ZA200301200B - Preparation of risperidone. - Google Patents
Preparation of risperidone. Download PDFInfo
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- ZA200301200B ZA200301200B ZA200301200A ZA200301200A ZA200301200B ZA 200301200 B ZA200301200 B ZA 200301200B ZA 200301200 A ZA200301200 A ZA 200301200A ZA 200301200 A ZA200301200 A ZA 200301200A ZA 200301200 B ZA200301200 B ZA 200301200B
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- ZA
- South Africa
- Prior art keywords
- risperidone
- isopropanol
- butanol
- risperidone form
- solvent
- Prior art date
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- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 title claims description 213
- 229960001534 risperidone Drugs 0.000 title claims description 211
- 238000002360 preparation method Methods 0.000 title description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 74
- 238000000034 method Methods 0.000 claims description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 46
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 39
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 35
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 29
- 238000001556 precipitation Methods 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 22
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 238000010438 heat treatment Methods 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 10
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 150000002576 ketones Chemical class 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 150000003462 sulfoxides Chemical class 0.000 claims 1
- 239000000243 solution Substances 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 12
- 239000006185 dispersion Substances 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- -1 for example Chemical compound 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 5
- CMWCQQUYLPYOMY-UHFFFAOYSA-N 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound C1CCCN2C(=O)C(CCCl)=C(C)N=C21 CMWCQQUYLPYOMY-UHFFFAOYSA-N 0.000 description 5
- MRMGJMGHPJZSAE-UHFFFAOYSA-N 6-fluoro-3-piperidin-4-yl-1,2-benzoxazole Chemical compound N=1OC2=CC(F)=CC=C2C=1C1CCNCC1 MRMGJMGHPJZSAE-UHFFFAOYSA-N 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical class [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 102100025490 Slit homolog 1 protein Human genes 0.000 description 1
- 101710123186 Slit homolog 1 protein Proteins 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 150000008316 benzisoxazoles Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000001144 powder X-ray diffraction data Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229940106887 risperdal Drugs 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Description
PREPARATION OF RISPERIDONE
4 CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of provisional application serial number 60/225,361, filed August 14, 2000; and provisional application serial number 60/243,263, filed October 25, 2000. Both of these applications are incorporated herein by reference.
The present invention relates to novel polymorphic forms of risperidone. The present invention also relates to methods of making polymorphic forms of risperidone.
RISPERDAL® (risperidone) is an antipsychotic agent belonging to a new chemical class, the benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2- benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4 H -pyrido[1,2- alpyrimidin-4-one.
U.S. Patent No. 4,804,663, the contents of which are incorporated by reference, describes a synthesis of risperidone. Risperidone may be prepared by condensation of the following two intermediates, 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (Compound I) and 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyridof1,2-a]pyrimidin-4-one (Compound II) in dimethylformamide (DMF) in basic conditions (Na,CO, or K,CO,) with catalytic amount of potassium iodide (KI). The crude risperidone product (Il) is crystallized from a mixture of DMF and isopropanol with an overall yield of 46 %. 0 N—0O a on OL ATO . HN. p K200;, KI, DMF, 12hrs, stirring CH, a at 85-90°C 6 oro. 3-Cpesidin- + ehloroeths)-6 8 teahycro a 1,2-benzisoxazole methy!-4H-pyrido[1,2-a]pyrimidin-4-one
Polymorphism is the occurrence of different crystalline forms of a single } compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct : physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. For a general review of polymorphs and the pharmaceutical applications of polymorphs see G.M. Wall, Pharm Manuf. 3, 33 (1986); J.X. Haleblian and W. McCrone, J. Pharm. Sci., 58, 911 (1969); and JK. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference.
An object of the processes of the present invention is to provide more efficient and quicker methods for making pure risperidone. We have now found that the synthesis of risperidone from compounds I'and II can done in acetonitrile and isopropanol, without using DMF, to give an improved and higher yield of about 75%.
The present invention provides a process for the preparation of risperidone from the following two intermediates, 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (Compound
I) and 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (Compound II) in acetonitrile.
It has also been found that the crude risperidone can be efficiently crystallized in . high yield from an alcohol, for example, isopropanol, butanol, ethanol, or methanol; or from a ketone, for example, acetone or ethyl methyl ketone, without the need of using
DMF, which is harmful to humans and is a very difficult solvent to remove.
Polymorphs of risperidone are mentioned in the Summary Basis of Approval (SBA) of New Drug Application 20-272 and 20-588, however the SBA does not identify : them by recognized methods of crystal structure identification such as x-ray diffraction.
The present invention also provides forms of risperidone designated risperidone
Form A, Form B and Form E.
The present invention further provides a process for making risperidone comprising reacting Compound I with Compound II to form crude risperidone (IIT) in a solvent selected from the group consisting of acetonitrile, isopropanol, methyl ethyl ketone and iso-butanol.
In another embodiment, the crude risperidone is recrystallized from an alcohol; a mixture of alcohols; a mixture of water and alcohol; or from a ketone, e.g., acetone. In another embodiment, the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, propanol, butanol, sec-butanol, iso-butanol and z-butanol. In another embodiment, the alcohol is isopropanol. In another embodiment, the alcohol is acetonitrile. In another embodiment, the alcohol is isopropanol. In another embodiment, the alcohol is iso-butanol. In another embodiment, the ketone is acetone. In another embodiment, the acetone is methyl ethyl ketone.
The present invention also provides risperidone Form A which is characterized by x-ray powder diffraction peaks at 14.2+0.2, 21.3+0.2 degrees two-theta. The present invention also provides risperidone Form A of further characterized by x-ray powder diffraction peaks at 10.6+0.2, 11.4+0.2, 16.4+0.2, 18.940.2, 19.9+0.2, 22.5+0.2, 23.3+0.2, 25.4+0.2, 27.62:0.2, 29.0+0.2 degrees two-theta.
The present invention also provides a risperidone polymorph that is characterized by a powder x-ray diffraction pattern substantially as depicted in Figure 1.
The present invention also provides risperidone Form B which is characterized by x-ray powder diffraction peaks at 14.0+:0.2 and 21.7+0.2 degrees two-theta. ' The present invention also provides a risperidone polymorph that is characterized by a powder x-ray diffraction pattern substantially as depicted in Figure 2.
The present invention also provides risperidone Form B which is further characterized by x-ray powder diffraction peaks at 10.8+0.2, 11.9+0.2, 12.6+0.2,
14.0+£0.2, 17.5+0.2, 18.3=0.2, 19.9+0.2, 21.0+0.2, 21.7+0.2 degrees two-theta.
The present invention also provides risperidone Form E which is characterized by : x-ray powder diffraction peaks at 16.5+0.2, 21.7+0.2degrees two-theta.
The present invention also provides risperidone Form E which is further characterized by x-ray powder diffraction peaks at 16.5+0.2, 12.6+0.2, 21 TJx0.2, 15.6+0.2, 17.0+0.2, 18.4+0.2, 19.1+0.2, 21.3+0.2, 24.0+0.2, 24.9+0.2, 27.0+0.2 degrees two-theta.
The present invention also provides a risperidone polymorph that is characterized by a powder x-ray diffraction pattern substantially as depicted in Figure 3.
The present invention also provides a process for preparing risperidone Form B comprising the steps of: dissolving risperidone in a substantially water soluble alcohol having 1 to 4 carbon atoms where the ratio of risperidone to alcohol is about 1:7.5 to about 1:9; adding water to facilitate precipitation; and isolating risperidone Form B.
The present invention also provides a process for preparing risperidone Form B comprising the steps of: dissolving risperidone in chloroform; adding cyclohexane or hexane to facilitate precipitation; and isolating risperidone Form B.
The present invention also provides a process for preparing risperidone Form B comprising the steps of: dissolving risperidone in an aqueous solution of HCI; adding an aqueous solution of Na,COs; and isolating risperidone Form B.
The present invention also provides a process for preparing risperidone Form A comprising the steps of: dissolving risperidone in an organic solvent selected from the group consisting of dimethylformamide, tetrahydrofuran, acetone, benzene, ethyl methyl ketone, n-butanol, methanol, isopropanol, absolute ethanol, acetonitrile, toluene, dimethyl sulfoxide, iso-butanol, and ethyl acetate or mixtures thereof; heating the solvent to reflux; cooling the solvent to facilitate precipitation; and isolating risperidone Form A.
The present invention also provides a process for preparing risperidone Form A comprising the steps of: dissolving risperidone in dichloromethane; adding cyclohexane or hexane to facilitate precipitation; and isolating risperidone Form A.
The present invention also provides a method for preparing risperidone Form A comprising the step of: heating risperidone Form B at a temperature of about 25°C to about 80°C for a time sufficient to induce to formation of risperidone Form A; and isolating risperidone Form A. In another embodiment, the heating takes place under - reduced pressure or at atmospheric pressure. In another embodiment, the temperature is about 80°C. In another embodiment, the time for heating is about 16 to about 20 hours.
The present invention also provides a process for preparing risperidone Form E comprising the steps of: dissolving risperidone in isopropanol where the ratio of risperidone to isopropanol is about 1:12; adding water to facilitate precipitation; and isolating risperidone Form E.
Figure 1 is a characteristic x-ray powder diffraction spectrum of risperidone Form A.
Figure 2 is a characteristic x-ray powder diffraction spectrum of risperidone Form B.
Figure 3 is a characteristic x-ray powder diffraction spectrum of risperidone Form E.
Synthesis of Risperidone
The present invention provides new processes for preparing risperidone from the following two intermediates, 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (I) and 3-(2- chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (II) using acetonitrile, isopropanol, iso-butanol, or methyl ethyl ketone as the solvent, which eliminates the need to use DMF as a solvent. By the methods of the present invention, risperidone is prepared by adding , 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H- pyrido[1,2-a]pyrimidin-4-one (Compound II or "the chlorine derivative"); 6-fluoro-3-(4- piperidinyl)-1,2-benzisoxazole (Compound I or "the piperidine derivative"); sodium carbonate; and potassium 1odide (66 mg) into a flask containing the solvent isopropanol, acetonitrile, methyl ethyl ketone or iso-butanol. Preferably, the Compound I and ‘ Compound II are present in a ratio of about 1:1. The reaction mixture is then heated by methods known in the art, such as, by placing the flask in an oil bath which is heated from about 60°C to about 85°C, and the reaction is allowed to reflux for a time sufficient to complete the formation of risperidone, about 9 hours to overnight. Preferably, the reaction mixture is heated to about 60°C to about 67°C. Preferably the reaction is heated for about 9 hours when the solvent is isopropanol. Preferably the reaction mixture is : heated overnight when the solvent is methyl ethyl ketone or iso-butanol. Preferably the reaction is heated for about 17 hours when the solvent is acetonitrile. Upon completion of the reaction, the mixture is cooled by methods known in the art to induce the precipitation of risperidone.
The resulting precipitated risperidone is filtered and the filter cake is washed in the filter with a small amount of isopropanol, acetone or a mixture of acetone and water. The filter cake is then slurried, filtered and easily dried by conventional methods to give crude risperidone in a yield of about 63 to 74 % yield. The present method eliminates the difficult step of removing DMF from the crude risperidone.
The present invention also relates to new processes for recrystallizing crude risperidone from; an alcohol, such as, methanol, ethanol, isopropanol, propanol, butanol, sec-butanol and z-butanol; a mixture of alcohols containing any combination of, methanol, ethanol, isopropanol, propanol, butanol, sec-butanol and #-butanol; or a mixture of water and alcohol where the alcohol is one or more of the following alcohols, methanol, ethanol, isopropanol, propanol, butanol, sec-butanol and z-butanol. The present recrystallization eliminates the use of the difficult to remove and potentially harmful solvent DMF.
Preferably, the solvent is isopropanol. By the methods of the present invention, crude risperidone is recrystallized by dissolving the crude risperidone in a solvent which is hot.
Preferably, the solvent is heated to reflux. Preferably the crude risperidone and solvent are present in a ratio of about 10 to about 15, more preferably the ratio is about 11 to 13, most preferably the ratio is about 11.5 to about 12.5. Preferably the solvent 1s isopropanol. The hot mixture is then filtered hot and allowed to cool where upon purified risperidone precipitates. The mixture is filtered by conventional methods to give high purity risperidone with a purity of about 99.7 to about 99.8 %. The overall yield of the : present method of synthesis and recrystallization of risperidone is about 60 to about 63 %.
The present invention also provides new processes for recrystallizing crude risperidone from a solvent that is a Ketone, such as, acetone. The present recrystallization eliminates the use of the difficult to remove and potentially harmful solvent DMF. ;
Preferably, the solvent is acetone. By the methods of the present invention, crude risperidone is recrystallized by dissolving the crude risperidone in a ketone, which is hot. : Preferably, the ketone is heated to reflux. Preferably the crude risperidone and solvent are present in a ratio of about 25 to about 40, more preferably the ratio is about 28 to about 32. Preferably the solvent is acetone. The hot mixture is then filtered hot and allowed to cool where upon purified risperidone precipitates. The mixture is filtered by conventional methods to give high purity risperidone with a purity of about 99.7 to about 99.8 %. The overall yield of the present method of synthesis and recrystallization of risperidone is about 60 to about 63 %.
Risperidone Form A
The present invention also relates to a novel risperidone crystalline form designated Form A and processes for making risperidone Form A. Risperidone Form A is characterized by unique strong powder x-ray diffraction peaks at 14.2+0.2, and 21.3+0.2 degrees two-theta and medium intensity peaks at 10.6+0.2, 11.4=0.2, 16.4+0.2, 18.9+0.2, 19.9+0.2, 22.5+0.2, 23.3+0.2, 27.6+0.2, 25.4+0.2, and 29.0+0.2 degrees two-theta.
Another aspect of this invention is a method of preparing risperidone Form A. In the method of preparing risperidone Form A, risperidone Form A is crystallized from risperidone at the reflux temperature of an organic solvent, such as, DMF, tetrahydrofuran (THF), acetone, benzene, ethyl methyl ketone, n-butanol, methanol, isopropanol, absolute ethanol, acetonitrile, toluene, dimethyl sulfoxide (DMSO), iso-butanol or ethyl acetate.
By the methods of the present invention, risperidone is added to in a minimum amount of organic solvent by heating the mixture to facilitate dissolution of the risperidone. Upon complete dissolution of the risperidone, the solution is left to cool to room temperature to induce the precipitation of risperidone Form A. After the solution has reached room temperature, it is further cooled in an ice bath and then filtered to isolate risperidone Form
A. Suitable volumes of solvent required for the present methods are listed below in
Example 11 and in Table 1.
Another aspect of this invention is a method of preparing risperidone Form A;ora mixture of risperidone Form A and other forms of risperidone, including risperidone Form
B, by dissolving risperidone in dichloromethane and adding cyclohexane or hexane to induce precipitation. By the methods of the present invention, risperidone is dissolved in dichloromethane in a ratio of about 1 to about 9. Hexane or cyclohexane is then added ) until a cloudy dispersion is formed. The risperidone Form A is then isolated by filtration.
Another aspect of this invention is a method of preparing risperidone Form A by heating risperidone Form B. By the methods of the present invention, risperidone Form A is prepared by heating risperidone Form B, or a mixture of risperidone Form A and B at temperatures above room temperature, preferably at about 80°C, under either reduced pressure or at atmospheric pressure, for a period of several minutes to several hours, preferably 16-20 hours. One embodiment of the present method for preparing risperidone
Form A is heating risperidone Form B, or a mixture of risperidone Form B and risperidone Form A, at 80°C overnight, under reduced pressure or at atmospheric pressure, and isolating the resulting crystals of risperidone Form A. An alternative method of preparing risperidone Form A by heating risperidone Form B includes, heating risperidone Form B in a differential scanning calorimeter, at the rate of 5 to 20 degrees per minute, to yield risperidone Form A.
Risperidone Form B
The present invention also relates to a novel crystalline form of risperidone, denominated risperidone Form B. Risperidone Form B is characterized by unique strong powder x-ray diffraction peaks at 14.0+0.2 and 21 .7+0.2 degrees two-theta, and medium peaks at 10.8+0.2, 11.9+0.2, 12.6+0.2, 17.5+0.2, 18.330.2, 19.9+0.2, 21.0+0.2, 21.3£0.2 degrees two-theta, and is well distinguished from risperidone Form A. The presence of risperidone Form B in a mixture with risperidone Form A is detected by the appearance mainly of the strongest peaks at 21.7+0.2, 17.5+0.2, 18.4+0.2, and also by the other peaks which appear at 11.9+0.2, 12.6+0.2 degrees two theta.
The DSC thermogram of risperidone Form B is characterized by a solid-solid transition to risperidone Form A detected in a small endotherm at 164°C followed by a small exotherm and a melting endotherm of risperidone Form A at 171°C. : Another aspect of this invention is a method of preparing risperidone Form B by dissolving risperidone in an alcohol having 1 to 4 carbon atoms, followed by the addition of water to facilitate the precipitation of risperidone Form B. Preferably the ratio of risperidone to alcohol is about 1:7.5 to about 1:9. Preferably the alcohol 1s ethanol or methanol. : Another aspect of this invention is a method of preparing risperidone Form B pure or in a mixture with another form of risperidone, such as, risperidone Form A, which includes dissolving risperidone in a hot solution of aqueous HCI followed by the addition of aqueous Na,CO; to induce precipitation of risperidone Form B. By the methods of the present invention, risperidone is added to 0.5 N HCl in a ratio of about 1:6. Water is added in an amount equal to about two thirds the volume of HCl used. The solution is heated to induce dissolution of the risperidone. Sodium carbonate is then added until a pH of about 8 is reached, to facilitate precipitation. The solution is cooled and risperidone
Form B is isolated by filtration.
Another aspect of this invention is a method of preparing risperidone Form B pure or in a mixture with another form of risperidone such as risperidone Form A, wherein risperidone is dissolved in chloroform followed by the addition of cyclohexane or hexane to facilitate precipitation. By the methods of the present invention, risperidone 1s dissolved in chloroform in a ratio of about 1:6 followed by the addition of hexane of cyclohexane in an amount sufficient to produce a cloudy dispersion. The risperidone
Form B is then isolated upon filtration.
Risperidone Form E
The present invention also relates to a novel crystalline form of risperidone, denominated risperidone Form E. Risperidone Form E is characterized by typical strong x-ray peaks at 16.5+0.2, 21.7+0.2 degrees two-theta, and medium x-ray peaks at 12.6+0.2, 15.6+0.2, 17.0+0.2, 18.4+0.2, 19.120.2, 21.3+0.2, 24.0+0.2, 24.9+0.2, 27.0+0.2 degrees two-theta
Another aspect of this invention is a method of preparing risperidone Form E. By the methods of the present invention, risperidone is dissolved in isopropanol in a ratio of : about 1 to 12. Water is then added until a cloudy dispersion is formed thereby facilitating the precipitation of risperidone Form E. Risperidone Form E is isolated upon filtration of the dispersion.
In accordance with the present invention, these new forms of risperidone may be prepared as pharmaceutical compositions that are particularly useful for the management of the manifestations of psychotic disorders. Such compositions comprise one of the new . forms of risperidone with pharmaceutically acceptable carriers and/or excipients known to one of skill in the art. : Preferably, these compositions are prepared as medicaments to be administered orally, or intravenously. Suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or gelatin capsules, sub-lingual tablets, syrups and suspensions. While one of ordinary skill in the art will understand that dosages will vary according to the indication, age of the patient, etc., generally polymorphic forms of risperidone of the present invention will be administered at a daily dosage of about 4 to about 16 mg per day, and preferably about 4 to about 8 mg per day.
The present invention will now be further explained in the following examples.
However, the present invention should not be construed as limited thereby.
Methods }
Conditions for obtaining Powder X-ray Diffraction (PXRD) patterns: The powder
X-ray diffraction patterns were obtained by methods known in the art using a Philips X- ray powder diffractometer, Phillips Generator TW 1830; Goniometer PW3020; MPD
Control PW3710; X-Ray tube with Cu target anode; Monochromator proportional counter; Divergence slits 1°, Receiving slit 0.2 mm, Scatter slit 1°; 40KV, 30mA; and
Scanning speed step 0.05 degrees to 2 degrees/min.
The differential scanning calorimeter thermograms were obtained by methods known in the art using a DSC Mettler 821 Star®. The weight of the samples was about 3-5 mg. The temperature range of scans was 30°C-250°C at a rate of 10°C/min. Samples were purged with nitrogen gas at a flow rate of 40 mL/min. Standard 40 pl aluminum crucibles were used having lids with three small holes.
Example 1
Synthesis of Risperidone
Isopropanol (20 mL), 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H- pyrido[1,2-alpyrimidin-4-one (Compound II)("the chlorine derivative")(2.63 g, 10 mmoles, 1 eq.). 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (Compound I){"the piperidine derivative") (2.17 g, 10 mmoles, 1 eq.), sodium carbonate (3.18 g, 30 mmoles, . 3 eq.), and potassium iodide (66 mg) were added to a 100 mL round bottom flask and stirred with a magnetic stir bar. The flask was placed in an oil bath at 80°C and allowed ' to reflux for 9 hours. The flask was then cooled in an ice bath and the contents was filtered. The filter cake was washed in the filter with a small amount of isopropanol. The filter cake was then slurried 3 times in 20 mL of water and filtered. The resulting shurry was dried to give 3 g of material in 73 % yield. The slurry was recrystallized by dissolving in 37 mL of boiling isopropanol, filtered hot and allowed to cool and filtered to give material which had a purity of 99.7 % and an overall yield of 60 %.
Example 2
Synthesis of Risperidone "The same materials and method as in Example 1 with the exception being that methyl ethyl ketone (MEK) (15 mL) was used instead of 20 mL of isopropanol. The flask was put in an oil bath at 79-83 °C overnight, cooled, filtered and washed with acetone and water to give 2.19 g, 53 % yield.
Example 3
Synthesis of Risperidone
The same materials and method as in Example 1 with the exception being that 20 mL of acetonitrile was used instead of 20 mL of isopropanol. The flask was put in an oil bath for 17 hours at 79-83°C, then put in the freezer for 2 hours, filtered, and the filter cake washed with acetone until the filtrate had no color. The filter cake was then slurried in 25 mL water 3 times and filtered and dried to give 3.03 g, 74 % yield, of crude risperidone. The crude risperidone was recrystallized from 35 mL of isopropanol, filtered hot, cooled, filtered and dried to give 2.47g of risperidone, 60 % overall yield, 99.8 % pure by HPLC. : Example 4
Synthesis of Risperidone
The same materials and method as in Example 1 with the exception being that 20 mL of acetonitrile was used instead of 20 mL of isopropanol. The flask was put in an oil bath for 17 hours at 79-83°C, then put in the freezer for 2 hours, filtered, and the filter cake washed with acetone until the filtrate had no color. The filter cake was then slurried in 25 mL water 3 times and filtered and dried to give 3.03 g, 74 % yield, of crude risperidone. The crude risperidone was recrystallized from 75 mL of acetone, filtered hot, cooled, filtered and dried to give 2.25 g of risperidone, 60 % overall yield, 99.9 % pure by
HPLC.
Example 5
Synthesis of Risperidone
The same materials and method as in Example 1 with the exception being that 20 mL of iso-butanol was used instead of 20 mL of isopropanol followed by stirring in an oil bath at 78 °C over night. Risperidone was isolated in 63 % yield.
Example 6
Preparation of Risperidone Form B
Risperidone (5.3 g) was dissolved in chloroform (30 mL). Cyclohexane (280 mL )was slowly added to the solution until a cloudy dispersion was formed. The suspension was filtered. The filtrate, analyzed by PXRD, contained risperidone Form B.
Further heating overnight at 80°C under reduced pressure produced risperidone Form A, which was confirmed by PXRD analysis.
Example 7
Preparation of Risperidone Form B
Risperidone (5.0 g) was dissolved in 30 mL chloroform. Hexane (250 mL) was added to the solution until a cloudy dispersion was formed. The suspension was filtered.
The isolated filtrate, analyzed by PXRD, contained risperidone Form B. Further heating of the filtrate overnight at 80°C under reduced pressure produced risperidone Form A, which was confirmed by PXRD analysis.
Example 8
Preparation of Risperidone Form B
Risperidone (5.3 g) was dissolved in 40 ml ethanol. Water (100 mL) was added to the solution until a cloudy dispersion was formed. The resulting suspension was filtered.
The isolated filtrate, analyzed by PXRD, contained risperidone Form B. Further heating of the filtrate overnight at 80°C, under reduced pressure, produced risperidone Form A, which was confirmed by PXRD analysis. } Example 9
Preparation of Risperidone Form B
Risperidone (5.0 g) was dissolved in methanol (45 mL). Water (70 ml) was added to the solution until a cloudy dispersion was formed. The suspension was filtered. The isolated filtrate, analyzed by PXRD, contained risperidone Form B. Further heating of the filtrate overnight at 80°C, under reduced pressure, produced risperidone Form A, which was confirmed by PXRD analysis.
Example 10
Preparation of Risperidone Form B in Water
Rispendone (6 g) was dissolved at room temperature in 60 mL of 0.5 N HC] and water (40 mL) was added. The solution was heated in a boiling water bath and stirred with a magnetic stir bar. Concentrated aqueous sodium carbonate was added portion-wise to the solution to facilitate precipitation until a pH of approximately 8 was attained. A precipitate was formed. After cooling to room temperature, the mixture was cooled in an ice bath and filtered to give a mixture of risperidone Form A and risperidone Form B in an 82 % yield.
Example 11
Preparation of Risperidone Form A by Crystallization in Organic Solvents
Risperidone (6 g) was added portion-wise and dissolved in a minimum amount of solvent by heating in a boiling water bath (about 95°C). Suitable solvents and the corresponding suitable volumes are listed below in Table 1. Solvents having a boiling point lower than 95°C were heated to their boiling point. The solutions were left to cool to room temperature to facilitate precipitation of risperidone Form A. The mixture was then further cooled in an ice bath and then filtered. The precipitate was analyzed by
PXRD and found to be risperidone Form A.
Table I. Preparation of Risperidone Form A
The volumes of solvents used per 6 grams of Risperidone 0al : 200 ml 2% ml meth] eibyl ketone: absolute ethanol 100m]
DMSO: 100 ml 150ml
Isopropanol: 100 ml
Example 12
Preparation of risperidone Form A
Risperidone (5.6 g) was dissolved in 50 mL dichloromethane. Cyclohexane (170 mL) was added to the solution until a cloudy dispersion was formed. The resulting suspension was filtered. The isolated filtrate, analyzed by PXRD, contained risperidone
Form A and a minor quantity of risperidone Form B.
Example 13
Preparation of Risperidone Form A
Risperidone (5.1 g) was dissolved in 30 mL dichloromethane. n-Hexane (150 mL) was added to the solution to facilitate precipitation until a cloudy dispersion was formed.
The resulting suspension was filtered. The filtrate, analyzed by PXRD, contained risperidone Form A and a minor quantity of risperidone Form B.
Example 14 ! Preparation of Risperidone Form E
Risperidone (5 g) was dissolved in 60 mL isopropanol. Water (950 mL) was added to the solution to facilitate precipitation until a cloudy dispersion was formed. The suspension was filtered. The filtrate, analyzed by PXRD, contained risperidone Form E.
Although certain presently preferred embodiments of the invention have been described herein, it will be apparent to those skilled in the art to which the invention } pertains that variations and modifications of the described embodiment may be made without departing from the spirit and scope of the invention.
Accordingly, it is intended ‘ that the invention be limited only to the extent required by the appended claims and the applicable rules of law.
Claims (1)
- WHAT IS CLAIMED IS:1. A process for making risperidone comprising the steps of reacting compound (I) . N—o0 SRS HN FE () with compound (IT) lo) N cl 8 N7 CH; 01) to form crude risperidone (III) N—O Suga! SN cH (I) in a solvent selected from the group consisting of acetonitrile, isopropanol, methyl ethyl ketone and iso-butanol.2. The process of claim 1, further comprising the steps of recrystallizing crude risperidone from an alcohol, a mixture of alcohols, or a mixture of water and alcohol.3. The process of claim 2, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, propanol, butanol, sec-butanol, and #- butanol.4. The process of claim 3, wherein the alcohol is isopropanol.- 5. The process of claim 1, wherein the solvent is acetonitrile.6. The process of claim 1, wherein the solvent is isopropanol.7. The process of claim 1, wherein the solvent is methyl ethyl ketone.8. The process of claim 1, wherein the solvent is iso-butanol.9. The process of claim 1, further comprising the steps of recrystallizing crude risperidone from a ketone.10. The process of claim 1 wherein the ketone is acetone.11. Risperidone Form A which is characterized by x-ray powder diffraction peaks at 14.2+0.2, 21.3+0.2 degrees two-theta.12. The nsperidone Form A of claim 11 which is further characterized by x- ray powder diffraction peaks at 10.6+0.2, 11.4+0.2, 16.4+0.2, 18.9+0.2, 19.9+0.2,22.5+0.2, 23.3+0.2, 25.4+0.2, 27.6£0.2, 29.0+0.2 degrees two-theta. :13. A risperidone polymorph that is characterized by a powder x-ray diffraction pattern substantially as depicted in Figure 1.14. Risperidone Form B which is characterized by x-ray powder diffraction : peaks at 14.0£0.2 and 21.7+0.2 degrees two-theta.15. The risperidone Form B of claim 14 which is further characterized by x-ray powder diffraction peaks at 10.8+0.2, 11.9+0.2, 12.6+0.2, 14.0+0.2, 17.5+0.2, 18.3+0.2,19.9£0.2, 21.0+0.2, 21.7=0.2 degrees two-theta. : 16. A risperidone polymorph that is characterized by a powder x-ray diffraction pattern substantially as depicted in Figure 2.17. Rusperidone Form E which is characterized by x-ray powder diffraction peaks at 16.5+0.2, 21.7+0.2 degrees two-theta. : 18. The nsperidone Form E of claim 17 which is further characterized by x- ray powder diffraction peaks at 16.5+0.2, 12.6+0.2, 21.7+0.2 , 15.6+0.2, 17.020.2,18.4+0.2, 19.1+0.2, 21.320.2, 24.0£0.2, 24.9+0.2, 27.0+0.2 degrees two-theta.19. A risperidone polymorph that is characterized by a powder x-ray diffraction pattern substantially as depicted in Figure 3.20. A process for preparing risperidone Form B comprising the steps of: (a) dissolving risperidone in a water soluble alcohol having 1 to 4 carbon atoms where the ratio of risperidone to alcohol is about 1:7.5 to about 1:9; (b) adding water to facilitate precipitation; and (©) isolating risperidone Form B.21. A process for preparing risperidone Form B comprising the steps of: (a) dissolving risperidone in chloroform; . (b) adding cyclohexane or hexane to facilitate precipitation; and (©) isolating risperidone Form B. - 22. A process for preparing risperidone Form B comprising the steps of: (2) dissolving risperidone in an aqueous solution of HCI; (b) adding aqueous Na,CO; to facilitate precipitation; and (©) isolating risperidone Form B.23. A process for preparing risperidone Form A comprising the steps of: (a) dissolving risperidone in an organic solvent selected from the group . consisting of dimethylformamide, tetrahydrofuran, acetone, benzene, ethyl methyl ketone, n-butanol, methanol, isopropanol, absolute ethanol, acetonitrile, toluene, dimethyl ) sulfoxide, iso-butanol, and ethyl acetate; (b) heating the solvent to reflux; (©) cooling the solvent to facilitate precipitation; and (d) isolating risperidone Form A.24. A process for preparing risperidone Form A comprising the steps of: (a) dissolving risperidone in dichloromethane; (b) adding cyclohexane or hexane to facilitate precipitation; and © isolating risperidone Form A.25. A process for preparing risperidone Form E comprising the steps of: (a) dissolving risperidone in isopropanol where the ratio of risperidone to isopropanol is about 1:12; (b) adding water to facilitate precipitation; and (©) isolating risperidone Form E.26. . A process for preparing risperidone Form A comprising the steps of: (a) heating risperidone Form B at a temperature of about 25°C to about 80°C for a time sufficient to induce to formation of risperidone Form A; and (b) isolating risperidone Form A.27. The process of claim 26 wherein the heating takes place under reduced pressure or at atmospheric pressure.28. The process of claim 26 wherein the temperature is about 80°C.
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