper of a dual piston pump241. The pump241was fed into fluid input conduits121of the crystallization chamber22through a 0.004″ opening701of a nozzle581. DI water with 0.1% Polysorbate 20, at 5° C. was fed into fluid input conduits122,123and124through 0.006″, 0.008″ and 0.008″ openings702,703, and704of nozzles582,583, and584respectively by an identical piston pump242. The pressure on both pumps241and242was adjusted to 1500 psi. The mixed streams exited through fluid output conduit32and into fluid reservoir34containing approximately 100 ml of distilled water (DI) water containing 0.1% Polysorbate 20. Approximately, the first third and last third of the mixture were discarded and only the central third collected in fluid reservoir34. The final solution was sampled and the particle size was measured, in DI water, using a Horiba L950 particle size analyzer. The median particle size was about 3.1 microns. The Span was about 1.078.

Five grams of Atorvastatin was dissolved in 132 grams of dimethyl sulfoxide. Five grams of Soy Lecithin was dissolved in 68 grams of tetrahydrofuran. The two solutions were combined and heated to 60° C. The solution was added to a fluid inlet port hopper of a dual piston pump241. The pump241was fed into fluid input conduits121of the crystallization chamber22through a 0.004″ opening701of a nozzle581. DI water with 0.1% hydroxypropyl methylcellulose (HPMC), at 5° C. was fed into fluid input conduits122,123and124through 0.008″, 0.010″ and 0.008″ openings702,703, and704of nozzles582,583, and584respectively by an identical piston pump242. The pressure on both pumps241and242was adjusted to 500 psi. The mixed streams exited through a 0.020″ fluid output conduit32and into fluid reservoir34containing approximately 100 ml of DI water containing 0.1% HPMC. Approximately, the first third and last third of the mixture were discarded and only the central third collected in fluid reservoir34. The final solution was sampled and the particle size was measured, in DI water, using a Horiba L950 particle size analyzer. The median particle size was about 126 nanometers (0.126 microns). The Span was about 0.99.

Example 5 Crystallization of itraconazole (2R,4S)-rel-1-(butan-2-yl)-4-{4-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-4,5-dihydro-1H-1,2,4-triazol-5-one

Two grams of Itraconazole, two grams of Soy Lecithin and two grams of Sorbitan Monostearate were dissolved in 100 grams of tetrahydrofuran. The solution was heated to 60° C. The solution was added to a fluid inlet port hopper of a dual piston pump241. The pump was fed into fluid input conduits121of the crystallization chamber22through a 0.004″ nozzle opening701of a nozzle581. DI water, at 5° C. was fed into fluid input conduits122,123and124through 0.008″, 0.008″ and 0.004″ openings702,703, and704of nozzles582,583, and584respectively by an identical piston pump242. The pressure on both pumps241and242was adjusted to 485 psi. The mixed streams exited through a 0.018″ fluid output conduit32and into a receiving fluid reservoir34containing approximately 100 ml of DI water. Approximately, the first third and last third of the mixture were discarded and only the central third collected in fluid reservoir34. The final solution was sampled and the particle size was measured, in DI water, using a Horiba L950 particle size analyzer. The median particle size was about 36 nanometers (0.036 microns). The Span was about 0.34.