US20050152981A1 - Process for making sterile aripiprazole of desired mean particle size - Google Patents
Process for making sterile aripiprazole of desired mean particle size Download PDFInfo
- Publication number
- US20050152981A1 US20050152981A1 US10/968,481 US96848104A US2005152981A1 US 20050152981 A1 US20050152981 A1 US 20050152981A1 US 96848104 A US96848104 A US 96848104A US 2005152981 A1 US2005152981 A1 US 2005152981A1
- Authority
- US
- United States
- Prior art keywords
- aripiprazole
- stream
- particle size
- solvent
- jet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 title claims abstract description 106
- 229960004372 aripiprazole Drugs 0.000 title claims abstract description 105
- 238000000034 method Methods 0.000 title claims abstract description 62
- 239000002245 particle Substances 0.000 title claims abstract description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000000203 mixture Substances 0.000 claims abstract description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 50
- 239000013078 crystal Substances 0.000 claims description 33
- 239000012296 anti-solvent Substances 0.000 claims description 30
- 238000010899 nucleation Methods 0.000 claims description 22
- 230000006911 nucleation Effects 0.000 claims description 20
- UXQBDXJXIVDBTF-UHFFFAOYSA-N 7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydro-1h-quinolin-2-one;hydrate Chemical compound O.ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl UXQBDXJXIVDBTF-UHFFFAOYSA-N 0.000 claims description 15
- 238000009826 distribution Methods 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 15
- 239000002002 slurry Substances 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000008367 deionised water Substances 0.000 claims description 5
- 229910021641 deionized water Inorganic materials 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 150000004682 monohydrates Chemical group 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 230000007423 decrease Effects 0.000 claims description 3
- 230000003247 decreasing effect Effects 0.000 claims description 3
- 230000000977 initiatory effect Effects 0.000 claims description 3
- 239000002510 pyrogen Substances 0.000 claims description 3
- ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical group OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 abstract description 24
- 230000008025 crystallization Effects 0.000 abstract description 21
- 238000009472 formulation Methods 0.000 abstract description 8
- 238000010255 intramuscular injection Methods 0.000 abstract 1
- 239000007927 intramuscular injection Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 34
- 239000000725 suspension Substances 0.000 description 14
- 239000012530 fluid Substances 0.000 description 13
- 238000000527 sonication Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000003801 milling Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000000889 atomisation Methods 0.000 description 2
- 238000000498 ball milling Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012527 feed solution Substances 0.000 description 2
- 238000000265 homogenisation Methods 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- -1 4-phenylpiperazino Chemical group 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229940123247 Neurotransmitter antagonist Drugs 0.000 description 1
- COAYMVLTWXLTOT-UHFFFAOYSA-N O.O=C1CCC2=C(C=C(OCCCCN3CCN(C4=C(Cl)C(Cl)=CC=C4)CC3)C=C2)N1.O=C1CCC2=C(C=C(OCCCCN3CCN(C4=C(Cl)C(Cl)=CC=C4)CC3)C=C2)N1 Chemical compound O.O=C1CCC2=C(C=C(OCCCCN3CCN(C4=C(Cl)C(Cl)=CC=C4)CC3)C=C2)N1.O=C1CCC2=C(C=C(OCCCCN3CCN(C4=C(Cl)C(Cl)=CC=C4)CC3)C=C2)N1 COAYMVLTWXLTOT-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229940045641 monobasic sodium phosphate Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 238000007669 thermal treatment Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/02—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of powders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0004—Crystallisation cooling by heat exchange
- B01D9/0009—Crystallisation cooling by heat exchange by direct heat exchange with added cooling fluid
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
- B01D9/0054—Use of anti-solvent
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0063—Control or regulation
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0081—Use of vibrations, e.g. ultrasound
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
- B01J2/02—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops
- B01J2/06—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops in a liquid medium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
Definitions
- the present invention related to a process for making sterile aripiprazole of desired particle size distribution and mean particle size which is especially adapted for use in preparing a controlled release formulation which releases aripiprazole over at least one week or more.
- U.S. provisional application No. 60/513,618, discloses a controlled release sterile injectable aripiprazole formulation in the form of a sterile suspension, and a method for preparing a sterile freeze-dried aripiprazole formulation (employed in forming the injectable formulation) which includes the steps of:
- sterile bulk aripiprazole preferably prepared in step (a) by means of the impinging jet crystallization method, has a desired small particle size and narrow particle size distribution, high surface area, high chemical purity, and high stability due to improved crystal structure.
- the impinging jet crystallization utilizes two jet streams that strike each other head-on.
- One of the streams carries a solution rich in the aripiprazole and the other carries an anti-solvent, such as water.
- the two streams strike each other which allows for rapid homogeneous mixing and supersaturation due to high turbulence and high intensity of micromixing upon impact. This immediate achievement of supersaturation initiates rapid nucleation.
- the average crystal size of the aripiprazole decreases with increasing supersaturation and decreasing temperature of the anti-solvent. Therefore, in order to obtain the smallest particle size, it is advantageous to have the highest possible concentration of the aripiprazole rich solution and the lowest temperature of the anti-solvent.
- the technique employed for forming sterile bulk aripiprazole is important since particle size of the aripiprazole formulation controls its release profile in the blood system over a period of one month.
- U.S. Pat. No. 5,006,528 to Oshiro et al. discloses 7-[(4-phenylpiperazino)-butoxy] carbostyrils, which include aripiprazole, as dopaminergic neurotransmitter antagonists.
- Aripiprazole which has the structure is an atypical antipsychotic agent useful in treating schizophrenia. It has poor aqueous solubility ( ⁇ 1 ⁇ g/mL at room temperature).
- U.S. Pat. No. 6,267,989 to Liversidge, et al. discloses a method for preventing crystal growth and particle aggregation in nanoparticulate compositions wherein a nanoparticulate composition is reduced to an optimal effective average particle size employing aqueous milling techniques including ball milling.
- U.S. Pat. No. 5,314,506 to Midler, et al. discloses a process for the direct crystallization of a pharmaceutical having high surface area particles of high purity and stability wherein impinging jet streams are employed to achieve high intensity micromixing of particles of the pharmaceutical followed by nucleation and direct production of small crystals.
- U.S. Pat. No. 6,302,958 to Lindrud et al. discloses a method and apparatus for crystallizing submicron-sized crystals of a pharmaceutical composition employing sonication to provide ultrasonic energy in the immediate vicinity of impinging fluid drug and solvent streams so as to effect nucleation and the direct production of small crystals.
- a process for preparing sterile bulk aripiprazole of desired small particle size and narrow particle size distribution preferably having an average particle size less than about 100 microns but preferably greater than 25 microns, which includes the steps of:
- ultasonic energy may be provided, by means of a sonication probe, as described in U.S. Pat. No. 6,302,958, the disclosure of which is incorporated herein by reference, the tip of which is positioned within a gap defined between the two jet streams, to cause the impinging jet streams to achieve high intensity micromixing of fluids prior to nucleation.
- a preferred process for preparing sterile bulk aripiprazole of desired average particle size of less than about 100 microns, but preferably greater than 25 microns, and narrow particle size distribution which includes the steps of:
- ultasonic energy may be provided, by means of a sonication probe, as described above, the tip of which is positioned within a gap defined between the two jet streams, to cause the impinging jet streams to achieve high intensity micromixing of fluids prior to nucleation.
- the volumetric ratio of solution of aripiprazole in organic solvent to anti-solvent is within the range from about 0.5:1 to about 1.5:1, preferably from about 0.9:1 to about 1.1:1.
- the above processes may also be employed to prepare crystals of aripiprazole monohydrate having an average particle size of less than 25 microns.
- the processes of the invention as described above employs jet streams which impinge on each other to achieve high intensity micromixing of the streams to enable formation of a homogeneous composition prior to the start of nucleation in a continuous crystallization process. Nucleation and precipitation are initiated utilizing the effect of antisolvent addition on the solubility of the aripiprazole in the solvent therefor.
- the aripiprazole produced by the process of the invention may be employed in forming sterile bulk aripiprazole having a desired particle size distribution, preferably 10% ⁇ 10 microns, 50% ⁇ 35 microns and 95% ⁇ 100 microns, and mean particle size within the range from about 25 to about 100 microns.
- the sterile bulk aripiprazole prepared by the process of the invention may be used in forming a sterile-freeze dried aripiprazole formulation which may be suspended in water to form an injectable aripiprazole formulation as described in U.S. provisional Application No. 10/419,647.
- the process of the invention employs impinging jet crystallization technology, an example of which is disclosed in U.S. Pat. No. 5,314,506 to Midler et al.
- the sterile bulk aripiprazole of desired small particle size and narrow particle size distribution as described above may be prepared employing the process and apparatus described and claimed in each of the Chendou Wei applications entitled “Crystallization System Using Atomization” and “Crystallization System Using Homogenization” described above and incorporated herein by reference.
- FIGURE is a schematic representation of an impinging jet crystallization process flow diagram used in carrying out the process of the invention, which includes a crystallizer vessel.
- low pyrogen aripiprazole starting material is employed to ensure that the sterile aripiprazole of desired particle size will be produced.
- the low pyrogen aripiprazole starting material may be either the anhydrous form or the monohydrate form. Either material will yield the desired monohydrate form from the impinging jet crystallization process of the invention.
- the process of the invention employs two jet nozzles to create two impinging jet streams to achieve high intensity micromixing of the streams prior to nucleation and formation of crystals of aripiprazole monohydrate.
- the two impinging jet streams should be substantially diametrically opposed to one another with the nozzles directed to face each other.
- the jet nozzles will be aligned and positioned so that the fluid streams will impact head-on and will impinge. When the jet nozzles are properly aligned and appropriate flow rates chosen, the two streams will form a plane when impinged.
- Each of the process streams namely the aripiprazole-organic solvent stream and the anti-solvent stream will be sterilized.
- both streams are preferably polish filtered and then sterile filtered through an appropriate size filter, such as a 0.2 micron filter.
- the aripiprazole stream should be filtered at an elevated temperature, for example, about 80° C., to prevent precipitation.
- each solution The temperature and composition of each solution are chosen so that 1) no material will crystallize upstream of the impinging jets, and, 2) sufficient supersaturation will be developed in the impinging jets to cause nucleation. Micromixing creates temperature and compositional uniformity throughout the mixture prior to the start of nucleation.
- the highest possible concentration of aripiprazole in the organic solvent should be employed.
- the starting solution of aripiprazole in organic solvent preferably ethanol, will contain from about 0.01 to about 0.1 kg/L aripiprazole, preferably from about 0.04 to about 0.06 kg/L aripiprazole.
- the aripiprazole will be present in an amount of about 0.05 kg/L.
- the organic solvent will preferably be ethanol, most preferably from about 92 to about 97% ethanol, with the remainder being water.
- organic solvents such as methanol, ethyl acetate, acetone, acetonitrile, acetic acid or isopropyl alcohol or mixtures of two or more thereof, or mixtures with water may be employed.
- the anti-solvent will preferably be deionized water.
- the two streams namely, the stream of the solution of aripiprazole in the organic solvent and the stream of anti-solvent, are characterized as jet streams in that they will be made to strike each other head on at high linear velocities with a minimum of 5 m/s.
- the flow rates will be determined by the diameter of the jet nozzles employed to deliver the streams and the rate at which the streams are pumped through the nozzles.
- the flow rate of each of the stream of aripiprazole/solvent and the stream of antisolvent will be essentially the same, but will of course be in opposite directions.
- flow rates will be chosen so that proper impinging is achieved.
- flow rates will be within the range from about 0.20 to about 0.30 kg/min, preferably from about 0.22 kg/min to about 0.28 kg/min, more preferably from about 0.24 kg/min to about 0.26 kg/min, and optimally about 0.25 kg/min.
- each of the streams is important in determining ultimate size of the particles of aripiprazole produced.
- the aripiprazole-solvent (preferably ethanol) stream should be heated at a temperature within the range from about 70 to about 85° C., preferably from about 75 to about 80° C.
- the anti-solvent stream preferably water
- the two streams strike each other head-on, from opposite directions, to cause rapid homogeneous mixing and supersaturation due to high turbulence and high intensity of mixing upon impact.
- the immediate achievement of supersaturation initiates rapid nucleation.
- the average crystal size decreases with increasing supersaturation and decreasing temperature of the anti-solvent.
- the smallest particle size of aripiprazole is obtained employing the highest possible concentration of the aripiprazole solution and the lowest temperature of the anti-solvent. Sonication is utilized where even smaller particles are desired.
- an impinging jet crystallization process flow diagram and crystallizer vessel used in carrying out the process of the invention which includes a jacketed impingement crystallization vessel 10 .
- Impinging jet nozzles 16 , 18 each having a 0.02-inch diameter, are spaced 10 mm apart.
- the impingement vessel 10 may include agitator 11 and a sonicator (as employed in U.S. Pat.
- Outlet 31 of impingement vessel 10 is connected to receiving vessel 32 , via line 33 .
- Overflow line 35 links impingement vessel 10 and line 33 and aids in maintaining a constant volume in impingement vessel 10 .
- the above description is of the sterile portion of the flow diagram.
- the non-sterile portion as shown includes a vessel 34 for holding a solution of aripiprazole in ethanol, preferably 95% ethanol, which is pumped via pump 36 through polish filter 38 and sterile filter 40 into vessel 12 and processed as described above.
- the jet nozzles 16 , 18 should be placed so that the fluid streams they emit will impinge, inside the stirred impingement vessel 10 or inside a separate jet chamber (not shown) which is linked directly to the vessel 10 .
- the fluid jets must impinge to create an immediate high turbulence impact.
- the two jet nozzles are preferably arranged so that they are substantially diametrically opposed to each other with their outlet tips directed to face each other; i.e., the two jet nozzles are at or close to a 180 degree angle to each other from an overhead view.
- each jet outlet nozzle can have a slight downward angle from the horizontal, for example, about 10 degrees, to help the flowing material move down and out of the chamber.
- each jet nozzle placed directly inside the stirred impingement vessel 10 are preferably arranged so that they are substantially diametrically opposed to each other with their outlet tips directed to face each other.
- each nozzle can have a slight upward or downward angle from the horizontal of from 0 degrees up to about 15 degrees, but preferably the two nozzles have just enough downward angle from the horizontal (ca. 13 degrees) to ensure that the fluid stream of one will not enter the outlet hole of the opposite nozzle.
- Jet nozzle 16 is used to transport aripiprazole solution into the vessel 10 (or separate jet chamber) and the other jet 18 is used to similarly transport water.
- the distance between the nozzle tips inside the jet chamber or vessel 10 should be such that the hydro-dynamic form of each fluid jet stream remains essentially intact up to the point of impingement. Therefore, the maximum distance between the nozzle tips will vary depending on the linear velocity of the fluids inside the jet nozzles.
- linear velocity in the jet nozzles should be at least about 5 meters/sec., more preferably above 10 meters/sec., and most preferably between about 20 to 25 meters/sec., although the upper limit of linear velocity is only limited by the practical difficulties involved in achieving it.
- Linear velocity and flow rate can both be controlled by various known methods, such as altering the diameter of the entry tube and/or that of the nozzle outlet tip, and/or varying the strength of the external force that moves the fluid into and through the nozzle.
- Each jet apparatus can be manipulated independently to attain a desired final fluid composition ratio.
- the desired flow ratio of one jet to the other differs from unity, preferably the difference is compensated for by appropriate sizing of the entry tubes. For example, if a 4:1 volumetric ratio of feed solution to anti-solvent is desired, the entry tube delivering feed solution should be twice the diameter of the entry tube delivering anti-solvent.
- residence time for the fluid inside the jet chamber is typically very short, i.e., less than ten seconds.
- Stirring in the vessel is provided by standard agitators 11 , preferably Rushton 10 turbines, Intermig impellers, or other agitators suitable for stirring a slurry suspension. Any impeller providing good circulation inside the vessel may be used. However, when the jet streams are arranged to impinge directly inside the stirred vessel, an agitator that does not interfere with the space occupied by the impinging jet streams inside the vessel is preferred, especially, e.g., a Rushton turbine.
- Impinging jet streams inside the vessel are most preferably placed in the effluent stream of the agitator, and the height of the liquid in the stirred vessel 10 when operated in continuous mode (i.e., flow in equals flow out, constant volume maintained), is most preferably between about two to four times the height of the impeller.
- the crystallization is preferably run in a continuous process and the appropriate residence time for the completion of crystal digestion is attained by adjusting the volume capacity of the stirred vessel, but the mixture can be held up in the vessel for any desired length of age time if batchwise processing is desired.
- Manual seeding can be done at any point in the system, e.g., in the stirred vessel 10 , the transfer line or the jet chamber itself.
- the continuous jet process may be “self-seeding”, i.e., the first crystals to form inside the jet chamber (if used), the transfer line (if used) or the stirred vessel 10 serve as seed for the material that flows through thereafter.
- micromixed material must be highly supersaturated to attain the beneficial results of the jet crystallization process. Aside from thermoregulated initiation of nucleation, temperature variation also affects product results when anti-solvent is used to initiate nucleation because of its effect on supersaturation. Generally, good results can be achieved using a volumetric ratio of aripiprazole to anti-solvent that provides a high degree of supersaturation in the jet chamber in a temperature range of about 24° C. to 70° C., although the temperature upper limit is limited only by the chosen solvent's boiling point.
- a 100 grams of aripiprazole anhydrous N 1 is charged into a 4-L vessel 12 and dissolved in 2 L of 95% ethanol at 75 to 80° C. The clear solution is then transferred to the product-rich 2-L jacketed vessel 10 and maintained at 75 to 80° C. In the anti-solvent vessel 14 , 2 L of deionized (DI) water is then charged and heated to 28 to 32° C.
- DI deionized
- the two streams are pumped simultaneously via pumps 20 and 22 through mass flow meters 24 , 26 , respectively, and sterile filters 28 , 30 , respectively, through the 0.02-inch internal diameter nozzles 16 , 18 and impinge at a rate of 0.22 to 0.28 kg/min to produce the monohydrate crystals.
- the crystals are continuously transferred to receiving vessel 32 to maintain a constant volume in the impingement vessel 10 . It takes approximately 5 to 7 minutes to impinge a 100-gram batch.
- the slurry is cooled to 20 to 25° C., filtered, and washed with 200 mL of deionized water. The cake is then dried at 35° C. under vacuum to obtain approximately 100 grams of aripiprazole monohydrate, H0, with a Karl Fisher % (KF%) of ca. 4% w/w.
- Sterile bulk API aripiprazole was prepared using impinging jet crystallization and an apparatus set up as shown in the accompanying figure.
- polish filter the aripiprazole solution into a holding vessel 12 and maintain at 80° C.
- An aripiprazole injectable aqueous suspension (200 mg aripiprazole/2 mL, 200 mg/vial) was prepared as follows.
- Aripiprazole prepared by impinging jet 100 g crystallization as described in Example 2: Carboxymethylcellulose, Sodium Salt 7L2P 9.0 g Mannitol 45 g Sodium Phosphate, Monobasic 0.8 g Sodium Hydroxide Solution, 1N q.s. to adjust pH to 7.0 Water, USP q.s. to 1000 g
- the sterile suspension was mixed at 500-1000 rpm for about 0.5 hour and then at 300-500 rpm for an additional 1 hour under 20 ′′Hg (+5′′Hg) vacuum.
- thermal treatment freeze product at ⁇ 40° C. over 0.1-1 h and keep at ⁇ 40° C. for at least 6 h,
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Crystallography & Structural Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Thermal Sciences (AREA)
- Physics & Mathematics (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
- Medicinal Preparation (AREA)
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/968,481 US20050152981A1 (en) | 2003-10-23 | 2004-10-19 | Process for making sterile aripiprazole of desired mean particle size |
US13/046,138 US20110166352A1 (en) | 2003-10-23 | 2011-03-11 | Process for making sterile aripiprazole of desired mean particle size |
US13/771,691 US9066848B2 (en) | 2003-10-23 | 2013-02-20 | Process for making sterile aripiprazole of desired mean particle size |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US51388603P | 2003-10-23 | 2003-10-23 | |
US10/968,481 US20050152981A1 (en) | 2003-10-23 | 2004-10-19 | Process for making sterile aripiprazole of desired mean particle size |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/046,138 Continuation US20110166352A1 (en) | 2003-10-23 | 2011-03-11 | Process for making sterile aripiprazole of desired mean particle size |
Publications (1)
Publication Number | Publication Date |
---|---|
US20050152981A1 true US20050152981A1 (en) | 2005-07-14 |
Family
ID=34549310
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/968,481 Abandoned US20050152981A1 (en) | 2003-10-23 | 2004-10-19 | Process for making sterile aripiprazole of desired mean particle size |
US13/046,138 Abandoned US20110166352A1 (en) | 2003-10-23 | 2011-03-11 | Process for making sterile aripiprazole of desired mean particle size |
US13/771,691 Active US9066848B2 (en) | 2003-10-23 | 2013-02-20 | Process for making sterile aripiprazole of desired mean particle size |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/046,138 Abandoned US20110166352A1 (en) | 2003-10-23 | 2011-03-11 | Process for making sterile aripiprazole of desired mean particle size |
US13/771,691 Active US9066848B2 (en) | 2003-10-23 | 2013-02-20 | Process for making sterile aripiprazole of desired mean particle size |
Country Status (16)
Country | Link |
---|---|
US (3) | US20050152981A1 (ko) |
EP (1) | EP1675593B1 (ko) |
JP (1) | JP4875984B2 (ko) |
KR (1) | KR101121345B1 (ko) |
CN (1) | CN1871007A (ko) |
AR (1) | AR046142A1 (ko) |
AU (1) | AU2004284904B2 (ko) |
BR (1) | BRPI0415754A (ko) |
CA (1) | CA2543248C (ko) |
CO (1) | CO5670354A2 (ko) |
ES (1) | ES2632499T3 (ko) |
IL (1) | IL175008A (ko) |
MX (1) | MXPA06004333A (ko) |
PE (1) | PE20050810A1 (ko) |
TW (1) | TWI371274B (ko) |
WO (1) | WO2005041970A1 (ko) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050203299A1 (en) * | 2003-12-16 | 2005-09-15 | Judith Aronhime | Methods of preparing aripiprazole crystalline forms |
US20050215791A1 (en) * | 2004-02-05 | 2005-09-29 | Ben-Zion Dolitzky | Process for preparing aripiprazole |
US20070116729A1 (en) * | 2005-11-18 | 2007-05-24 | Palepu Nageswara R | Lyophilization process and products obtained thereby |
US20070148100A1 (en) * | 2005-09-15 | 2007-06-28 | Elan Pharma International, Limited | Nanoparticulate aripiprazole formulations |
US20070161794A1 (en) * | 2003-12-16 | 2007-07-12 | Hagit Eisen-Nevo | Methods of preparing anhydrous aripiprazole form II |
US20070272777A1 (en) * | 2005-12-22 | 2007-11-29 | Guy Samburski | Processes for reducing particle size of aripiprazole |
WO2008051541A3 (en) * | 2006-10-24 | 2008-06-19 | Cambrex Charles City Inc | Process for preparing anhydrous aripirazole type i |
WO2012102216A1 (en) * | 2011-01-24 | 2012-08-02 | Otsuka Pharmaceutical Co., Ltd. | Medical device containing a cake composition comprising aripiprazole as an active ingredient, and a cake composition comprising aripiprazole as an active ingredient |
US20140112993A1 (en) * | 2011-06-07 | 2014-04-24 | Shogo Hiraoka | Freeze-dried aripiprazole formulation |
US9156015B2 (en) | 2009-04-09 | 2015-10-13 | Beijing Univesity Of Chemical Technology | Microchannel double pipe device and usage thereof |
US9241876B2 (en) | 2011-06-27 | 2016-01-26 | Shanghai Zhongxi Pharmaceutical Corporation | Aripiprazole medicament formulation and preparation method therefor |
US9469630B2 (en) | 2010-10-18 | 2016-10-18 | Sumitomo Dainippon Pharma Co., Ltd. | Sustained-release formulation for injection |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7507823B2 (en) * | 2004-05-06 | 2009-03-24 | Bristol-Myers Squibb Company | Process of making aripiprazole particles |
EP1812397A1 (en) * | 2004-11-18 | 2007-08-01 | Synthon B.V. | Process of making crystalline aripiprazole |
US8420122B2 (en) | 2006-04-28 | 2013-04-16 | Merck Sharp & Dohme Corp. | Process for the precipitation and isolation of 6,6-dimethyl-3-aza-bicyclo [3.1.0] hexane-amide compounds by controlled precipitation and pharmaceutical formulations containing same |
SG172690A1 (en) * | 2006-04-28 | 2011-07-28 | Schering Corp | Process for the precipitation and isolation of 6,6-dimethyl-3-aza-bicyclo [3.1.0] hexane-amide compounds by controlled precipitation and pharmaceutical formulations containing same |
CN101172966B (zh) * | 2007-04-06 | 2012-08-29 | 重庆医药工业研究院有限责任公司 | 一种阿立哌唑微晶的制备方法 |
PL2170279T3 (pl) | 2007-07-31 | 2018-05-30 | Otsuka Pharmaceutical Co., Ltd. | Sposoby wytwarzania zawiesiny arypiprazolu i liofilizowanej formulacji |
GB0909154D0 (en) * | 2008-09-25 | 2009-07-08 | Nanomaterials Tech Pte Ltd | A process for making particles for delivery of drug nanoparticles |
DE102009008478A1 (de) * | 2009-02-11 | 2010-08-19 | PHAST Gesellschaft für pharmazeutische Qualitätsstandards mbH | Vorrichtung und Verfahren zur Herstellung pharmazeutisch hochfeiner Partikel sowie zur Beschichtung solcher Partikel in Mikroreaktoren |
PT2550092T (pt) * | 2010-03-22 | 2018-11-13 | Instillo Gmbh | Método para produção de micro ou nanopartículas |
CN101816913B (zh) * | 2010-05-20 | 2015-10-21 | 吴传斌 | 一种微球制造方法及制造设备 |
MX344235B (es) | 2010-08-24 | 2016-12-07 | Otsuka Pharmaceutical Co Ltd * | Suspension y composicion en torta que contiene un derivado de carbostirilo y aceite de silicona y/o un derivado de aceite de silicona. |
CN102850268B (zh) | 2011-06-27 | 2015-07-15 | 上海中西制药有限公司 | 阿立哌唑ⅰ型微晶、阿立哌唑固体制剂及制备方法 |
JOP20200109A1 (ar) | 2012-04-23 | 2017-06-16 | Otsuka Pharma Co Ltd | مستحضر قابل للحقن |
US9732068B1 (en) * | 2013-03-15 | 2017-08-15 | GenSyn Technologies, Inc. | System for crystalizing chemical compounds and methodologies for utilizing the same |
AR096131A1 (es) | 2013-04-30 | 2015-12-09 | Otsuka Pharma Co Ltd | Preparado oral sólido que comprende aripiprazol y un método para producir un preparado oral sólido que comprende aripiprazol |
CA2959329C (en) * | 2014-08-25 | 2023-06-27 | Alkermes Pharma Ireland Limited | Crystallization process of aripiprazole derivatives in extended release formulations for treatment of schizophrenia |
CN107683131B (zh) * | 2015-06-04 | 2021-09-28 | 克里蒂泰克公司 | 紫杉烷颗粒及其用途 |
EP3490529A1 (en) | 2016-07-28 | 2019-06-05 | Mylan Laboratories Ltd. | Process for preparing sterile aripiprazole formulation |
CN111346397B (zh) * | 2020-03-11 | 2022-03-29 | 天津大学 | 适用于溶析结晶或反应结晶的加料设备 |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5006528A (en) * | 1988-10-31 | 1991-04-09 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
US5314506A (en) * | 1990-06-15 | 1994-05-24 | Merck & Co., Inc. | Crystallization method to improve crystal structure and size |
US6267989B1 (en) * | 1999-03-08 | 2001-07-31 | Klan Pharma International Ltd. | Methods for preventing crystal growth and particle aggregation in nanoparticulate compositions |
US6302958B1 (en) * | 1999-01-29 | 2001-10-16 | Bristol-Myers Squibb Company | Sonic impinging jet crystallization apparatus and process |
US6558435B2 (en) * | 2000-05-26 | 2003-05-06 | Pfizer, Inc. | Reactive crystallization method to improve particle size |
US20040058935A1 (en) * | 2001-09-25 | 2004-03-25 | Takuji Bando | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US20050032811A1 (en) * | 2003-08-06 | 2005-02-10 | Josiah Brown | Methods for administering aripiprazole |
US20050159429A1 (en) * | 2003-03-21 | 2005-07-21 | Hetero Drugs Limited | Novel crystalline forms of aripiprazole |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1649655A (zh) * | 2002-04-29 | 2005-08-03 | 布里斯托尔-迈尔斯斯奎布公司 | 雾化结晶系统 |
CN1652852A (zh) * | 2002-05-10 | 2005-08-10 | 布里斯托尔-迈尔斯斯奎布公司 | 使用均化作用的结晶系统 |
-
2004
- 2004-10-18 TW TW093131588A patent/TWI371274B/zh active
- 2004-10-19 US US10/968,481 patent/US20050152981A1/en not_active Abandoned
- 2004-10-20 BR BRPI0415754-0A patent/BRPI0415754A/pt not_active IP Right Cessation
- 2004-10-20 CN CNA2004800313867A patent/CN1871007A/zh active Pending
- 2004-10-20 WO PCT/US2004/034634 patent/WO2005041970A1/en active Application Filing
- 2004-10-20 MX MXPA06004333A patent/MXPA06004333A/es active IP Right Grant
- 2004-10-20 EP EP04795750.1A patent/EP1675593B1/en active Active
- 2004-10-20 CA CA2543248A patent/CA2543248C/en active Active
- 2004-10-20 JP JP2006536732A patent/JP4875984B2/ja active Active
- 2004-10-20 AU AU2004284904A patent/AU2004284904B2/en active Active
- 2004-10-20 ES ES04795750.1T patent/ES2632499T3/es active Active
- 2004-10-22 AR ARP040103850A patent/AR046142A1/es unknown
- 2004-10-25 PE PE2004001020A patent/PE20050810A1/es not_active Application Discontinuation
-
2006
- 2006-04-20 IL IL175008A patent/IL175008A/en active IP Right Grant
- 2006-04-21 KR KR1020067007687A patent/KR101121345B1/ko active IP Right Grant
- 2006-04-24 CO CO06038472A patent/CO5670354A2/es not_active Application Discontinuation
-
2011
- 2011-03-11 US US13/046,138 patent/US20110166352A1/en not_active Abandoned
-
2013
- 2013-02-20 US US13/771,691 patent/US9066848B2/en active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5006528A (en) * | 1988-10-31 | 1991-04-09 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
US5314506A (en) * | 1990-06-15 | 1994-05-24 | Merck & Co., Inc. | Crystallization method to improve crystal structure and size |
US6302958B1 (en) * | 1999-01-29 | 2001-10-16 | Bristol-Myers Squibb Company | Sonic impinging jet crystallization apparatus and process |
US6267989B1 (en) * | 1999-03-08 | 2001-07-31 | Klan Pharma International Ltd. | Methods for preventing crystal growth and particle aggregation in nanoparticulate compositions |
US6558435B2 (en) * | 2000-05-26 | 2003-05-06 | Pfizer, Inc. | Reactive crystallization method to improve particle size |
US20040058935A1 (en) * | 2001-09-25 | 2004-03-25 | Takuji Bando | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US20050159429A1 (en) * | 2003-03-21 | 2005-07-21 | Hetero Drugs Limited | Novel crystalline forms of aripiprazole |
US20050032811A1 (en) * | 2003-08-06 | 2005-02-10 | Josiah Brown | Methods for administering aripiprazole |
Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7504504B2 (en) | 2003-12-16 | 2009-03-17 | Teva Pharmaceutical Industries Ltd. | Methods of preparing aripiprazole crystalline forms |
US20050203299A1 (en) * | 2003-12-16 | 2005-09-15 | Judith Aronhime | Methods of preparing aripiprazole crystalline forms |
US20070161794A1 (en) * | 2003-12-16 | 2007-07-12 | Hagit Eisen-Nevo | Methods of preparing anhydrous aripiprazole form II |
US7714129B2 (en) | 2003-12-16 | 2010-05-11 | Teva Pharmaceutical Industries Ltd. | Methods of preparing anhydrous aripiprazole form II |
US20090156813A1 (en) * | 2003-12-16 | 2009-06-18 | Judith Aronhime | Methods of preparing aripiprazole crystalline forms |
US20050215791A1 (en) * | 2004-02-05 | 2005-09-29 | Ben-Zion Dolitzky | Process for preparing aripiprazole |
US20070148100A1 (en) * | 2005-09-15 | 2007-06-28 | Elan Pharma International, Limited | Nanoparticulate aripiprazole formulations |
US8158152B2 (en) | 2005-11-18 | 2012-04-17 | Scidose Llc | Lyophilization process and products obtained thereby |
US20070116729A1 (en) * | 2005-11-18 | 2007-05-24 | Palepu Nageswara R | Lyophilization process and products obtained thereby |
US20070272777A1 (en) * | 2005-12-22 | 2007-11-29 | Guy Samburski | Processes for reducing particle size of aripiprazole |
WO2008051541A3 (en) * | 2006-10-24 | 2008-06-19 | Cambrex Charles City Inc | Process for preparing anhydrous aripirazole type i |
EP2079723A2 (en) * | 2006-10-24 | 2009-07-22 | Cambrex Charles City, Inc. | Process for preparing anhydrous aripirazole type i |
US20100317857A1 (en) * | 2006-10-24 | 2010-12-16 | Cambrex Charles City, Inc. | Process for preparing anhydrous aripirazole type i |
EP2079723A4 (en) * | 2006-10-24 | 2011-04-13 | Cambrex Charles City Inc | PROCESS FOR THE PREPARATION OF TYPE I ANHYDROUS ARIPIRAZOLE |
US8039621B2 (en) | 2006-10-24 | 2011-10-18 | Cambrex Charles City, Inc. | Process for preparing anhydrous Aripirazole type I |
US9156015B2 (en) | 2009-04-09 | 2015-10-13 | Beijing Univesity Of Chemical Technology | Microchannel double pipe device and usage thereof |
US9469630B2 (en) | 2010-10-18 | 2016-10-18 | Sumitomo Dainippon Pharma Co., Ltd. | Sustained-release formulation for injection |
CN103327968A (zh) * | 2011-01-24 | 2013-09-25 | 大塚制药株式会社 | 含有以阿立哌唑作为有效成分的块状组合物的医疗用器具、及以阿立哌唑作为有效成分的块状组合物 |
WO2012102216A1 (en) * | 2011-01-24 | 2012-08-02 | Otsuka Pharmaceutical Co., Ltd. | Medical device containing a cake composition comprising aripiprazole as an active ingredient, and a cake composition comprising aripiprazole as an active ingredient |
CN105125509A (zh) * | 2011-01-24 | 2015-12-09 | 大塚制药株式会社 | 以阿立哌唑作为有效成分的块状组合物 |
AU2012209853B2 (en) * | 2011-01-24 | 2016-06-16 | Otsuka Pharmaceutical Co., Ltd. | Medical device containing a cake composition comprising aripiprazole as an active ingredient, and a cake composition comprising aripiprazole as an active ingredient |
EA024814B1 (ru) * | 2011-01-24 | 2016-10-31 | Оцука Фармасьютикал Ко., Лтд. | Медицинское устройство, содержащее композицию сухого остатка, содержащую арипипразол в качестве активного ингредиента, и композиция сухого остатка, содержащая арипипразол в качестве активного ингредиента |
CN105125509B (zh) * | 2011-01-24 | 2019-01-11 | 大塚制药株式会社 | 以阿立哌唑作为有效成分的块状组合物 |
EP2667856B1 (en) | 2011-01-24 | 2021-07-28 | Otsuka Pharmaceutical Co., Ltd. | Medical device containing a cake composition comprising aripiprazole as an active ingredient, and a cake composition comprising aripiprazole as an active ingredient |
US11648347B2 (en) | 2011-01-24 | 2023-05-16 | Otsuka Pharmaceutical Co., Ltd. | Medical device containing a cake composition comprising aripiprazole as an active ingredient, and a cake composition comprising aripiprazole as an active ingredient |
US20140112993A1 (en) * | 2011-06-07 | 2014-04-24 | Shogo Hiraoka | Freeze-dried aripiprazole formulation |
US11154507B2 (en) * | 2011-06-07 | 2021-10-26 | Otsuka Pharmaceutical Co., Ltd. | Freeze-dried aripiprazole formulation |
US9241876B2 (en) | 2011-06-27 | 2016-01-26 | Shanghai Zhongxi Pharmaceutical Corporation | Aripiprazole medicament formulation and preparation method therefor |
Also Published As
Publication number | Publication date |
---|---|
CO5670354A2 (es) | 2006-08-31 |
EP1675593B1 (en) | 2017-05-31 |
US20130161848A1 (en) | 2013-06-27 |
US9066848B2 (en) | 2015-06-30 |
JP4875984B2 (ja) | 2012-02-15 |
AU2004284904A1 (en) | 2005-05-12 |
TWI371274B (en) | 2012-09-01 |
TW200518783A (en) | 2005-06-16 |
EP1675593A4 (en) | 2007-04-25 |
AR046142A1 (es) | 2005-11-23 |
IL175008A0 (en) | 2006-08-20 |
MXPA06004333A (es) | 2006-06-05 |
EP1675593A1 (en) | 2006-07-05 |
CA2543248C (en) | 2013-04-02 |
CA2543248A1 (en) | 2005-05-12 |
US20110166352A1 (en) | 2011-07-07 |
PE20050810A1 (es) | 2005-09-25 |
KR20070090070A (ko) | 2007-09-05 |
BRPI0415754A (pt) | 2006-12-19 |
AU2004284904B2 (en) | 2010-05-20 |
ES2632499T3 (es) | 2017-09-13 |
JP2007509153A (ja) | 2007-04-12 |
CN1871007A (zh) | 2006-11-29 |
WO2005041970A1 (en) | 2005-05-12 |
IL175008A (en) | 2014-11-30 |
KR101121345B1 (ko) | 2012-03-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9066848B2 (en) | Process for making sterile aripiprazole of desired mean particle size | |
US5314506A (en) | Crystallization method to improve crystal structure and size | |
EP1173265B1 (en) | Sonic impinging jet crystallization apparatus and process | |
US6558435B2 (en) | Reactive crystallization method to improve particle size | |
AU2016240294B2 (en) | Continuous production of particles | |
US20060160841A1 (en) | Crystallization via high-shear transformation | |
EP1619198B1 (en) | Process for the preparation of amorphous cefuroxime axetil | |
WO2003035673A9 (en) | Supercritical fluids processing: preparation of protein microparticles and their stabilisation | |
CN105031963B (zh) | 一种集成反溶剂-真空蒸发-冷却或反溶剂的结晶方法 | |
US20040098839A1 (en) | Crystallization method and apparatus using an impinging plate assembly | |
CN109438372A (zh) | 一种甲基吡嗪衍生物甲醇合物 | |
CN115944742A (zh) | 一种用于制备纳米药物的离子液体及其制备方法和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: BRISTOL-MYERS SQUIBB COMPANY, NEW JERSEY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GLEESON, MARGARET M.;KIM, SOOJIN;KIENTZLER, DONALD C.;AND OTHERS;REEL/FRAME:015957/0064;SIGNING DATES FROM 20050303 TO 20050321 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |