Novel polymorphs and pseudopolymorphs of risedronate sodium
OwnerJudith Aronhime, Revital Lifshitz-Liron +2inventors
InventorsJudith Aronhime, Revital Lifshitz-Liron, Eti Kovalevski-Ishai, Rami Lidor-Hadas
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Abstract
Provided are novel polymorphs and pseudopolymorphs of risedronate sodium and risedronate disodium, methods for making them, and pharmaceutical compositions containing them.
Claims139
Risedronate sodium in crystalline form B characterized by X-ray peaks at 6.0, 14.4, 19.6, 24.9 and 25.4 degrees two-theta.
Risedronate sodium in crystalline form B stable against transformation to risedronate sodium in crystalline form A when exposed to 75% RH at 40° C. for at least about three months.
Risedronate sodium form B wherein not more that about 20% by weight of the form B transforms to form A when exposed to 75% RH at 40° C. for at least 3 months.
Risedronate sodium in a crystalline form characterized by x-ray diffraction peaks at 6.0, 14.4, 19.6, 24.9 and 25.4 degrees two-theta.
Risedronate sodium in a crystalline form characterized by FTIR absorption bands at 624, 951, 796, 912, 931, 1046, 1105, 1123, 1373, and 1641 cm−1.
A method for preparing risedronate sodium having at least one characteristic of form B comprising the steps of:
- refluxing a mixture of risedronic acid, a sodium base, and a liquid comprising about 40% to about 60% v/v lower alkanol in water, and
- isolating risedronate sodium having at least one characteristic of form B from the resulting mixture.
A method for preparing risedronate sodium having at least one characteristic of form B comprising the steps of:
- refluxing a mixture of risedronic acid, a sodium base, and a liquid comprising about 20% to about 70%, v/v, methanol in water, and
- isolating risedronate having at least one characteristic of form B from the resulting mixture.
Risedronate sodium in a crystalline form characterized by x-ray peaks at about 8.5, 9.1, 9.5, and 12.2+/−0.2 degrees two-theta.
Risedronate sodium in form BB.
A method of making risedronate sodium having at least one characteristic of form BB comprising the steps of:
- a) providing a solution of risedronate sodium in water at a temperature of about 70° C. or more,
- b) adding iso-propanol to the solution to obtain a solid-in-liquid suspension,
- c) isolating the solid from the suspension,
- d) refluxing the isolated solid in suspension in iso-propanol for at least about 10 hours, and
- e) isolating risedronate sodium having at least one characteristic of form BB from the suspension.
A method of making risedronate sodium having at least one characteristic of form BB comprising the step of exposing risedronate sodium having at least one characteristic of form F to an atmosphere having a relative humidity of at least about 80%.
Risedronate disodium salt in a crystalline form characterized by x-ray diffraction peaks at about 6.5, 14.7, 21.2, 27.7, and 32.4+/−0.2 degrees two-theta.
A method of making risedronate sodium in crystalline form B in admixture with crystalline form B1 comprising the steps of:
- refluxing a combination of risedronic acid and a sodium base in a liquid comprising between about 5% and about 25%, v/v, ethanol, the remainder consisting essentially of water, and
- isolating the risedronate sodium form B from the combination.
A method of making risedronate disodium in a crystalline form having at least one characteristic of form B1 comprising the steps of;
- refluxing a mixture of risedronic acid, at least about two equivalents of a sodium base, and a liquid comprising water and ethanol, 50/50 v/v, and
- isolating risedronate disodium having at least one characteristic of form B1 from the mixture.
Risedronate sodium in a crystalline form characterized by X-ray peaks at about 5.6, 10.3, 12.9, 26.5, and 30.9°+/−0.2 degrees two-theta.
Risedronate sodium in a crystalline form characterized by absorption bands at about 615, 666, 1089, 1563 and 1615 cm−1 in FTIR spectroscopy.
The risedronate sodium of form 61 characterized by an FTIR spectrum substantially as shown in FIG. 13.
A method of making risedronate sodium having at least one characteristic of form C comprising the step of refluxing a mixture of risedronic acid, a sodium base, and a liquid comprising about 3%, v/v, ethanol, the remainder of the mixture by volume consisting essentially of water.
Risedronate sodium in a crystalline form characterized by x-ray diffraction peaks at about 9.9, 17.2, 22.1, 27.9, and 29.2+/−0.2 degrees two-theta.
Risedronate sodium in a crystalline form characterized by absorption bands at 697, 807, 854, 955, 1187, 1218, 1576, 1646, and 1719 cm−1 in FTIR spectroscopy.
A method of making risedronate sodium having at least one characteristic of form D comprising the step of refluxing a mixture of risedronic acid, a sodium base, and a liquid that is selected from the group consisting of ethanol, methanol, and mixtures of methanol and water having up to about 11%, v/v, water.
A method of making risedronate sodium comprising crystalline form B comprising the step of exposing risedronate sodium crystalline form D to an atmosphere of 80% to 100% relative humidity.
Risedronate sodium in a crystalline form characterized by x-ray peaks at about 8.4, 8.9, 13.6, 27.6, and 27.9+/−0.2 degrees two-theta.
Risedronate sodium in crystalline a crystalline form characterized by absorption bands at 801, 890, 935, 1656, and 1689 cm−1 in FTIR spectroscopy.
A method of making risedronate sodium having at least one characteristic of form E comprising the step of refluxing a combination of risedronic acid, a sodium base, and a liquid comprising 80%, v/v water, the remainder being methanol.
A method of making risedronate sodium comprising crystalline form E comprising the steps of:
- a) refluxing a combination of risedronic acid, sodium hydroxide, and water,
- b) cooling the combination to a temperature of about room temperature, and
- c) isolating risedronate sodium comprising form E from the combination.
Risedronate sodium in a crystalline form characterized by x-ray peaks at about 6.6, 8.4, 8.9, 12.2, and 18.6+/−0.2 degrees two-theta.
Risedronate sodium in a crystalline form characterized by absorption bands at 971, 1133, and 1306 cm−1 in FTIR spectroscopy.
Risedronate sodium having at least one characteristic of form F stable against transformation to form A in an atmosphere having a relative humidity up to 60%.
A method of making risedronate sodium having at least one characteristic of form F comprising the step of heating risedronate sodium form A, form B, or a mixture of these at 160° C.
Risedronate sodium in a crystalline form characterized by x-ray peaks at about 8.0, 9.9, 12.2, 15.2, and 19.6+/−0.2 degrees two-theta.
Risedronate sodium in a crystalline form characterized by absorption bands at 724, 871, 1174, and 1285 cm−1 in FTIR spectroscopy.
A method of making risedronate sodium having at least one characteristic of form G comprising the step of heating a mixture of risedronate sodium forms A and E at a temperature between about 120° and about 180° C.
Risedronate sodium in a crystalline form characterized by x-ray diffraction reflections at about 6.9, 9.8, 10.9, 13.7, 16.0, and 18.0+/−0.2 degrees two theta.
A method for making risedronate sodium having at least one characteristic of form H comprising the step of exposing risedronate sodium form C in an atmosphere having a relative humidity between about 60% and about 100%.
A method of making risedronate sodium form B comprising the steps of:
- a) combining a solution of sodium hydroxide in a mixture of water and ethanol, 60% v/v, with risedronic acid, wherein the amount of sodium hydroxide combined is about one equivalent based on risedronic acid,
- b) heating the combination at reflux for a reflux time,
- c) cooling the mixture to about room temperature,
- d) further cooling the mixture to a temperature of about 5° C. or less, and
- e) isolating risedronate sodium form B.
A method of making risedronate sodium having at least one characteristic of form A comprising the step of refluxing a mixture of risedronic acid, a sodium base, and a liquid comprising about 20%, v/v, iso-propanol and water.
A method of making risedronate sodium having at least one characteristic of form A comprising the steps of:
- a) refluxing a water solution of sodium risedronate,
- b) cooling the solution to obtain a suspension, and
- c) isolating risedronate sodium having at least one characteristic of form A from the suspension.
A method of making risedronate sodium form A comprising the step of exposing risedronate sodium form E, risedronate sodium form G, or a mixture of risedronate sodium forms E and G to an atmosphere having a relative humidity of at least about 80% for a period of about one week.
A method of making risedronate sodium form A comprising the step of incubating risedronate sodium form E at 60° C. for a period of at least about 5 hours.
A method of making risedronate sodium form A comprising the step of treating risedronate sodium form B or form D, or a mixture of these, with water at a temperature between about room temperature and about reflux temperature.
A method of making risedronate sodium having at least one characteristic form B comprising the step of treating risedronate sodium form A with 1:1, v/v, mixture of a lower alkanol and water at a temperature between about room temperature and about reflux temperature.
A method of making risedronate sodium having at least one characteristic of form D comprising the step of treating risedronate sodium comprising form BB in ethanol at a temperature between about room temperature and about reflux temperature.
A pharmaceutical composition comprising pure risedroante sodium form B and at least one pharmaceutically acceptable excipient.
125 The pharmaceutical composition of claim 124 wherein at least about 60% by weight of the risedronate sodium form B remains untransformed to form A when the composition is stored for at least 3 months at 40° C. and 75% RH.
The pharmaceutical composition of claim 125 wherein at least about 60% by weight of the risedronate sodium form B remains untransformed to form A when the composition is stored for at least 6 months at 40° C. and 75% RH.
The pharmaceutical composition of claim 125 wherein at least about 60% by weight of the risedronate sodium form B remains untransformed to form A when the composition is stored for at least about 2 years at a temperature of about 25° C. and 75% RH. 6 months at 40° C. and 75% RH.
The pharmaceutical composition of claim 125 in the form of a tablet.
A pharmaceutical composition comprising stable risedronate sodium form B and at least one pharmaceutically acceptable excipient.
A pharmaceutical composition comprising risedronate sodium crystalline form C and at least one pharmaceutically acceptable excipient.
A pharmaceutical composition comprising risedronate sodium crystalline form B1 and at least on pharmaceutically acceptable excipient.
A pharmaceutical composition comprising risedronate sodium crystalline form D and at least one pharmaceutically acceptable excipient.
A pharmaceutical composition comprising risedronate sodium crystalline form BB and at least one pharmaceutically acceptable excipient.
A pharmaceutical composition comprising risedronate sodium crystalline form E and at least one pharmaceutically acceptable excipient.
A pharmaceutical composition comprising risedronate sodium crystalline form F and at least one pharmaceutically acceptable excipient.
A pharmaceutical composition comprising risedronate sodium crystalline form G and at least one pharmaceutically acceptable excipient.
A pharmaceutical composition comprising risedronate sodium crystalline form H and at least one pharmaceutically acceptable excipient.
A method of treating osteoporosis comprising the step of administering to a patient suffering from osteoporosis an osteoporosis treating effective amount of risedronate sodium pure form B.
A method of treating osteoporosis comprising the step of administering to a patient suffering from osteoporosis an osteoporosis treating effective amount of at least one of risedronate sodium crystal forms B, C, D, B1, BB, E, F, G, and H.
Dependencies are inferred from the claim text.