Claims
- 1. A composition comprising ziprasidone and an amount of des-chloro ziprasidone not greater than about 1000 ppm.
- 2. A composition according to claim 1, wherein the amount of des-chloro ziprasidone is not greater than about 500 ppm.
- 3. A composition according to claim 2, wherein the amount of des-chloro ziprasidone is not greater than about 100 ppm.
- 4. A composition according to claim 1, wherein the ziprasidone is ziprasidone free base, ziprasidone hydrochloride monohydrate, ziprasidone mesylate dihydrate, or ziprasidone mesylate trihydrate.
- 5. A composition according to claim 4, wherein the ziprasidone is ziprasidone hydrochloride monohydrate.
- 6. A composition according to claim 4, wherein the ziprasidone is ziprasidone mesylate trihydrate.
- 7. A pharmaceutical composition for treating in a mammal a disorder or condition selected from schizophrenia, anxiety, migraine pain, Tourette's Syndrome, glaucoma, ischemic retinopathy, dementia of the Alzheimer's type, a bipolar disorder, a mood disorder, agoraphobia, social phobia, panic disorder, post-traumatic stress disorder, acute stress disorder, substance-induced anxiety disorder, an anxiety disorders not otherwise specified (NOS), dyskinesias, a behavioral manifestation of mental retardation, conduct disorder, and autistic disorder comprising an amount of the composition of claim 1 effective in treating said disorder or condition and a pharmaceutically acceptable carrier.
- 8. A method for treating in a mammal in need thereof a disorder or condition selected from schizophrenia, anxiety, migraine pain, Tourette's Syndrome, glaucoma, ischemic retinopathy, dementia of the Alzheimer's type, a bipolar disorder, a mood disorder, agoraphobia, social phobia, panic disorder, post-traumatic stress disorder, acute stress disorder, substance-induced anxiety disorder, an anxiety disorders not otherwise specified (NOS), dyskinesias, a behavioral manifestation of mental retardation, conduct disorder, and autistic disorder, which method comprises administering to said mammal an amount of a composition of claim 1 effective in treating said disorder or condition.
- 9. A method of synthesizing a ziprasidone composition that comprises an amount of des-chloro ziprasidone of not greater than about 1000 ppm, which method comprises:
a) obtaining one or more samples of one or more 6-chloro-1,3-dihydro-2H-indol-2-one batches; b) measuring the level of oxindole impurity in each of the samples of (a); c) selecting a 6-chloro-1,3-dihydro-2H-indol-2-one batch that comprises a level of oxindole of not greater than about 0.3% based on the measurement or measurements conducted in (b); and d) using the batch selected in (c) to synthesize said ziprasidone composition.
- 10. A method according to claim 9, wherein (c) comprises selecting a 6-chloro-1,3-dihydro-2H-indol-2-one batch that comprises a level of oxindole of not greater than about 0.15%.
- 11. A method according to claim 10, wherein (c) comprises selecting a 6-chloro-1,3-dihydro-2H-indol-2-one batch that comprises a level of oxindole of not greater than about 0.03%.
- 12. A method of synthesizing a ziprasidone composition that comprises an amount of des-chloro ziprasidone of not greater than about 1000 ppm, which method comprises:
a) acylating a composition comprising 6-chloro-1,3-dihydro-2H-indol-2-one and an oxindole impurity with chloroacetyl chloride by Friedel-Crafts Acylation to synthesize a composition comprising 6-chloro-5-(chloroacetyl)-1,3-dihydro-2H-indol-2-one; b) treating the composition resulting from (a) to reduce of the oxo of the chloroacetyl group therein to form a composition comprising 6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one and a 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one impurity; c) isolating a sample of the composition resulting from (b); d) measuring the quantity of 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one impurity in the isolated sample from (c); e) determining whether or not the quantity in (d) is not greater than about 0.28%; and f) purifying by recrystallization and/or reslurry the composition resulting from (b) if the quantity measured in (d) is greater than about 0.28% until the quantity of the 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one impurity is not greater than about 0.28%, and synthesizing a ziprasidone composition from the composition so purified; or, g) if the quantity in (d) is not greater than about 0.28%, synthesizing a ziprasidone composition from the composition of (b).
- 13. A method according to claim 12, wherein the quantity of 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one is measured in step (d) by Detection Method A.
- 14. A method according to claim 12, wherein step (e) comprises determining whether or not the quantity in (d) is not greater than about 0.14%;
step (f) comprises purifying by recrystallization and/or reslurry the composition resulting from (b) if the quantity measured in (d) is greater than about 0.14% until the quantity of the 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one impurity is not greater than about 0.14%, and synthesizing a ziprasidone composition from the composition so purified; and step (g) comprises that if the quantity in (d) is not greater than about 0.14%, synthesizing a ziprasidone composition from the composition of (b).
- 15. A method according to claim 12, wherein step (e) comprises determining whether or not the quantity in (d) is not greater than about 0.028%;
step (f) comprises purifying by recrystallization and/or reslurry the composition resulting from (b) if the quantity measured in (d) is greater than about 0.028% until the quantity of the 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one impurity is not greater than about 0.028%, and synthesizing a ziprasidone composition from the composition so purified; and step (g) comprises that if the quantity in (d) is not greater than about 0.028%, synthesizing a ziprasidone composition from the composition of (b).
- 16. A method using HPLC for measuring the quantity of 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one in a composition comprising 6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one, which method comprises
a) preparing sample solution from said composition comprising 6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one by dissolving a portion of said composition in an organic solvent, followed by dilution with an organic solvent of the dissolved portion so that a concentration (weight/volume), based on the weight of said portion and volume of solvent, of about 1 mg/mL is obtained; b) running the sample solution through a stable-bond cyano HPLC column using a mobile phase consisting essentially of (75:13-17:8-12 v/v/v/) 0.05 M KH2PO4, pH=from 5.5-6.5,:Acetonitrile:Methanol; at a column temperature of from 30° C. to 400 C; with detection by UV light at 254 nm UV; c) detecting a peak appearing at from between 8 to 10 minutes on a chromatogram resulting from (b); d) measuring the peak area (named Ac) of the peak detected in (c); e) preparing a standard from a composition consisting essentially of 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one by dissolving and diluting a portion of said composition in an organic solvent such that the concentration (weight/volume) of 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one, based on the weight of the portion and volume of the solvent, is about equal to a selected fraction value at or above which detection of 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one in the composition comprising 6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one is desired; f) running the standard through a stable-bond cyano HPLC column using a mobile phase consisting essentially of (75:13-17:8-12 v/v/v/) 0.05 M KH2PO4, pH=from 5.5-6.5,:Acetonitrile:Methanol; at a column temperature of from 30° C. to 40° C.; with detection by UV light at 254 nm UV; g) measuring the peak area (named Apur1) of the peak on a chromatogram resulting from (f); and h) calculating the quantity of 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one in the composition comprising 6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one by
i) calculating the Response Factor for 5-(2-chloroethyl)-1,3-dihyrdo-2H-indol-2-one according to the following formula: Rpur1=(Apur1)(DF)/(Wpur1)(PF) wherein:
Apur1 is as defined above; Wpur1=weight of composition in the standard; PF=potency factor for 5-(2-chloroethyl)-1,3-dihyrdo-2H-indol-2-one; and DF=dilution factor for the standard; and ii) calculating the % w/w of 5-(2-chloroethyl)-1,3-dihyrdo-2H-indol-2-one according to the following formula: % w/w=(Ac)(DF)(100)/(Rpur1)(WS2) wherein:
Ac is as defined above; Rpur1=Response Factor calculated in (h)(i) above; WS2=weight of the portion of the composition used in step (a); and DF=dilution factor for sample solution.
- 17. A method of synthesizing a ziprasidone composition that comprises an amount of des-chloro ziprasidone of not greater than about 1000 ppm, which method comprises:
a) reducing a composition comprising 6-chloro-5-(chloroacetyl)-1,3-dihydro-2H-indol-2-one and a 5-(chloroacetyl)-1,3-dihydro-2H-indol-2-one impurity by treatment with triethylsilane in the presence of a strong acid to obtain a composition comprising 6-chloro-5-(2-chloroetheyl-1,3-dihydro-2H-indol-2-one and a 5-(2-chloroetheyl-1,3-dihydro-2H-indol-2-one impurity; and b) synthesizing a composition comprising ziprasidone from the composition resulting from (a).
- 18. A method according to claim 17, further comprising
i) isolating prior to step (b) a sample of the composition from (a), and measuring the quantity of 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one impurity in said sample; ii) determining whether or not the quantity in (i) is not greater than about 0.28%; and iii) purifying by recrystallization and/or reslurry the composition from (a) if the quantity in (i) is greater than about 0.28% until the quantity of the 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one impurity is not greater than about 0.28%, and then proceeding to step (b) using the composition from (a) so purified; or iv) if the quantity in (i) is not greater than about 0.28%, then proceeding to step (b).
- 19. A method according to claim 17, further comprising
i) isolating prior to step (b) a sample of the composition from (a), and measuring the quantity of 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one impurity in said sample; ii) determining whether or not the quantity in (i) is not greater than about 0.14%; and iii) purifying by recrystallization and/or reslurry the composition from (a) if the quantity in (i) is greater than about 0.14% until the quantity of the 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one impurity is not greater than about 0.14%, and then proceeding to step (b) using the composition from (a) so purified; or iv) if the quantity in (i) is not greater than about 0.14%, then proceeding to step (b).
- 20. A method according to claim 17, further comprising:
i) isolating prior to step (b) a sample of the composition from (a), and measuring the quantity of 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one impurity in said sample; ii) determining whether or not the quantity in (i) is not greater than about 0.028%; and iii) purifying by recrystallization and/or reslurry the composition from (a) if the quantity in (i) is greater than about 0.028% until the quantity of the 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one impurity is not greater than about 0.028%, and then proceeding to step (b) using the composition from (a) so purified; or iv) if the quantity in (i) is not greater than about 0.028%, then proceeding to step (b).
- 21. A method according to claim 17, wherein the strong acid in step (a) comprises trifluoroacetic acid or methanesulfonic acid.
- 22. A method according to claim 17, wherein the quantity of 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one in the sample of the composition comprising 6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one is measured by a method comprising Detection Method A.
- 23. A method of synthesizing a ziprasidone composition that comprises an amount of des-chloro ziprasidone of not greater than about 1000 ppm, which method comprises:
a) purifying a composition comprising 6-chloro-1,3-dihydro-2H-indol-2-one and an oxindole impurity until a composition comprising not greater than about 0.3% of said oxindole impurity is obtained; and b) using the composition resulting from (a) to synthesize a ziprasidone composition.
- 24. A method according to claim 23 for synthezising a ziprasidone composition that comprises an amount of des-chloro ziprasidone of not greater than about 500 ppm, wherein step (a) comprises purifying a composition comprising 6-chloro-1,3-dihydro-2H-indol-2-one and an oxindole impurity until a composition comprising not greater than about 0.15% of said oxindole impurity is obtained.
- 25. A method according to claim 23 for synthezising a ziprasidone composition that comprises an amount of des-chloro ziprasidone of not greater than about 100 ppm, wherein step (a) comprises purifying a composition comprising 6-chloro-1,3-dihydro-2H-indol-2-one and an oxindole impurity until a composition comprising not greater than about 0.03% of said oxindole impurity is obtained.
- 26. A method of synthesizing a ziprasidone composition that comprises an amount of des-chloro ziprasidone of not greater than about 1000 ppm, which method comprises:
a) recrystallizing and/or reslurrying a composition comprising 6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one and a 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one impurity until a composition comprising not greater than about 0.3% of said 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one impurity is obtained; and b) using the composition resulting from (a) to synthesize a ziprasidone composition.
- 27. A method according to claim 26 for synthezising a ziprasidone composition that comprises an amount of des-chloro ziprasidone of not greater than about 500 ppm, wherein step (a) comprises recrystallizing and/or reslurrying a composition comprising 6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one and a 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one impurity until a composition comprising not greater than about 0.15% of said 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one impurity is obtained.
- 28. A method according to claim 26 for synthezising a ziprasidone composition that comprises an amount of des-chloro ziprasidone of not greater than about 100 ppm, wherein step (a) comprises recrystallizing and/or reslurrying a composition comprising 6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one and a 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one impurity until a composition comprising not greater than about 0.03% of said 5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one impurity is obtained.
- 29. The method of claim 26, wherein the recrystallization and relurrying conditions in step (a) comprise treatment with an aqueous miscible solvent.
- 30. The method of claim 29, wherein the aqueous miscible solvent is acetonitrile/water.
Parent Case Info
[0001] This application claims priority under 35 USC 119 of U.S. Provisional No. 60/358,806, filed Feb. 20, 2002, and of U.S. Provisional No. 60/359,038, filed Feb. 21, 2002.
Provisional Applications (2)
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Number |
Date |
Country |
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60359038 |
Feb 2002 |
US |
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60358806 |
Feb 2002 |
US |