System and method for producing particles of organic material - Patents.com

Abstract

The present invention relates to a system (400) and method for producing particles of organic materials, particularly nanoparticles and microparticles of active pharmaceutical ingredients, which are collected with the aid of an extension member (407) that engages a collection chamber (402) and positions a nozzle (405).

Description

[Technical field]

[0001] The present invention relates to a system and method for producing particles of organic substances, particularly nano- and micro-sized active pharmaceutical ingredients, with the aid of dry ice formation. [Background technology]

[0002] In the pharmaceutical industry, many drugs are insoluble or poorly soluble in water, which leads to a slow dissolution rate and therefore low bioavailability of these drugs. One of the solutions is to reduce the particle size, which leads to improved dissolution behavior. Rapid Expansion of Supercritical Solutions (RESS) is one of the most used methods. Controlled Expansion of Supercritical Solutions (CESS) then represents an improvement of the RESS technology by using controlled mass transfer, flow and reduced pressure.

[0003] In a typical RESS process, a supercritical fluid is used to melt solid materials under high pressure and temperature, thus forming a homogeneous supercritical phase. The solution is then expanded through a nozzle, forming small particles.

[0004] A system suitable for producing micro- and nanoparticles of organic materials using RESS and CESS techniques is shown in Figure 1. The system 100 comprises a pressure chamber 101 for a mixture of organic material A and supercritical carbon dioxide (scCO2), a collection chamber 102 and an outlet tube 103 therebetween. The system also typically comprises one or more pressure control means 104 adapted to control the pressure within the system, and a nozzle 105 adapted to allow expansion of the mixture from the outlet tube into the collection chamber.

[0005] As the mixture rapidly expands through the nozzle to atmospheric pressure, small particles of the organic material a are formed and the initially formed solid CO2 sublimes and leaves the system via exhaust port 106. The nozzle is typically mounted directly into the collection chamber so that the particles also tend to exit the collection chamber.

[0006] Thus, there is a need for additional systems and methods for producing microparticles and nanoparticles. Summary of the Invention

[0007] The following presents a simplified summary in order to provide a basic understanding of some aspects of various embodiments of the invention. This summary is not an extensive overview of the invention. It is not intended to identify essential or critical elements of the invention, nor does it delineate the scope of the invention. The following summary merely presents some concepts of the invention in a simplified form as a prelude to a more detailed description of example embodiments of the invention.

[0008] It has been observed that if a system for producing particles of organic matter includes an extension member between the nozzle and the collection chamber, loss of particles of organic matter along with gaseous CO2 from the system can be avoided or at least mitigated.

[0009] It is therefore an aspect of the present invention to provide a new system for producing particles of organic material, the system comprising: a) a pressure chamber for a mixture of organic substances and supercritical carbon dioxide; b) collection room; c) an exhaust tube including a first end and a second end that engages the pressure chamber; d) a nozzle engaged with the second end and adapted to allow expansion of the mixture from the discharge tube into a collection chamber; Including, The system includes an extension member that engages the exhaust tube and the collection chamber and positions the nozzle.

[0010] It is also an aspect of the present invention to provide a method of producing particles of organic material using the system according to claim 1.

[0011] A further aspect of the present invention is to provide a novel use of carbon dioxide snowhorns as a means to collect particles of organic material.

[0012] A number of illustrative and non-limiting embodiments of the present invention are set forth in the accompanying dependent claims.

[0013] Various illustrative and non-limiting embodiments and methods of operation of the present invention, together with additional objects and advantages thereof, are best understood from the following description of specific illustrative embodiments when read in connection with the accompanying figures.

[0014] The verbs "to comprise" and "to include" are used in this document as an open limitation which neither excludes nor requires the presence of features not recited. Features recited in the dependent claims may be freely combined with each other, unless expressly stated otherwise. Furthermore, it is to be understood that throughout this document the use of "a" or "an", i.e. the singular, does not exclude a plurality. [Brief description of the drawings]

[0015] Exemplary and non-limiting embodiments of the invention are described in more detail below with reference to the accompanying figures.

[0016] [Figure 1] 1 shows a system for producing particles of organic material in the prior art.

[0017] [Diagram 2] 1 illustrates an exemplary non-limiting system suitable for producing particles of organic material in accordance with an embodiment of the present invention.

[0018] [Diagram 3] 1 illustrates an exemplary non-limiting system suitable for producing particles of organic material in accordance with an embodiment of the present invention.

[0019] [Figure 4] 1 illustrates an exemplary non-limiting system suitable for producing particles of organic material in accordance with an embodiment of the present invention.

[0020] [Diagram 5]1 illustrates an exemplary carbon dioxide snowhorn suitable for the systems and methods of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] The specific examples provided in the following description should not be construed as limiting the scope and / or applicability of the appended claims. The lists and groups of examples provided in the following description are not exhaustive, unless expressly stated.

[0022] The system of Figure 1 is described in the Background section of this document.

[0023] 2 illustrates a system 200 in an exemplary and non-limiting embodiment of the present invention. The system includes a pressure chamber 201 for a mixture of organic substance A to be micronized or nanoized and supercritical carbon dioxide (scCO2), a collection chamber 202 including an exhaust port 206, an exhaust pipe 203 and a nozzle 205. A first end 203a of the exhaust pipe is engaged with the pressure chamber and a second end 203b of the exhaust pipe is engaged with the nozzle. The system includes a pressure control means 204 adapted to control the pressure in the system.

[0024] The system also includes an extension member 207 engaged with the discharge tube and the collection chamber. The outer surface of the extension member is preferably coated with an insulating material. A nozzle is disposed within the extension member. The nozzle is adapted to allow expansion of the mixture from the discharge tube into the collection chamber. When the system is operating, solid carbon dioxide forms within the extension member as snow containing organic matter particles a. As the carbon dioxide snow sublimes, the carbon dioxide is exhausted from the system via exhaust port 206 while the formed particles remain within the system.

[0025] FIG. 3 illustrates another system 300 in an exemplary and non-limiting embodiment of the present invention. The system includes a pressure chamber 301 for a mixture of organic material A to be micronized or nanoized and supercritical carbon dioxide (scCO2), a collection chamber 302 including an exhaust port 306, an exhaust pipe 303 and a nozzle 305. A first end 303a of the exhaust pipe is engaged with the pressure chamber and a second end 303b of the exhaust pipe is engaged with the nozzle. The system also includes a pressure control means 304 adapted to control the pressure in the system. The system includes an extension member 307 engaged with the exhaust pipe and the collection chamber. The nozzle is disposed within the extension member and adapted to allow the expansion of the mixture from the exhaust pipe to the collection chamber. The centerline 307a of the extension member is at an angle α with the sidewall 302a of the collection chamber so that gravity helps to keep the CO2 snow and particles in the vicinity of the nozzle and the extension member, thus further preventing the particles a from being exhausted from the collection chamber via the exhaust port. The angle α is typically 10°-80°, with 0° and 90° being the y- and x-directions, respectively, of coordinate system 399. An exemplary angle α is 45°. Thus, the extension member is aligned substantially upward when the system is in the operating position.

[0026] FIG. 4 illustrates another system 400 in an exemplary and non-limiting embodiment of the present invention. The system includes a pressure chamber 401 for a mixture of organic substance A to be micronized or nanoized and supercritical carbon dioxide (scCO2), a collection chamber 402 including an exhaust port 406, an outlet tube 403 and a nozzle 405. A first end 403a of the outlet tube is engaged with the pressure chamber and a second end 403b of the outlet tube is engaged with the nozzle. The system also includes a pressure control means 404 adapted to control the pressure in the system. The system includes an extension member 407 engaged with the outlet tube and the collection chamber. The nozzle is disposed within the extension member and adapted to allow the expansion of the mixture from the outlet tube into the collection chamber. The extension member is aligned to open upwards, i.e. in the y-direction of the coordinate system 499, when the system is in the operating position. Thus, gravity helps to keep the carbon dioxide snow in the vicinity of the nozzle and the extension member, thus further reducing the ejection of particles a from the collection chamber.

[0027] The system 400 also includes a mechanical means 408 adapted to hold the carbon dioxide snow containing the organic matter particles in proximity to the nozzle and extension member. Exemplary mechanical means are a screw conveyor and a shutter including an energy storage means, such as a spring loaded shutter.

[0028] In another embodiment, the present invention relates to a method of producing particles of organic material using the above-described system. In an exemplary, non-limiting embodiment, the method comprises: a) mixing an organic material with supercritical carbon dioxide in a pressure chamber 201, 301, 401 to form a mixture at a first pressure (P1); b) passing the mixture through the discharge pipe 203, 303, 403 towards the nozzle 205, 305, 405 c) The mixture is pumped through a nozzle disposed on the extension member 206, 306, 406 to a final pressure (P F ) to form solid carbon dioxide containing particles of organic matter. d) collecting the solid carbon dioxide containing particles of organic matter within the elongated member; and e) Sublimating the solid carbon dioxide Includes.

[0029] In a particular embodiment, step b) comprises reducing the first pressure to a second pressure (P2) during the passage, which reduction is preferably performed gradually.

[0030] Step c) reduces the second pressure to a final pressure (P F ) to the ratios (P1) / (P2) and (P2 / P F ) is preferably less than 15, more preferably less than 10.

[0031] The pressure and temperature in the pressure chamber are such that the carbon dioxide is in a supercritical state. The final pressure is typically atmospheric pressure. An exemplary temperature in the collection chamber is ambient temperature.

[0032] The particle size of the organic material obtained by the process of the present invention is generally less than 200 nm, preferably less than 100 nm, more preferably less than 50 nm, and most preferably less than 20 nm.

[0033] As defined herein, a "nanoparticle" is a particle having an average diameter of 200 nm or less.

[0034] As defined herein, "organic materials" are molecules that contain carbon, excluding carbon-containing alloys and the relatively few carbon-containing compounds such as metal carbonates and carbonyls, simple oxides and cyanides of carbon, as well as allotropes of carbon and simple carbon halides and sulfides that are considered inorganic. Exemplary organic materials for use in the present technology are biologically active materials, including pharmaceutical agents and their pharma- ceutically acceptable organic and inorganic salts.

[0035] A non-limiting list of exemplary classes of biologically active substances includes active pharmaceutical ingredients of interest, such as analgesics, antagonists, anti-inflammatory drugs, anthelmintics, antianginal drugs, antiarrhythmic drugs, antibiotics (including penicillin), anticholesterol drugs, anticoagulants, anticonvulsants, antidepressants, antidiabetics, antiepileptic drugs, antigonadotropins, antihistamines, antihypertensive drugs, muscarinic receptor antagonists, mycobacterial drugs, antineoplastic drugs, antipsychotics, immunosuppressants, antithyroid drugs, antivirals, antifungals, anxiolytics (hypnotics and neuroleptics), astringents, β-adrenergic receptor antagonists, blood products and substitutes thereof. supplies, anti-cancer drugs, cardiac inotropes, contrast media, corticosteroids, antitussives and expectorants (expectorants and mucolytics), diuretics, dopamine agonists (anti-Parkinson's drugs), haemostatics, immunosuppressants and immunoactivators, lipid regulating drugs, muscle relaxants, parasympathomimetics, parathyroid calcitonin and bisphosphonates, prostaglandins, radiopharmaceuticals, sex hormones (including steroids), antiallergics, stimulants and anorexics, adrenergic drugs, thyroid drugs, vasodilators, neuronal blocking drugs, anticholinergics and cholinergics, antimuscarinics and muscarinics, vitamins, and xanthines.

[0036] The organic material, such as the active pharmaceutical ingredient, may be crystalline, amorphous or a mixture thereof. In one embodiment, the nanoparticles comprise an active pharmaceutical ingredient and one or more excipients.

[0037] Exemplary active pharmaceutical ingredients suitable for the methods of the present invention are entacapone, esomeprazole, atorvastatin, rabeprazole, piroxicam and olanzapine.An exemplary active pharmaceutical ingredient is piroxicam (4-hydroxy-2-methyl-N-(2-pyridinyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide).

[0038] The combination of an extension member and nozzle that acts as a carbon dioxide snow horn is well known in the art. A carbon dioxide snow horn is an orifice that allows the expansion of liquid carbon dioxide.

[0039] In another embodiment, the present invention relates to a novel use of a carbon dioxide snow horn as a means for collecting particles of organic matter. An exemplary carbon dioxide snow horn 509 is shown in FIG. 5. The carbon dioxide snow horn includes a nozzle 505 and an extension member 506. The outer surface 506a of the extension member is preferably coated with an insulating material. The nozzle is disposed at a first end 509a of the carbon dioxide snow horn. When used in the system of the present invention, the first and second ends 509a and 509b of the snow horn are adapted to engage the collection chamber 502 and the exhaust pipe 503, respectively. The shape of the extension member, the type of nozzle, and the size of the carbon dioxide snow horn can be varied depending on the requirements of the system.

[0040] The specific examples provided in the above description should not be construed as limiting the scope and / or applicability of the appended claims. Examples of embodiments of the present invention are listed in the following items [Aspect 1] to [Aspect 16]. [Aspect 1] a) Pressure chambers (201, 301, 401) for the mixture of organic material and supercritical carbon dioxide b) Collection chamber (202, 302, 402) c) an exhaust pipe (203, 303, 403) including a first end (203a, 303a, 403a) that engages the pressure chamber and a second end (203b, 303b, 403b); d) a nozzle (205, 305, 405) adapted to engage said second end and allow expansion of said mixture from said discharge tube into said collection chamber; A system (200, 300, 400) for producing particles of an organic material, comprising: The system further comprises an extension member (207, 307, 407) that engages the collection chamber and the discharge tube and positions the nozzle. [Aspect 2] The system of embodiment 1, wherein the system comprises one or more means (204, 304, 404) adapted to control pressure within the system. [Aspect 3] 3. The system of embodiment 1 or 2, wherein the collection chamber comprises an exhaust vent (206, 306, 406) for carbon dioxide. [Aspect 4] The system of any one of aspects 1-3, wherein an outer surface of the extension member is coated with an insulating material. [Aspect 5] The system of any one of aspects 1-4, wherein the extension member (307, 407) is aligned substantially upwardly when the system is in an operating position. [Aspect 6] 6. The system of any one of aspects 1-5, wherein the system further comprises a mechanical means (408) adapted to maintain solid carbon dioxide containing the particles of organic material in proximity to the nozzle and the extension member. [Aspect 7] A method of producing particles of organic material by using a system according to any one of aspects 1-6, comprising the steps of: a) mixing the organic material with supercritical carbon dioxide in the pressure chamber (201, 301, 401) and subjecting the organic material to a first pressure (P 1 ) forming a mixture. b) passing said mixture through said discharge pipe (203, 303, 403) towards said nozzle (205, 305, 405) c) passing the mixture through the nozzle disposed on the extension member (206, 306, 406) to a final pressure (P F ) to form solid carbon dioxide containing particles of said organic material. d) collecting the solid carbon dioxide containing particles of organic matter within the extension member (206, 306, 406); and e) sublimating the solid carbon dioxide A method comprising: [Aspect 8] The step b) is performed by increasing the first pressure (P 1 ) to the second pressure (P 2 8. The method of embodiment 7, comprising reducing the concentration of [Aspect 9] The method of embodiment 8, wherein the decreasing is effected gradually. [Aspect 10] The step c) is the second pressure (P 2 ) to the final pressure (P F 10. The method of claim 8 or 9, comprising reducing the concentration of [Aspect 11] The second pressure (P 2 11. The method according to any one of aspects 8-10, wherein the pressure in the pressure vessel is less than 100 bar, preferably 10-50 bar. [Aspect 12] Ratio(P 1 ) / (P 2 ) and (P 2 / P F 12. The method according to any one of aspects 8-11, wherein n is less than 15, preferably less than 10. [Aspect 13] 13. The method of any one of aspects 7-12, wherein the final pressure is atmospheric pressure. [Aspect 14] The method according to any one of aspects 7-13, wherein the particles are microparticles or nanoparticles, preferably nanoparticles. [Aspect 15] The method of any one of aspects 7-14, wherein the organic substance is an active pharmaceutical ingredient. [Aspect 16] Use of a carbon dioxide snow horn (509) including an extension member (506) and a nozzle (505) adapted to engage an outlet tube (503) for supercritical carbon dioxide or liquid carbon dioxide as a means for collecting particles of organic matter.

Claims

1. a) A pressure chamber (401) for the mixture of organic material and supercritical carbon dioxide. b) Collection Chamber (402) c) an exhaust tube (403) including a first end (403a) that engages the pressure chamber and a second end (403b); d) a nozzle (405) adapted to engage said second end and allow expansion of said mixture from said discharge tube into said collection chamber; A system (400) for producing particles of an organic material, comprising: the system includes an extension member (407) that engages the collection chamber and the exhaust pipe and positions the nozzle, the system including a spring-loaded shutter adapted to hold solid carbon dioxide containing particles of organic matter in proximity to the nozzle and the extension member.

2. The system of claim 1 , wherein the system includes one or more means (404) adapted to control pressure within the system.

3. The system of claim 1 or 2, wherein the collection chamber includes an exhaust vent (406) for carbon dioxide.

4. The system of any one of claims 1 to 3, wherein the extension member (407) is aligned upwardly when the system is in an operating position.

5. A method for producing particles of organic material by using a system according to any one of claims 1 to 4, comprising the steps of: a) mixing the organic material with supercritical carbon dioxide in the pressure chamber (401) and subjecting the organic material to a first pressure (P １ ) forming a mixture b) passing said mixture through said outlet pipe (403) towards said nozzle (405); c) pumping the mixture through the nozzle disposed on the extension member (407) to a final pressure (P Ｆ ) to form solid carbon dioxide containing particles of said organic material. d) collecting the solid carbon dioxide containing the particles of organic matter within the extension member (407); and e) sublimating the solid carbon dioxide A method comprising:

6. The step b) is performed by applying the first pressure (P １ ) to the second pressure (P ２ 6. The method of claim 5, comprising reducing the concentration of

7. The step c) is the second pressure (P ２ ) to the final pressure (P Ｆ 7. The method of claim 6, comprising reducing the concentration of

8. The second pressure (P ２ 8. The method according to claim 6 or 7, wherein the pressure in the heating chamber is less than 100 bar.

9. Ratio (P １ ) / (P ２ ) and (P ２ / P Ｆ 9. The method of claim 6, wherein the n is less than 15.

10. The method according to any one of claims 5 to 9, wherein the final pressure is atmospheric pressure.

11. The method according to any one of claims 5 to 10, wherein the particle size of the organic substance is 200 nm or less.

12. The method according to any one of claims 5 to 11, wherein the organic substance is an active pharmaceutical ingredient.

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