ES2241507T1 - NEW FORMS OF CRYSTAL OF SEMICALCID ATORVASTATIN AND PROCEDURES FOR THEIR PREPARATION, AS WELL AS NEW PROCEDURES FOR THE PREPARATION OF FORMS I, VIII AND IX OF SEMICALCICA ATORVASTATIN. - Google Patents

NEW FORMS OF CRYSTAL OF SEMICALCID ATORVASTATIN AND PROCEDURES FOR THEIR PREPARATION, AS WELL AS NEW PROCEDURES FOR THE PREPARATION OF FORMS I, VIII AND IX OF SEMICALCICA ATORVASTATIN.

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ES2241507T1
ES2241507T1 ES03713610T ES03713610T ES2241507T1 ES 2241507 T1 ES2241507 T1 ES 2241507T1 ES 03713610 T ES03713610 T ES 03713610T ES 03713610 T ES03713610 T ES 03713610T ES 2241507 T1 ES2241507 T1 ES 2241507T1
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atorvastatin
semi
calcic
approximately
characteristic
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Limor Tessler
Judith Aronhime
Revital Lifshitz-Liron
Dalia Maidan-Hanoch
Nir Hasson
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Teva Pharmaceutical Industries Ltd
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Teva Pharmaceutical Industries Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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

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Abstract

Atorvastatina semicálcica sólida cristalina y solvatos de la misma, caracterizada porque presenta un esquema de difracción de rayos X en polvo con unos picos de dos theta de 9, 3 y 9, 50, 2 grados.Solid crystalline semi-calcic atorvastatin and solvates thereof, characterized in that it presents a powder X-ray diffraction scheme with two theta peaks of 9, 3 and 9, 50, 2 degrees.

Claims (46)

1. Atorvastatina semicálcica sólida cristalina y solvatos de la misma, caracterizada porque presenta un esquema de difracción de rayos X en polvo con unos picos de dos theta de 9,3 y 9,5\pm0,2 grados.1. Solid crystalline semi-calcic atorvastatin and solvates thereof, characterized in that it has a powder X-ray diffraction scheme with two theta peaks of 9.3 and 9.5 ± 0.2 degrees. 2. Atorvastatina semicálcica sólida cristalina y solvatos de la misma según la reivindicación 1, caracterizada además porque presenta unos picos en el esquema de difracción de rayos X en polvo de dos theta de 15,7, 20,5, 21,1, 22,8, 23,8, 24,0, 25,3, 26,4, 26,8, 27,2, 29,2 y 31,6 grados.2. Solid crystalline semi-calcic atorvastatin and solvates thereof according to claim 1, further characterized in that it has peaks in the two-ray powder diffraction scheme of two theta of 15.7, 20.5, 21.1, 22, 8, 23.8, 24.0, 25.3, 26.4, 26.8, 27.2, 29.2 and 31.6 degrees. 3. Atorvastatina semicálcica sólida cristalina y solvatos de la misma según la reivindicación 1, caracterizada además porque presenta un esquema de difracción de rayos X en polvo generado mediante la utilización de radiación de CuK_{\alpha} sustancialmente tal como se representa en la figura 2.3. Solid crystalline semi-calcic atorvastatin and solvates thereof according to claim 1, further characterized in that it has a powder X-ray diffraction scheme generated by the use of CuKα radiation substantially as depicted in Figure 2 . 4. Procedimiento para la preparación de atorvastatina semicálcica que presenta por lo menos una característica de la Forma IXa que comprende las etapas siguientes:4. Procedure for the preparation of semi-calcic atorvastatin that has at least one characteristic of Form IXa comprising the stages following:
a)to)
suspender la Forma V de la atorvastatina semicálcica en una mezcla seleccionada de entre el grupo constituido por unas mezclas de entre aproximadamente 85% y aproximadamente 95% de 1-butanol y de entre aproximadamente 5% y aproximadamente 15% de agua y mezclas de entre aproximadamente 5% y aproximadamente 15% de 1-butanol y de entre aproximadamente 85% y aproximadamente 95% de agua durante un periodo de tiempo suficiente para convertir la Forma V en atorvastatina semicálcica que presenta por lo menos una característica de la Forma IXa, ysuspend Form V of the semi-calcium atorvastatin in a mixture selected from the group consisting of mixtures between approximately 85% and approximately 95% of 1-butanol and between approximately 5% and approximately 15% water and mixtures between about 5% and about 15% of 1-butanol and between approximately 85% and approximately 95% water for a sufficient period of time to convert Form V into semi-calcic atorvastatin at least one characteristic of Form IXa, and
b)b)
recuperar de la suspensión la atorvastatina semicálcica sólida cristalina que presenta por lo menos una característica de la Forma IXa.recover from the suspension the solid crystalline semi-calcic atorvastatin presenting at less a characteristic of Form IXa.
5. Procedimiento según la reivindicación 4, en el que la mezcla es de aproximadamente 90% de 1-butanol y aproximadamente 10% de agua sobre la base de un volumen.5. Method according to claim 4, in the that the mixture is about 90% 1-butanol and about 10% water based on a volume. 6. Procedimiento según la reivindicación 4, en el que la mezcla es de aproximadamente 10% de 1-butanol y aproximadamente 90% de agua sobre la base de un volumen.6. Method according to claim 4, in the that the mixture is about 10% 1-butanol and approximately 90% water based on a volume. 7. Procedimiento según la reivindicación 4, en el que la mezcla está presente en una cantidad de por lo menos aproximadamente 20 mililitros por gramo de la Forma V de atorvastatina semicálcica.7. Method according to claim 4, in the that the mixture is present in an amount of at least approximately 20 milliliters per gram of Form V of semi-calcium atorvastatin 8. Procedimiento según la reivindicación 4, en el que la suspensión se calienta hasta una temperatura elevada antes de recuperar de la suspensión la atorvastatina semicálcica sólida cristalina que presenta por lo menos una característica de la Forma IXa.8. Method according to claim 4, in the that the suspension is heated to an elevated temperature before recover solid semi-calcium atorvastatin from the suspension crystalline that has at least one characteristic of the Form IXa. 9. Procedimiento según la reivindicación 8, en el que la temperatura elevada es aproximadamente la temperatura de reflujo de la mezcla.9. Method according to claim 8, in the that the elevated temperature is approximately the temperature of Reflux of the mixture. 10. Procedimiento según la reivindicación 9, en el que la temperatura de reflujo es aproximadamente 85ºC.10. Method according to claim 9, in The reflux temperature is approximately 85 ° C. 11. Procedimiento según la reivindicación 4, en el que el periodo de tiempo suficiente para convertir la Forma V en la atorvastatina semicálcica sólida cristalina que presenta por lo menos una característica de la Forma IXa es de aproximadamente 16 horas o menos.11. Method according to claim 4, in the period of time sufficient to convert Form V into the solid crystalline semi-calcic atorvastatin that presents less one characteristic of Form IXa is approximately 16 hours or less 12. Procedimiento según la reivindicación 4, en el que la Forma V es impura y la atorvastatina semicálcica sólida cristalina que presenta por lo menos una característica de la Forma IXa es más pura que la Forma V en aproximadamente 50% o más.12. Method according to claim 4, in the one that Form V is impure and solid semi-calcic atorvastatin crystalline that has at least one characteristic of the Form IXa is purer than Form V at approximately 50% or more. 13. Atorvastatina semicálcica sólida cristalina y solvatos de la misma que presenta por lo menos una característica de la Forma IXa preparada mediante un procedimiento que comprende las etapas siguientes:13. Crystalline solid semi-calcic atorvastatin and solvates thereof that have at least one characteristic of Form IXa prepared by a procedure comprising the following stages:
a)to)
suspender la Forma V de la atorvastatina semicálcica en una mezcla seleccionada de entre el grupo constituido por unas mezclas de entre aproximadamente 85% y aproximadamente 95% de 1-butanol y de entre aproximadamente 5% y aproximadamente 15% de agua y mezclas de entre aproximadamente 5% y aproximadamente 15% de 1-butanol y de entre aproximadamente 85% y aproximadamente 95% de agua durante un periodo de tiempo suficiente para convertir la Forma V en atorvastatina semicálcica que presenta por lo menos una característica de la Forma IXa, ysuspend Form V of the semi-calcium atorvastatin in a mixture selected from the group consisting of mixtures between approximately 85% and approximately 95% of 1-butanol and between approximately 5% and approximately 15% water and mixtures between about 5% and about 15% of 1-butanol and between approximately 85% and approximately 95% water for a sufficient period of time to convert Form V into semi-calcic atorvastatin at least one characteristic of Form IXa, and
b)b)
recuperar de la suspensión la atorvastatina semicálcica sólida cristalina que presenta por lo menos una característica de la Forma IXa.recover from the suspension the solid crystalline semi-calcic atorvastatin presenting at less a characteristic of Form IXa.
14. Atorvastatina semicálcica sólida cristalina de alta pureza y solvatos de la misma que presenta por lo menos una característica de la Forma IX preparada mediante un procedimiento que comprende las etapas siguientes:14. Crystalline solid semi-calcic atorvastatin of high purity and solvates thereof that has at least one characteristic of Form IX prepared by a procedure which comprises the following stages:
a)to)
suspender la Forma V de la atorvastatina semicálcica en una mezcla de 90% de 1-butanol y 10% de agua sobre una base de volumen durante un periodo de tiempo suficiente para convertir la Forma V en atorvastatina semicálcica que presenta por lo menos una característica de la Forma IXa, ysuspend Form V of the atorvastatin semi-calcium in a mixture of 90% of 1-butanol and 10% water on a volume basis for a sufficient period of time to convert Form V into semi-calcic atorvastatin that has at least one characteristic of Form IXa, and
b)b)
recuperar de la suspensión la atorvastatina semicálcica sólida cristalina que presenta por lo menos una característica de la Forma IXa con una pureza química de 99,3% o superior tal como se determina mediante la separación cromatográfica líquida de alta resolución y la cuantificación mediante la absorción de UV a 254 nanómetros.recover from the suspension the solid crystalline semi-calcic atorvastatin presenting at less a characteristic of Form IXa with a chemical purity of 99.3% or higher as determined by separation High performance liquid chromatographic and quantification by absorbing UV at 254 nanometers.
15. Atorvastatina semicálcica sólida cristalina y solvatos de la misma, caracterizada porque presenta un esquema de difracción de rayos X en polvo con unos picos de dos theta 7,6, 9,8, 16,5, 29,4\pm0,2 grados.15. Crystalline solid semi-calcic atorvastatin and solvates thereof, characterized in that it has a powder X-ray diffraction scheme with two theta peaks 7.6, 9.8, 16.5, 29.4 ± 0.2 degrees . 16. Atorvastatina semicálcica sólida cristalina y solvatos de la misma según la reivindicación 15, caracterizada además porque presenta unos picos de dos grados de 18,1, 20,0, 20,4, 21,9, 22,4 y 23,6\pm0,2 grados en su esquema de difracción de rayos X en polvo.16. Crystalline solid semi-calcium atorvastatin and solvates thereof according to claim 15, further characterized in that it has two-degree peaks of 18.1, 20.0, 20.4, 21.9, 22.4 and 23.6 \ PM0.2 degrees in its powder X-ray diffraction scheme. 17. Atorvastatina semicálcica sólida cristalina y solvatos de la misma según la reivindicación 15, caracterizada además porque presenta un esquema de difracción de rayos X en polvo generado mediante la utilización de la radiación de CuK_{\alpha} sustancialmente tal como se representa en la figura 3.17. Solid crystalline semi-calcic atorvastatin and solvates thereof according to claim 15, further characterized in that it has a powder X-ray diffraction scheme generated by the use of CuKα radiation substantially as depicted in the figure 3. 18. Procedimiento para la preparación de la atorvastatina semicálcica sólida y cristalina que presenta por lo menos una característica de la Forma XIV y solvatos de la misma, que comprende las etapas siguientes:18. Procedure for the preparation of solid and crystalline semi-calcic atorvastatin that presents less a characteristic of Form XIV and solvates thereof, which comprises the following stages:
a)to)
suspender la atorvastatina semicálcica en agua, ysuspend semi-calcium atorvastatin in water, and
b)b)
recuperar los granos de la suspensión.recover the beans from the suspension.
19. Procedimiento según la reivindicación 18, en el que la atorvastatina semicálcica que está suspendida es la Forma V.19. Method according to claim 18, in the one that the semi-calcic atorvastatin that is suspended is the Form V. 20. Procedimiento según la reivindicación 18, en el que la conversión se produce en aproximadamente 5 días.20. Method according to claim 18, in which the conversion occurs in about 5 days. 21. Procedimiento según la reivindicación 18, en el que un sólido fino suspendido se forma entre aproximadamente dos y aproximadamente 10 horas después de haber suspendido la atorvastatina semicálcica en agua.21. Method according to claim 18, in which a suspended fine solid forms between approximately two and approximately 10 hours after having suspended the atorvastatin semi-calcium in water. 22. Procedimiento según la reivindicación 18, en el que el sólido fino suspendido se convierte en granos entre aproximadamente un día y aproximadamente cinco días.22. Method according to claim 18, in which the suspended fine solid becomes grains between approximately one day and approximately five days. 23. Procedimiento según la reivindicación 22, en el que la conversión del sólido fino suspendido se produce en aproximadamente cinco días.23. Method according to claim 22, in which the conversion of the suspended fine solid occurs in approximately five days 24. Atorvastatina semicálcica sólida cristalina y solvatos de la misma, caracterizada porque presenta unos picos de dos theta de 16,5, 21,9, 29,5\pm0,2 grados en el esquema de difracción de rayos X en polvo.24. Solid crystalline semi-calcic atorvastatin and solvates thereof, characterized in that it has two theta peaks of 16.5, 21.9, 29.5 ± 0.2 degrees in the powder X-ray diffraction scheme. 25. Atorvastatina semicálcica sólida cristalina y solvatos de la misma según la reivindicación 24, caracterizada además porque presenta unos picos de dos theta de 7,7, 9,9, 16,5, 17,7, 18,3, 20,0 21,9, 29,5\pm0,2 grados en el esquema de difracción de rayos X en polvo.25. Solid crystalline semi-calcium atorvastatin and solvates thereof according to claim 24, further characterized in that it has two theta peaks of 7.7, 9.9, 16.5, 17.7, 18.3, 20.0 21 , 9, 29.5 ± 0.2 degrees in the powder X-ray diffraction scheme. 26. Atorvastatina semicálcica sólida cristalina y solvatos de la misma según la reivindicación 24, caracterizada además porque presenta un esquema de difracción de rayos X en polvo generado mediante la utilización de radiación de CuK_{\alpha} sustancialmente tal como se representa en la figura 4.26. Solid crystalline semi-calcium atorvastatin and solvates thereof according to claim 24, further characterized in that it has a powder X-ray diffraction scheme generated by the use of CuKα radiation substantially as depicted in Figure 4 . 27. Procedimiento para la preparación de atorvastatina semicálcica sólida cristalina que presenta por lo menos una característica de la Forma XVI y solvatos de la misma que comprende las siguientes etapas:27. Procedure for the preparation of solid crystalline semi-calcic atorvastatin presenting at less a characteristic of Form XVI and solvates of it that It comprises the following stages:
a)to)
mantener los cristales de la Forma XIV de la atorvastatina semicálcica a una temperatura comprendida entre aproximadamente 20ºC y aproximadamente 50ºC, ykeep the crystals of Form XIV of semi-calcium atorvastatin at a temperature between about 20 ° C and about 50 ° C, and
b)b)
recuperar los cristales en forma de atorvastina semicálcica sólida cristalina que presenta por lo menos una característica de la Forma XVI.recover the crystals in the form of solid crystalline semi-calcic atorvastine that has at least a characteristic of Form XVI.
28. Procedimiento según la reivindicación 27, en el que la atorvastatina semicálcica se mantiene a 22ºC.28. Method according to claim 27, in that the semi-calcium atorvastatin is maintained at 22 ° C. 29. Procedimiento según la reivindicación 27, en el que la atorvastatina semicálcica está expuesta al aire mientras se mantiene.29. Method according to claim 27, in which the semi-calcium atorvastatin is exposed to the air while it keeps. 30. Atorvastatina semicálcica sólida cristalina y solvatos de la misma, caracterizada porque presenta un esquema de difracción de rayos X en polvo con unos picos de dos theta 19,1, 20,6, 21,4, y 23,6\pm0,2 grados.30. Solid crystalline semi-calcic atorvastatin and solvates thereof, characterized in that it has a powder X-ray diffraction scheme with two theta peaks 19.1, 20.6, 21.4, and 23.6 ± 0.2 degrees. 31. Atorvastatina semicálcica sólida cristalina y solvatos de la misma según la reivindicación 30, caracterizada además porque presenta unos picos adicionales de dos theta de 7,8, 9,5, 10,2, 18,2, 19,1, 25,3, 26,2, 30,1\pm0,2 grados en el esquema de difracción de rayos X en polvo.31. Solid crystalline semi-calcic atorvastatin and solvates thereof according to claim 30, further characterized in that it has additional peaks of two theta of 7.8, 9.5, 10.2, 18.2, 19.1, 25.3 , 26.2, 30.1 ± 0.2 degrees in the powder X-ray diffraction scheme. 32. Atorvastatina semicálcica sólida cristalina y solvatos de la misma según la reivindicación 30, caracterizada además porque presenta un esquema de difracción de rayos X generado mediante la utilización de radiación de CuK_{\alpha} sustancialmente tal como se representa en la figura 5.32. Solid crystalline semi-calcium atorvastatin and solvates thereof according to claim 30, further characterized in that it has an X-ray diffraction scheme generated by the use of CuKα radiation substantially as depicted in Figure 5. 33. Procedimiento para la preparación de atorvastatina semicálcica sólida cristalina que presenta por lo menos una característica de la Forma XVII y solvatos de la misma, que comprende las siguientes etapas:33. Procedure for the preparation of solid crystalline semi-calcic atorvastatin presenting at less a characteristic of Form XVII and solvates thereof, which comprises the following stages:
a)to)
suspender la Forma V de la atorvastatina semicálcica en una mezcla de aproximadamente 96% de etanol y aproximadamente 4% de agua,suspend Form V of the semi-calcium atorvastatin in a mixture of approximately 96% of ethanol and about 4% water,
b)b)
calentar la suspensión,heat the suspension,
c)C)
enfriar la suspensión, ycool the suspension, and
d)d)
recuperar de la suspensión la atorvastatina semicálcica sólida que presenta por lo menos una característica de la Forma XVII.recover from the suspension the solid semi-calcic atorvastatin that has at least one characteristic of Form XVII.
34. Procedimiento según la reivindicación 33, en el que la mezcla se utiliza en una cantidad de por lo menos aproximadamente 500 ml.34. Method according to claim 33, in which the mixture is used in an amount of at least approximately 500 ml 35. Procedimiento según la reivindicación 33, en el que la suspensión se calienta a una temperatura comprendida entre aproximadamente 78 y 80ºC.35. Method according to claim 33, in which the suspension is heated to a temperature comprised between approximately 78 and 80 ° C. 36. Composición farmacéutica que comprende atorvastatina semicálcica seleccionada de entre el grupo constituido por la Forma IXa, XIV, XVI y XVII o una mezcla de las mismas y un vehículo farmacéuticamente aceptable.36. Pharmaceutical composition comprising semi-calcic atorvastatin selected from the group constituted by Form IXa, XIV, XVI and XVII or a mixture thereof and a pharmaceutically acceptable vehicle. 37. Utilización de la Forma IXa, XIV, XVI y XVII de la atorvastatina o mezclas de las mismas, para la preparación de una forma de administración farmacéutica.37. Use of Form IXa, XIV, XVI and XVII of atorvastatin or mixtures thereof, for the preparation of a form of pharmaceutical administration. 38. Forma de administración farmacéutica que comprende la Forma IXa, XIV, XVI y XVII de la atorvastatina semicálcica o mezclas de las mismas.38. Form of pharmaceutical administration that includes Form IXa, XIV, XVI and XVII of atorvastatin semi-calcium or mixtures thereof. 39. Procedimiento para la reducción del nivel de lipoproteína de baja densidad de plasma de un paciente que padece o que es susceptible de padecer hipercolesterolemia mediante la administración al paciente de la forma de dosificación farmacéutica según la reivindicación 38.39. Procedure for reducing the level of low plasma density lipoprotein of a patient suffering from or that is susceptible to hypercholesterolemia by administration to the patient of the pharmaceutical dosage form according to claim 38. 40. Procedimiento para la preparación de atorvastatina semicálcica sólida cristalina que presenta por lo menos una característica de la Forma I y solvatos de la misma que comprende las siguientes etapas:40. Procedure for the preparation of solid crystalline semi-calcic atorvastatin presenting at less a characteristic of Form I and solvates of it that It comprises the following stages:
a)to)
calentar los cristales de la Forma XIV de la atorvastatina semicálcica hasta aproximadamente 50ºC o más, yheat the crystals of Form XIV of semi-calcium atorvastatin up to about 50 ° C or more, Y
b)b)
recuperar los cristales como atorvastatina semicálcica sólida cristalina que presenta por lo menos una característica de la Forma I.retrieve the crystals as solid crystalline semi-calcic atorvastatin presenting at less a characteristic of Form I.
41. Procedimiento según la reivindicación 40, en el que la Forma XIV de la atorvastatina semicálcica se calienta a aproximadamente 65ºC.41. Method according to claim 40, in that Form XIV of semi-calcic atorvastatin is heated to approximately 65 ° C. 42. Procedimiento para la preparación de atorvastatina semicálcica sólida cristalina que presenta por lo menos una característica de la Forma VIII que comprende las siguientes etapas:42. Procedure for the preparation of solid crystalline semi-calcic atorvastatin presenting at less a characteristic of Form VIII that includes following stages:
a)to)
proporcionar la Forma XVII de la atorvastatina semicálcica,provide Form XVII of the semi-calcium atorvastatin,
b)b)
secar la Forma XVII para transformarla en atorvastatina semicálcica que presenta por lo menos una característica de la Forma VIII, ydry off Form XVII to transform it into semi-calcic atorvastatin that It has at least one characteristic of Form VIII, Y
c)C)
recuperar la atorvastatina que presenta por lo menos una característica de la Forma VIII.recover the atorvastatin you have at least one characteristic of Form VIII.
43. Procedimiento según la reivindicación 42, en el que el secado comprende calentar la Forma XVII a una temperatura elevada.43. Method according to claim 42, in that drying comprises heating Form XVII at a temperature high. 44. Procedimiento según la reivindicación 43, en el que la temperatura elevada está comprendida entre aproximadamente 40ºC y aproximadamente
70ºC.44. A method according to claim 43, wherein the elevated temperature is between about 40 ° C and about
70 ° C 45. Procedimiento para la preparación de atorvastatina semicálcica sólida cristalina que presenta por lo menos una característica de la Forma IX que comprende las siguientes etapas:45. Procedure for the preparation of solid crystalline semi-calcic atorvastatin presenting at less a characteristic of Form IX that includes following stages:
a)to)
suspender la Forma V de la atorvastatina semicálcica en una mezcla de aproximadamente 50% de 1-butanol y 50% de otro diluyente orgánico, ysuspend Form V of the semi-calcium atorvastatin in a mixture of approximately 50% of 1-butanol and 50% other organic diluent, Y
b)b)
recuperar de la suspensión la atorvastatina semicálcica que presenta por lo menos una característica de la Forma IX.recover from the suspension the semi-calcic atorvastatin that has at least one characteristic of Form IX.
46. Procedimiento según la reivindicación 45, en el que el diluyente orgánico se selecciona de entre el grupo constituido por acetona, 2-propanol, tetrahidrofurano, 1-propanol y metil t-butil éter.46. Method according to claim 45, in which the organic diluent is selected from the group consisting of acetone, 2-propanol, tetrahydrofuran, 1-propanol and methyl t-butyl ether.
ES03713610T 2002-02-15 2003-02-19 NEW FORMS OF CRYSTAL OF SEMICALCID ATORVASTATIN AND PROCEDURES FOR THEIR PREPARATION, AS WELL AS NEW PROCEDURES FOR THE PREPARATION OF FORMS I, VIII AND IX OF SEMICALCICA ATORVASTATIN. Pending ES2241507T1 (en)

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