MX2007002286A - Solid and crystalline ibandronate sodium and processes for preparation thereof - Google Patents

Abstract

The present invention relates to solid amorphous and crystalline forms of ibandronate sodium.

Description

SODIUM OF SOLID AND CRYSTAL IBANDRONATE AND PROCESSES FOR THE PREPARATION OF THE SAME The present patent application claims priority of the US Provisional Patent Application Act No. 60 / 604,026 filed on August 23, 2004 and of the provisional US patent application Act No. 60 / 690,867 filed on June 16, 2005.

Field of the invention The present invention relates to the chemical composition of the sodium solid state of ibandronate.

BACKGROUND OF THE INVENTION The empirical formula for ibandronate sodium is CgH22 07P2 aH20. The chemical name of ibandronate sodium is monosodium salt of (l-hydroxy-3- (N-methyl-N-pentylamino) propylidene) bisphosphonic acid. The chemical structure of ibandronate sodium is as follows: The chemical structure of ibandronic acid (IBD-Ac) is as follows: Ibandronate sodium is a bisphosphonate containing third generation nitrogen characterized by a side chain of aliphatic tertiary amine. Ibandronate sodium is a white powder.

U.S. Patent No. 4,972,814 discloses diphosphonic acid derivatives, processes for the preparation thereof, and pharmaceutical compositions containing them.

Boniva® (ibandronate sodium) was developed by Hoffmann-La Roche for the treatment of bone disorders such as tumor hypercalcemia, osteolysis, Piaget's disease, osteoporosis, and metastatic bone disease. It exists as an intravenous injection administered every 2-3 months and as an oral formulation.

Boniva® is also marketed in Europe under the name Bondranat® for bone complications related to cancer. Bondranat® exists in ampoules with 1 ml of concentrate for solution containing 1,125 mg of monosodium ibandronic monohydrate salt, which corresponds to 1 mg of ibandronic acid.

The present invention relates to the physical properties of ibandronate sodium solid state. These properties can be influenced by controlling the conditions in which ibandronate sodium is obtained in solid form. Physical properties of solid state include, for example, the fluidity of the ground solid. Fluidity affects the ease with which the material is handled during processing in a pharmaceutical product. When the particles of the powdered compound do not flow together easily, a formulations specialist must need to use dislifters such as colloidal silicon dioxide, talc, starch, or tribasic calcium phosphate.

Another important solid state property of a pharmaceutical compound is its rate of dissolution in an aqueous liquid. The rate of dissolution of an active ingredient in the stomach fluid of a patient may have therapeutic consequences since it imposes an upper limit on the rate at which an orally administered ingredient may reach the patient's bloodstream. The rate of dissolution 'should also be considered in the formulation of syrups, elixirs and other liquid medicines. The solid state form of a compound can also affect its behavior when compacted and its storage stability.

These practical physical characteristics are influenced by the conformation and orientation of the molecules in the unit cell, which define a particular polymorphic form of a substance. The polymorphic form can give rise to a thermal behavior different from that of the amorphous material or another polymorphic form. The thermal behavior is measured in the laboratory by techniques such as capillary melting point, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form can also give rise to distinguishable spectroscopic properties that can be detected by X-ray crystallography, solid spectrometry and infrared spectrometry.

Generally, the crystalline solid has improved chemical and physical stability compared to the amorphous form, and forms with low crystallinity. It may also exhibit improved solubility, hygroscopicity, global properties and / or fluidity.

The discovery of new polymorphic forms of a pharmaceutically useful compound offers a new opportunity to improve the performance characteristics of a pharmaceutical product. It broadens the repertoire of materials that a formula scientist has at their disposal to design, for example, a pharmaceutical dosage form of a drug with a desired release profile or other desired characteristics. There is a need in the art for additional polymorphic forms of ibandronate sodium.

Extract of the invention In one aspect, the present invention provides novel crystalline forms of ibandronate sodium, an amorphous form of ibandronate sodium, and processes for preparing these forms.

In another aspect, the present invention provides solid crystalline ibandronate sodium solvate.

In another aspect, the present invention provides solid crystalline ibandronate sodium alcoholate.

In another aspect, the present invention provides solid crystalline ibandronate sodium ethanolate.

In another aspect, the present invention provides solid crystalline ibandronate sodium butanolate.

In another aspect, the present invention provides solid crystalline ibandronate sodium denominated Form C, characterized by X-ray powder diffraction reflections at 4.7, 5.0, 17.2, 18.3, and 19.5 + 0. , 2 degrees two theta. Form C can exist as a monoethanolate.

In another aspect, the present invention provides solid crystalline ibandronate sodium denominated Form D, characterized by X-ray powder diffraction reflections at 4.8, 9.3, 18.5, 23.1 and 36.1 ± 0, 2 degrees two theta.

In another aspect, the present invention provides solid crystalline ibandronate sodium called Form E, characterized by X-ray powder diffraction reflections at 4.6, 4.8, 5.3, 9.3 and 34.7 ± 0, 2 degrees two theta. Form E can exist as a hemibutanolate.

In another aspect, the present invention provides solid crystalline ibandronate sodium denominated Form F, characterized by X-ray powder diffraction reflections at 4.9, 5.1, 6.0, 20.0 and 36.4 ± 0, 2 degrees two theta.

In another aspect, the present invention provides solid crystalline ibandronate sodium denominated Form G, characterized by X-ray powder diffraction reflections at 4.7, 9.2, 17.4, 18.4, and 19.9 ± 0. , 2 degrees two theta.

In another aspect, the present invention provides solid crystalline ibandronate sodium designated Form H, characterized by X-ray powder diffraction reflections at 4.8, 5.7, 17.3, 19.5 and 26.0 ± 0, 2 degrees two theta.

In another aspect, the present invention provides solid crystalline ibandronate sodium denominated Form J, characterized by X-ray powder diffraction reflections at 4.6, 9.2, 18.3, 19.6 and 25.6 ± 0, 2 degrees two theta.

In another aspect, the present invention provides solid crystalline ibandronate sodium designated Form K, characterized by X-ray powder diffraction reflections at 5.0, 5.9, 17. 2, 20.0 and 25.9 + 0.2 degrees two theta.

In another aspect, the present invention provides solid crystalline ibandronate sodium designated Form K2, characterized by X-ray powder diffraction reflections at 5.1, 6.1, 17. 3, 20.1 and 21.5 ± 0.2 degrees two theta.

In another aspect, the present invention provides solid crystalline ibandronate sodium designated Form K3, characterized by X-ray powder diffraction reflections at 5.1, 6.2, 17.3, 19.7 and 20.1 ± 0, 2 degrees two theta.

In another aspect, the present invention provides solid crystalline ibandronate sodium called Form Q, characterized by X-ray powder diffraction reflections at 5.0, 6.1, 17.2, 25.7 and 30.9 ± 0, 2 degrees two theta.

In another aspect, the present invention provides solid crystalline ibandronate sodium called Form Ql, characterized by X-ray powder diffraction reflections at 4.7, 6.0, 17.2, 26.2 and 31.0 ± 0, 2 degrees two theta.

In another aspect, the present invention provides solid crystalline ibandronate sodium denominated Form Q2, characterized by X-ray powder diffraction reflections at 4.9, 6.2, 25.9, 31.0 and 37.1 ± 0, 2 degrees two theta.

In another aspect, the present invention provides solid crystalline ibandronate sodium denominated Form Q3, characterized by X-ray powder diffraction reflections at 5.9, 17.1, 19.6, 20.2 and 21.3 ± 0, 2 degrees two theta.

In another aspect, the present invention provides solid crystalline ibandronate sodium denominated Form Q4, characterized by X-ray powder diffraction reflections at 6.1, 17.2, 19.6, 20.3 and 21.4 ± 0, 2 degrees two theta.

In another aspect, the present invention provides solid crystalline ibandronate sodium denominated Form Q5, characterized by X-ray powder diffraction reflections at 6.1, · 17.2, 19.6, 20.1 and 21.5 + 0 , 2 degrees two theta. In another aspect, the present invention provides solid crystalline ibandronate sodium denominated Form Q6, characterized by X-ray powder diffraction reflections at 6.1, 17.3, 19. 6, 21.5 and 30.8 ± 0.2 degrees two theta.

In another aspect, the present invention provides solid crystalline ibandronate sodium called Form QQ, characterized by X-ray powder diffraction reflections at 6.2, 25.9, 26. 7, 31.1 and 37.2 + 0.2 degrees two theta.

In another aspect, the present invention provides solid crystalline ibandronate sodium designated Form R, characterized by X-ray powder diffraction reflections at 5.3, 6.0, 17.2, 18.7 and 20.0 ± 0, 2 degrees two theta.

In another aspect, the present invention provides solid crystalline ibandronate sodium called Form S, characterized by X-ray powder diffraction reflections at 4.8, 5.1, 5.3, 5.4 and 6.1 ± 0, 2 degrees two theta.

In another aspect, the present invention provides solid crystalline ibandronate sodium called Form 'T, characterized by X-ray powder diffraction reflections at 6.2, 15.7, 26.3, 32.6 and 35.6 ± 0. , 2 degrees two theta. In still another aspect, the present invention provides solid amorphous ibandronate sodium.

Brief Description of the Drawings Figure 1 is an X-ray powder diffractogram of ibandronate sodium Form C.

Figure 2 is an X-ray powder diffractogram of ibandronate sodium Form D.

Figure 3 is an X-ray powder diffractogram of ibandronate sodium Form E.

Figure 4 is an X-ray powder diffractogram of ibandronate sodium Form F.

Figure 5 is an X-ray powder diffractogram of ibandronate sodium Form G.

Figure 6 is an X-ray powder diffractogram of ibandronate sodium Form H.

Figure 7 is an X-ray powder diffractogram of ibandronate sodium Form J.

Figure 8 is an X-ray powder diffractogram of ibandronate sodium Form K.

Figure 9 is an X-ray powder diffractogram of ibandronate sodium Form K2.

Figure 10 is an X-ray powder diffractogram of ibandronate sodium Form K3.

Figure 11 is an X-ray powder diffractogram of ibandronate sodium Form Q.

Figure 12 is an X-ray powder diffractogram of the ibandronate sodium Ql form.

Figure 12a is an X-ray powder diffractogram of the ibandronate sodium form.

Figure 13 is an X-ray powder diffractogram of ibandronate sodium Form Q2.

Figure 13a is a diffractogram of X-ray powder of the Form Q2 of ibandronate sodium.

Figure 14 is an X-ray powder diffractogram of the Form Q3 of ibandronate sodium.

Figure 15 is an X-ray powder diffractogram of the Form Q4 of ibandronate sodium.

Figure 16 is an X-ray powder diffractogram of ibandronate sodium Form Q5.

Figure 17 is an X-ray powder diffractogram of the Form Q6 of ibandronate sodium.

Figure 18 is an X-ray powder diffractogram of ibandronate sodium QQ Form.

Figure 19 is an X-ray powder diffractogram of ibandronate sodium Form R.

Figure 20 is a diffractogram of X-ray powder of the S-Form of ibandronate sodium.

Figure 20a is an X-ray powder diffractogram of the S-Form of ibandronate sodium.

Figure 21 is an X-ray powder diffractogram of ibandronate sodium Form T.

Figure 22 is a diffractogram of amorphous ibandronate sodium X-ray powder.

Detailed description of the invention The present invention provides novel crystalline forms of sodium of inbandronate, as well as an amorphous form of ibandronate sodium. In one embodiment, the present invention provides each crystalline form substantially free of other crystalline forms, ie containing no more than 5% of other crystalline forms. The present invention also provides processes for preparing each described solid form of ibandronate sodium.

The present invention also provides forms of ibandronate sodium solvate. The range of solvent content for these solvates is defined below: Solvate Form Solvent Content Range (by weight) 1/3 ethanolate: 4% -5% Monoethanolate: 8% -12% Hemibutanolate: 8% -10% The present invention provides solid crystalline ibandronate sodium alcoholates.

The present invention provides solid crystalline ibandronate sodium ethanolate. The present invention also provides solid crystalline ibandronate sodium monoethanolate and hemietanolate.

The present invention also provides solid crystalline ibandronate sodium butanolate. The present invention also provides solid crystalline ibandronate sodium hemibutanolate.

In one embodiment, the present invention provides a solid crystalline form of ibandronate sodium designated Form C. Form C is characterized by diffraction, X-ray powder reflections at 4.7, 5.0, 17.2, 18, 3, and 19.5 ± 0.2 degrees two theta. Form C can also be characterized by X-ray powder diffraction reflections at 17.6, 19.7, 20.2, 20.6 and 23.8 ± 0.2 degrees two theta. Figure 1 shows a powder X-ray diffraction diagram representative of Form C. Form C can be monohydrate and / or monoethanolate. Form C can be further characterized by TGA, which shows a weight loss of 15% to 16%.

In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium designated Form D. Form D is characterized by X-ray powder diffraction reflections at 4.8, 9.3, 18.5, 23.1 and 36.1 ± 0.2 degrees two theta. Form D can also be characterized by X-ray powder diffraction reflections at 15.3, 19.9, 26.3, 27.2 and 30.4 ± 0.2 degrees two theta. Figure 2 shows a powder X-ray diffraction diagram representative for Form D. Form D can be a hexahydrate. Form D can be further characterized by TGA, which shows a weight loss of 24% to 26%.

In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium designated Form E. Form E is characterized by X-ray powder diffraction reflections at 4.6, 4.8, 5.3, 9.3 , and 34.7 ± 0.2 degrees two theta. Form E can also be characterized by X-ray powder diffraction reflections at 18.6, 23.3, 24.5, 27.1 and 30.1 + 0.2 degrees two theta. Figure 3 shows a powder X-ray diffraction diagram representative for Form E. Form E can be a hemibutanolate and / or a sesquihydrate. Form E can be further characterized by TGA, which shows a weight loss of 14% to 21%.

In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium called Form F. Form F is characterized by X-ray powder diffraction reflections at 4.9, 5.1, 6.0, 20.0 and 36.4 ± 0.2 degrees two theta. Form F can also be characterized by X-ray powder diffraction reflections at 18.6, 26.0, 28.5, 30.4 and 31.3 ± 0.2 degrees two theta. Figure 4 shows a powder X-ray diffraction diagram representative for Form F. Form F can be further characterized by TGA, which shows a weight loss of 10% to 32%.

In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium designated Form G. Form G is characterized by X-ray powder diffraction reflections at 4.7, 9.2, 17.4, 18.4 and 19.9 ± 0.2 degrees two theta. Form G can also be characterized by X-ray powder diffraction reflections at 10.1, 15.2, 18.7, 26.3 and 27.1 + 0.2 degrees two theta. Figure 5 shows a powder X-ray diffraction diagram representative for Form G. Form G can be a hexahydrate. Form G can be further characterized by TGA, which shows a weight loss of 22% to 25%.

In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium designated Form H. Form H is characterized by X-ray powder diffraction reflections at 4.8, 5.7, 17.3, 19.5 and 26.0 ± 0.2 degrees two theta. Form H can also be characterized by X-ray powder diffraction reflections at 18.5, 20.1, 23.8, 31.1 and 37.1 ± 0.2 degrees two theta. Figure 6 shows a powder X-ray diffraction diagram representative for Form H. Form H can be further characterized by TGA, which shows a weight loss of 13% to 16%.

In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium designated Form J. Form J is characterized by X-ray powder diffraction reflections at 4.6, 9.2, 18.3, 19.6 and 25.6 ± 0.2 degrees two theta. Form D can also be characterized by X-ray powder diffraction reflections at 17.5, 18.9, 21.7, 22.9 and 29.5 ± 0.2 degrees two theta. Figure 7 shows a powder X-ray diffraction diagram representative for Form J. Form J can be a hexahydrate. Form J can be further characterized by TGA, which shows a weight loss of 22% to 23%.

In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium designated Form K. Form K is characterized by X-ray powder diffraction reflections at 5.0, 5.9, 17.2, 20.0 and 25.9 ± 0.2 degrees two theta. The K-form can also be characterized by X-ray powder diffraction reflections at 18.5, 19.7, 21.4, 26.5 and 31.1 ± 0.2 degrees two theta. Figure 8 shows a powder X-ray diffraction diagram representative for Form K. Form K can be a sesquihydrate. Form K can be further characterized by TGA, which shows a weight loss of 10% to 15%.

In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium. called Form K2. Form K2 is characterized by X-ray powder diffraction reflections at 5.1, 6.1, 17.3, 20.1 and 21.5 ± 0.2 degrees two theta. The K2 form can also be characterized by X-ray powder diffraction reflections at 18.6, 19.6, 26.1, 26.8 and 31.1 ± 0.2 degrees two theta. Figure 9 shows a powder X-ray diffraction diagram representative for Form K2. Form K2 can be further characterized by TGA ,. which shows a weight loss of 9% to 10%.

In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium designated Form K3. Form K3 is characterized by X-ray powder diffraction reflections at 5.1, 6.2, 17.3, 19.7 and 20.1 ± 0.2 degrees two theta. The K3 form can also be characterized by X-ray powder diffraction reflections at 18.5, 21.5, 23.8, 25.8 and 31.1 ± 0.2 degrees two theta. Figure 10 shows a powder X-ray diffraction diagram representative for Form K3. Form K3 can be further characterized by TGA, which shows a weight loss of 7% to 8%.

In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium called Form Q. Form Q is characterized by X-ray powder diffraction reflections at 5.0, 6.1, 17.2, 25.7 and 30.9 ± 0.2 degrees two theta. The Q-shape can also be characterized by X-ray powder diffraction reflections at 16.8, 21.4, 26.7, 29.1 and 36.9 ± 0.2 degrees two theta. Figure 11 shows a powder X-ray diffraction pattern representative for Form Q. Form Q may be in the range of a monohydrate to a hexahydrate. Form Q can be further characterized by TGA, which shows a weight loss of 5% to 25%.

In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium called Form Ql. Form Ql is characterized by X-ray powder diffraction reflections at 4.7, 6.0, 17.2, 26.2, and 31.0 + 0.2 degrees two theta. The Ql form can also be characterized by X-ray powder diffraction reflections at 19.5, 21.4, 25.8, 29.1 and 37.1 + 0.2 degrees two theta. Figures 12 and 12a show representative X-ray powder diffraction diagrams for Form Ql. Form Ql may be in the range of a dihydrate to a trihydrate. Form Ql can be further characterized by TGA, which shows a weight loss of 9% to 16%.

In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium designated Form Q2. Form Q2 is characterized by X-ray powder diffraction reflections at 4.9, 6.2, 25.9, 31.0 and 37.1 ± 0.2 degrees two theta. The Q2 form can also be characterized by X-ray powder diffraction reflections at 16.9, 17.3, 19.0, 26.6 and 29.2 ± 0.2 degrees two theta. Figures 13 and 13a show representative X-ray powder diffraction diagrams for Form Q2. Form Q2 may be in the range of a dihydrate to a tetrahydrate. Form Q2 can be further characterized by TGA, which shows a weight loss of 8% to 17%.

In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium called Form Q3. Form Q3 is characterized by X-ray powder diffraction reflections at 5.9, 17.1, 19.6, 20.2 and 21.3 ± 0.2 degrees two theta. The Q3 form can also be characterized by X-ray powder diffraction reflections at 28.0, 18.5, 23.6, 24.7 and 30.8 ± 0.2 degrees two theta. Figure 14 shows a diffraction diagram of. X-rays of representative powder for Form Q3. Form Q3 can be further characterized by TGA, which shows a weight loss of 7% to 9%.

In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium designated Form Q4. Form Q4 is characterized by X-ray powder diffraction reflections at 6.1, 17.2, 19.6, 20.3 and 21.4 ± 0.2 degrees two theta. The Q4 form can also be characterized by X-ray powder diffraction reflections at 16.9, 18.1, 18.5, 23.7 and 24.8 ± 0.2 degrees two theta. Figure 15 shows a powder X-ray diffraction diagram representative for Form Q4. Form Q4 can be further characterized by TGA, which shows a weight loss of 7% to 8%.

In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium designated Form Q5. Form Q5 is characterized by X-ray powder diffraction reflections at 6.1, 17.2, 19.6, 20.1 and 21.5 ± 0.2 degrees two theta. Form Q5 can also be characterized by X-ray powder diffraction reflections at 16.8, 24.7, 25.7, 29.0 and 30.9 ± 0.2 degrees two theta. Figure 16 shows a powder X-ray diffraction diagram representative for Form Q5. Form Q5 can be further characterized by TGA, which shows a weight loss of 5% to 11%.

In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium called Form Q6. Form Q6 is characterized by X-ray powder diffraction reflections at 6.1, 17.3, 19.6, 21.5 and 30.8 ± 0.2 degrees two theta. The Q6 form can also be characterized by X-ray powder diffraction reflections at 16.9, 20.2, 25.6, 26.9 and 29.1 ± 0.2 degrees two theta. Figure 17 shows a powder X-ray diffraction diagram representative for Form Q6. Form Q6 can be further characterized by TGA, which shows a weight loss of 9% to 10%. In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium called Form QQ. Form QQ is characterized by X-ray powder diffraction reflections at 6.2, 25.9, 26, 7, 31.1 and 37.2 ± 0.2 degrees two theta. The QQ form can also be characterized by X-ray powder diffraction reflections at 16.9, 17.3, 21.5, 24.7 and 29.2 ± 0.2 degrees two theta. Figure 18 shows a powder X-ray diffraction diagram representative for Form QQ. This crystalline form does not transform into other polymorphic forms by more than 5% when stored, for example, at 100% relative humidity at 40 ° C for 3 days. Form QQ also has a particle size distribution of not more than 100 μ, preferably not greater than 60 μ. Form Q2 may be in the range of a monohydrate to a trihydrate. Form QQ can be further characterized by TGA, which shows a weight loss of 5% to 12%.

An optical microscope can be used to directly observe and evaluate the maximum size and shape of the particles. A suspension of material (such as a sample in silicone fluid) can be placed on a slide and viewed through different lenses of the microscope. The size of these particles can be established by a calibrated internal rule. In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium designated Form R. Form R is characterized by X-ray powder diffraction reflections at 5.3, 6.0, 17.2, 18.7 and 20.0 + 0.2 degrees two theta. The R-form can also be characterized by X-ray powder diffraction reflections at 20.5, 25.0, 26.5, 29.1 and 31.0 ± 0.2 degrees two theta. Figure 19 shows a powder X-ray diffraction diagram representative for Form R. Form R can be a hemiethanolate and / or a monohydrate. Form R can be further characterized by TGA, which shows a weight loss of 10% to 11%.

In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium designated Form S. Form S is characterized by X-ray powder diffraction reflections at 4.8, 5.1, 5.3, 5.4. and 6.1 ± 0.2 degrees two theta. The S-form can also be characterized by X-ray powder diffraction reflections at 10.5, 21.0, 26.3, 33.0 and 38.2 + 0.2 degrees two theta. Figures 20 and 20a show powder X-ray diffraction diagrams representative for Form S. Form S can be a hemiethanolate and / or a hemihydrate. Form S can be further characterized by TGA, which shows a weight loss of 11% to 12%.

In another embodiment, the present invention provides a solid crystalline form of ibandronate sodium called Form T. Form T is characterized by X-ray powder diffraction reflections at 6.2, 15.7, 26.3, 32.6 and 35.6 ± 0.2 degrees two theta. The T-shape can also be characterized by X-ray powder diffraction reflections at 17.6, 19.4, 26.9, 31.7 and 38.7 ± 0.2 degrees two theta. Figure 21 shows a powder X-ray diffraction diagram representative for Form T. Form T can be further characterized by TGA, which shows a weight loss of 5% to 7%.

In another embodiment, the present invention provides solid amorphous ibandronate sodium. Figure 22 shows an X-ray diffraction diagram of amorphous ibandronate sodium powder. The amorphous form can be characterized by TGA, which shows a weight loss of 6.8% to 24.4%.

In another embodiment, the present invention provides processes for preparing crystalline forms of ibandronate sodium that include the steps of dissolving ibandronate sodium in a solvent and isolating the crystalline form of ibandronate sodium from the reaction mixture.

In another embodiment, the present invention provides processes for preparing crystalline forms of ibandronate sodium that include the steps of combining sodium hydroxide with ibandronic acid, preferably amorphous ibandronic acid, with a solvent and isolating the crystalline form of ibandronate sodium from the combination . The solvent may be an organic solvent such as a C3-C7 ketone or ester, a C1-C3 alcohol, or acetonitrile; Water; or a mixture of them. Preferred solvents for use in this embodiment of the present invention include acetone, methanol, ethanol, isopropanol, acetonitrile, water, and mixtures thereof. The sodium hydroxide can be solid, aqueous or preferably, the sodium hydroxide is in solution in the solvent with which sodium hydroxide and ibandronic acid are combined. The sodium of crystalline ibandronate preferably precipitates from a solution having a pH of 3 to 5, preferably.

The initial combination can be and usually is a solution. The processes may further comprise combining the solution with an antisolvent. As used herein, an antisolvent is a liquid that causes a substance X to precipitate from a solution more rapidly or to a greater extent than would precipitate X from the same solution under the same conditions but without the antisolvent. A solution can be added to an antisolvent or vice versa. The antisolvent can be added drop by drop or all at once. The antisolvent can be, for example, an organic solvent that includes a ketone or C3-C7 ester such as acetone; a C1-C4 alcohol such as methanol, ethanol, isopropanol, 1-butanol or 2-butanol, DMSO; acetonitrile; tetrahydrofuran; or a cyclic or acyclic saturated hirocarbide of C5-C7 such as hexane.

The processes may also comprise heating the combination (which may be a solution) and / or cooling the combination. For example, the combination can be heated to a temperature above room temperature to a temperature of 50 ° C to 130 ° C, preferably at reflux temperature. The combination can be cooled to a temperature from room temperature to 0 ° C, preferably at room temperature. The solution can be cooled at once or step by step. When a cooling step is used with the processes starting with ibandronic acid and NaOH, the solution is preferably cooled step by step, more preferably first by cooling to room temperature and then again cooling with an ice bath.

Preferably, the combination is a solution and the solution is stirred during one or more steps to facilitate complete precipitation. Preferably, the solution is stirred for one or more steps for 10 minutes to 72 hours, preferably for one hour to 20 hours, more preferably for 16 hours.

The isolation of the crystalline form can be carried out by any means known in the art. For example, the crystalline form can be isolated by suction filtration. The processes may also include washing and / or drying the precipitated crystalline form. For example, the crystalline form can be washed with the same solvent used for the dissolution. It can be dried in a vacuum oven at 50 ° C for 24 hours or it can be dried by evaporation.

In one embodiment, the present invention provides a process for preparing ibandronate sodium Form C which includes the steps of dissolving ibandronate sodium in dimethyl sulfoxide (DMSO) to form a solution, combining the solution with butanol to form a suspension, and isolate Form C sodium from ibandronate from the suspension. Preferably, the solution is heated to a temperature of 120 ° C to 125 ° C. Preferably, the suspension is stirred at the heated temperature for 1 to 5 hours, more preferably for 3 hours. Preferably, the process further includes cooling the suspension to room temperature.

In one embodiment, the present invention provides a process for preparing ibandronate sodium Form D which includes the steps of dissolving ibandronate sodium in water to form a solution, combining the solution with acetone to form a suspension, and isolating sodium from Crystalline ibandronate from the suspension. Preferably, the process includes heating the solution to reflux temperature. Preferably, the suspension is stirred at the reflux temperature for 1 to 5 hours, more preferably for 4.5 hours. Preferably, the process further includes cooling the suspension to room temperature.

In another embodiment, the present invention provides a process for preparing ibandronate sodium Form E which includes the steps of dissolving ibandronate sodium in water to form a solution, combining the solution with methanol or 1-butanol to form a suspension, and Isolate the E-form of ibandronate sodium from the suspension. The process may include heating and cooling the solution. When the process includes heating the solution, the solution is preferably heated to reflux temperature. When the solution is heated, the suspension is preferably stirred at reflux temperature for 1 to 5 hours, more preferably for 4 to 4.5 hours. The heated suspension can be cooled to room temperature. Optionally, when 1-butanol is used, the process is carried out at room temperature.

In one embodiment, the present invention provides a process for preparing Form I of ibandronate sodium which includes the steps of dissolving ibandronate sodium in water to form a solution, combining the solution with isopropanol to form a suspension, and isolating the Form F of ibandronate sodium from the suspension. Preferably, the process includes heating the solution to reflux temperature. Preferably, the suspension is stirred at the reflux temperature for 1 to 5 hours, more preferably for 4 hours. Preferably, the process further includes cooling the suspension to room temperature.

In one embodiment, the present invention provides a process for preparing ibandronate sodium Form F which includes the steps of combining sodium hydroxide with ibandronic acid in a mixture of water and isopropanol having a water to isopropanol ratio of 20:80. at 60:40 and isolate Form F sodium of ibandronate from the reaction mixture. Preferably, the process includes heating the reaction mixture to reflux temperature. Preferably, the suspension is stirred at the reflux temperature for 0.5 to 5 hours. Preferably, the process further includes cooling the suspension to room temperature.

In one embodiment, the present invention provides a process for preparing Form I sodium ibandronate which includes the steps of dissolving ibandronate sodium in water to form a solution, combining the solution with DMSO to form a suspension, and isolating Form G of ibandronate sodium from the suspension. Preferably, the solution is at room temperature. Preferably, the suspension is stirred at room temperature for 16 hours.

Alternatively, the process may include the steps of dissolving ibandronate sodium in DMSO to form a solution, combining the solution with ethanol to form a suspension, and isolating Form G sodium from ibandronate from the solution. Preferably, the process includes heating the solution to a temperature of 120 ° C to 125 ° C, more preferably to 120 ° C. Preferably, the solution is cooled to room temperature and stirred for 16 hours. Preferably, the suspension is stirred at room temperature for 1 to 3 hours, more preferably for 2 hours.

In one embodiment, the present invention provides a process for preparing ibandronate sodium Form H which includes the steps of dissolving ibandronate sodium in water to form a solution, combining the solution with methanol, ethanol or isopropanol to form a suspension, and isolate Form H sodium from ibandronate from the suspension.

Preferably, the solution is at room temperature. Preferably, the suspension is stirred for 16 hours at room temperature.

In one embodiment, the present invention provides a process for preparing ibandronate sodium Form J which includes the steps of dissolving ibandronate sodium in water to form a solution, combining the solution with D SO to form a suspension, and isolating the Form J of ibandronate sodium from the suspension. Preferably, the process includes heating the solution to reflux temperature. Preferably, the suspension is stirred at the reflux temperature for 1 to 10 hours, more preferably for 6 hours. Preferably, the process further includes cooling the suspension to room temperature.

In one embodiment, the present invention provides a process for preparing ibandronate sodium Form K which includes the steps of combining sodium hydroxide with ibandronic acid in isopropanol and isolating ibandronate sodium Form K from the solution. Preferably, the process includes heating the reaction mixture to reflux temperature. Preferably, the reaction mixture is stirred at the reflux temperature for 1 to 5 hours, more preferably for 4 hours. Preferably, the process further includes cooling the suspension to room temperature.

In one embodiment, the present invention provides a process for preparing ibandronate sodium form K2 which includes the steps of dissolving ibandronate sodium in water to form a solution and isolating ibandronate sodium form K2 from the reaction mixture. Preferably, the process includes quenching the reaction mixture at reflux temperature. Preferably, the process further includes cooling the suspension to room temperature.

In one embodiment, the present invention provides a process for preparing ibandronate sodium Form K3 which includes the steps of combining sodium hydroxide with ibandronic acid in water to form a solution, combining the solution with isopropanol to form a suspension and isolating the Form K3 of ibandronate sodium from the suspension. Preferably, the process includes heating the ibandronic acid solution in water at 70 ° C. Preferably, the isopropanol is cold, and the suspension is further cooled, preferably at 0 ° C. Preferably, the suspension is stirred at 0 ° C for 16 hours.

In one embodiment, the present invention provides a process for preparing ibandronate sodium Form Q which includes the steps of dissolving ibandronate sodium in water to form a solution, combining the solution with acetone or acetonitrile to form a suspension, and isolating the Form Q of ibandronate sodium from the solution. Preferably, the solution is at room temperature. Preferably, the suspension is stirred at room temperature for 16 hours. Optionally, when the solvent is acetone, the solution is heated to reflux temperature, and the suspension is stirred at reflux temperature for 4 to 5 hours. Preferably, when the suspension is at reflux temperature, the process further includes cooling the suspension to room temperature.

In another embodiment, the present invention provides a process for preparing Form I sodium ibandronate which includes the steps of combining sodium hydroxide with ibandronic acid in acetone, ethanol, water or a mixture of water and acetonitrile having a water ratio to acetonitrile from 20:80 to 60:40 and isolate Form Q from ibandronate sodium from the reaction mixture. When the solvent is water, the process also includes the step of combining the reaction mixture with acetone. When the solvent is water, the reaction mixture is preferably at room temperature. When the solvent is acetone, ethanol or a mixture of water and acetonitrile having a water to acetonitrile ratio of 20:80 to 60:40, the reaction mixture is preferably at reflux temperature and subsequently, the reaction mixture it is cooled to room temperature.

In one embodiment, the present invention provides a process for preparing the ibandronate sodium Ql Form including the steps of dissolving ibandronate sodium in water to form a solution, combining the solution with 2-butanol or tetrahydrofuran to form a suspension, and isolate the Ql form of ibandronate sodium from the suspension. Preferably, the solution is at room temperature. Preferably, the suspension is stirred at room temperature for 16 hours.

In one embodiment, the present invention provides a process for preparing Form I2 of ibandronate sodium which includes the steps of dissolving ibandronate sodium in water to form a solution, combining the solution with acetonitrile to form a suspension, and isolating Form Q2 of ibandronate sodium from the suspension. Preferably, the process includes heating the reaction mixture to reflux temperature. Preferably, the process includes stirring the suspension at reflux temperature for 1 to 5 hours, preferably for 4.5 hours. Preferably, the process further includes cooling the suspension to room temperature.

In one embodiment, the present invention provides a process for preparing Form I2 of ibandronate sodium which includes the steps of combining sodium hydroxide with ibandronic acid in water to form a solution, combining the solution with 2-butanol and isolating Form Q2 of ibandronate sodium from the reaction mixture. Preferably, the solution is at room temperature. Preferably, the reaction mixture is stirred at room temperature for 16 hours.

In another embodiment, the present invention provides a process for preparing Form I3 of ibandronate sodium which includes the steps of combining sodium hydroxide with ibandronic acid in methanol or a mixture of water and methanol having a water to methanol ratio of 60. : 40 and isolate Form Q3 from ibandronate sodium from the reaction mixture. Preferably, the reaction mixture is heated to reflux temperature. Preferably the process includes stirring the suspension at reflux temperature for 1 to 5 hours. Preferably, the process further includes cooling the suspension to room temperature. In another embodiment, the present invention provides a process for preparing ibandronate sodium Form Q4 which includes the steps of combining sodium hydroxide with ibandronic acid in water to form a solution, combine the solution with acetone and isolate Form Q4 from ibandronate sodium from the reaction mixture. Preferably, the solution is heated to reflux temperature. Preferably, acetone is a cold acetone. Preferably, when acetone is added, the reaction mixture is cooled to 0 ° C to 5 ° C, more preferably to 3 ° C, for 1 to 5 hours, more preferably to 2 hours.

In one embodiment, the present invention provides a process for preparing Form I5 of ibandronate sodium which includes the steps of combining sodium hydroxide with ibandronic acid in a mixture of water and acetonitrile having a water to acetonitrile ratio of 40:60. , ethanol, or methanol and isolate Form Q5 from ibandronate sodium from the reaction mixture. When the solvent is ethanol, the sodium hydroxide is preferably aqueous NaOH. Preferably, when the solvent is ethanol or methanol, the reaction mixture is at room temperature. Preferably, when the solvent is water and acetonitrile having a water to acetonitrile ratio of 40:60, the reaction mixture is preferably heated to reflux temperature and then cooled to room temperature.

In one embodiment, the present invention provides a process for preparing ibandronate sodium Form Q6 which includes the steps of combining sodium hydroxide with ibandronic acid in 96% ethanol and isolating ibandronate sodium form Q6 from the mixture of the reaction. Preferably the sodium hydroxide is added to a solution of ibandronic acid and 96% ethanol at reflux temperature. Preferably the process includes stirring the reaction mixture for 10 to 30 hours, preferably 20 hours.

In one embodiment, the present invention provides a process for preparing ibandronate sodium QQ Form which includes the steps of dissolving ibandronate sodium in water to form a solution, combining the solution with THF to form a suspension, and isolating Form QQ of ibandronate sodium from the suspension. Preferably, the suspension is stirred at room temperature for 16 hours.

In one embodiment, the present invention provides a process for preparing ibandronate sodium QQ Form which includes the steps of combining sodium hydroxide and inbandronic acid in a mixture of water and acetone having a water to acetone ratio of 40: 60, ethanol or water to form a solution and isolate the QQ form of ibandronate sodium from the solution. When the solvent is ethanol, it is preferably 93% ethanol. Alternatively, the solvent can be ethanol and the ibandronic acid is added in a solution with water. When the solvent is water, the ibandronic acid is added in a suspension with ethanol.

In yet another embodiment, the present invention provides a process for preparing the ibandronate sodium QQ Form which includes the steps of dissolving ibandronate sodium in water to form a solution, maintaining the solution under a saturated acetone medium, and decanting the solution to obtain the QQ form of ibandronate sodium.

In one embodiment, the present invention provides a process for preparing ibandronate sodium Form R which includes the steps of dissolving ibandronate sodium in water to form a solution, combining the solution with ethanol to form a suspension, and isolating Form R of ibandronate sodium from the suspension. Preferably, the suspension is stirred at room temperature for 16 hours.

In another embodiment, the present invention provides a process for preparing Form I sodium ibandronate which includes the steps of combining sodium hydroxide with ibandronic acid in a mixture of water and ethanol having a water to ethanol ratio of 60:40. or a mixture of water and methanol having a water to methanol ratio of 20:80 to 40:60 and isolating Form I of ibandronate sodium from the reaction mixture. Preferably, the reaction mixture is at reflux temperature. Preferably, the process further includes cooling the reaction mixture to room temperature.

In another embodiment, the present invention provides a process for preparing Form S sodium of ibandronate which includes the steps of combining sodium hydroxide with ibandronic acid in a mixture of water and ethanol having a water to ethanol ratio of 40: 60 and isolate the S-Form of ibandronate sodium from the reaction mixture. Preferably, the process includes stirring the suspension at reflux temperature for 1 to 5 hours, more preferably for 3.5 hours.

In one embodiment, the present invention provides a process for preparing ibandronate sodium Form T which includes the steps of combining sodium hydroxide with ibandronic acid in a mixture of water and acetone having a water to acetone ratio of 20:80. and isolate the ibandronate sodium Form T from the reaction mixture. Preferably, the process includes stirring the suspension at reflux temperature for 1 to 5 hours, more preferably for 1.5 hours. Preferably, the process further includes cooling the suspension to room temperature.

In one embodiment, the present invention provides a process for preparing amorphous ibandronate sodium that includes the steps of dissolving ibandronate sodium in DMSO to form a solution, combining the solution with acetone to form a suspension, and isolating the amorphous ibandronate sodium from the suspension.

Preferably, the process includes heating the solution to a temperature of 120 ° C. Preferably, the suspension is stirred at reflux temperature for 10 minutes to 5 hours, more preferably for 10 minutes to 3.5 hours. Preferably, the process further includes cooling the suspension to room temperature.

In another embodiment, the present invention provides a process for preparing amorphous ibandronate sodium which includes the steps of combining sodium hydroxide with ibandronic acid in a mixture of water and ethanol having a water to ethanol ratio of 80:20, a mixture of water and isopropanol that has a ratio of water to 80:20 isopropanol, acetonitrile, a mixture of water and acetonitrile that has a water to acetonitrile ratio of 60:40 to 80:20, or water and isolate sodium from amorphous ibandronate from the reaction mixture. The process may further include combining the solution with an antisolvent. For example, when the solvent is acetonitrile, it can be combined with the reaction mixture. When the solvent is water, hexanes can be combined with the solution.

In one embodiment, amorphous ibandronate sodium is obtained by spray drying a sodium ibandronate solution. The term "spray drying" refers broadly to processes that consist of breaking liquid mixtures into small droplets (atomization) and rapidly removing the solvent from the mixture. In a typical spray drying apparatus, a strong driving force evaporates the solvent from the droplets, which can be provided by providing a drying gas. Spray drying can be performed in conventional manner in the processes of the present invention, see Remington: The Science and Practice of Pharmacy 681 (20th ed., 2000). The drying gas used in the invention can be any suitable gas, although inert gases such as nitrogen, air enriched with nitrogen, and argon are preferred. Nitrogen gas is a particularly preferred gas dryer for use in the process of the invention, the product ibandronate sodium produced by spray drying can be recovered by techniques commonly used in the art, such as using a cyclone or a filter. Preferably, amorphous ibandronate sodium is obtained by spray drying a sodium ibandronate solution in water.

The pharmaceutical compositions of the present invention contain crystalline ibandronate sodium, such as a form disclosed herein, or amorphous ibandronate sodium, and optionally another or other forms of ibandronate sodium. In addition to the active ingredient, the pharmaceutical formulations of the present invention may contain one or more excipients. The excipients are added to the formulation for a variety of purposes.

The diluents increase the volume of a solid pharmaceutical composition, and can. making a pharmaceutical dosage form containing the composition easier to handle for the patient and for the caregiver. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., AVICEL®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, calcium phosphate dibasic dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium, maltodextrin, mannitol, polymethacrylates (for example, EUDRAGIT®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc. Solid pharmaceutical compositions that are compacted in a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. The binders for solid compositions include acacia, alginic acid, carbomer (for example, carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (for example, KLUCEL®), hydroxypropyl methyl cellulose (eg, METHOCEL®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (eg, KOLLIDON®, PLASDONE®), pregelatinized starch, sodium alginate and starch.

The dissolution rate of a solid pharmaceutical composition compacted in the stomach of the patient can be increased by adding a disintegrator to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, sodium carboxymethylcellulose (eg, Ac-Di-Sol®, PRIMELLOSE®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (eg, KOLLIDON®, POLYPLASDONE®), gum guar, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (for example, EXPLO ®) and starch.

Glidants can be added to improve the flowability of a non-compacted solid composition and to improve dosing precision. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

When a dosage form such as a tablet is made by compaction of a powder composition, the composition is pressurized by a punch and die. Some excipients and active ingredients have a tendency to adhere to punch and die surfaces, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and facilitate the release of the product from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmito-stearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc fumarate. Flavoring and flavoring agents make the dosage form more palatable to the patient. Flavoring and flavoring agents common for pharmaceuticals that can be included in the composition of the present invention include maltol, vanilla, ethyl vanilla, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

The solid and liquid compositions can also be stained using any pharmaceutically acceptable dye to improve their appearance and / or facilitate the identification of the product and the unit dosage level by the patient.

In the liquid pharmaceutical compositions of the present invention, the ingredient and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.

The liquid pharmaceutical compositions may contain emulsifying agents to uniformly disperse throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be useful in the liquid compositions of the present invention include, for example. example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetoestaryl alcohol, and cetyl alcohol.

The liquid pharmaceutical compositions may also contain a viscosity enhancing agent to improve the mouthfeel of the product and / or coat the gastrointestinal tract lining. These agents include acacia, alginic acid bentonite, carbomer, calcium or sodium of carboxymethylcellulose, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, tragacanth starch, and xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve flavor.

Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at safe levels for ingestion to improve storage stability.

In accordance with the present invention, a liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. The selection of excipients and the quantities used can be determined quickly by the scientist formulator based on experience and on the consideration of the standard procedures and reference works of the field.

The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. Dosages include suitable dosages for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation, and ophthalmic administration. Although the most appropriate administration in any given case depends on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages can conveniently be presented in a unit dosage form and prepared by any of the methods known in the pharmaceutical art.

Dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, chips and capsules, as well as liquid syrups, suspensions and elixirs.

The dosage form of the present invention may be a capsule containing the composition, preferably a solid powder or granule composition of the invention, within a hard or soft capsule. The capsule can be made with gelatin and optionally can contain a plasticizer such as glycerin or sorbitol, and an opacifying or coloring agent.

The active ingredient and the excipients can be formulated into compositions and dosage forms according to methods known in the art.

A composition for making tablets or for filling capsules can be prepared by wet granulation. In wet granulation, some or all of the ingredients and excipients in powder form are mixed and then further mixed in the presence of a liquid, generally water, which causes the powders to clump together into granules. The granulate is screened and / or milled, dried and then sieved and / or milled to the desired particle size. With the granulate tablets can then be made or other excipients, such as a glidant and / or a lubricant, can be added prior to the manufacture of tablets.

A composition for making tablets can be prepared conventionally by dry blending. For example, the mixed composition of the active ingredients and excipients can be compacted into a piece or a sheet and then comminuted into compacted granules. The compacted granules can then be compressed into a tablet.

As an alternative for dry granulation, a blended composition can be directly compressed into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. The excipients that are particularly well suited for the manufacture of tablets by direct compression include microcrystalline cellulose, spray-dried lactose, dicalcium phosphate dihydrate and colloidal silica. The correct use of these and other excipients in the manufacture of tablets by direct compression is known to those who belong to the art and have experience and expertise in the challenge of particular formulation of the manufacture of tablets by direct compression.

A capsule filler of the present invention may comprise any of the mixtures and granulates that were described with reference to the manufacture of tablets, although they do not undergo the final step of tablet manufacture.

The present invention also provides methods comprising administering a pharmaceutical ibandronate sodium formulation. The ibandronate sodium is preferably formulated for administration to a mammal, preferably a human, by injection. Ibandronate sodium can be formulated, for example, as a viscous liquid solution or suspension, preferably a clear solution, for injection. The formulation may contain one or more solvents. A suitable solvent can be selected by considering the physical and chemical stability at different pH levels, viscosity (which would allow it to be applicable with a syringe), fluidity, boiling point, miscibility, and purity. Suitable solvents include USP alcohol, benzyl alcohol NF, benzyl benzoate USP and castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et al, Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th. Ed.

Boniva® and / or Bondronat® can be used as a guide for the formulation. Boniva® exists as an intravenous injection administered every 2-3 months and as an oral formulation. Bondronat® exists in an ampoule with 1 ml of concentrate for solution for infusion that contains 1,125 mg of monosodic ibandronic salt monohydrate, which corresponds to 1 mg of ibandronic acid.

Having described the invention, it is further illustrated with the following non-exhaustive examples. Table 1 presents a summary of the Examples, which are described in more detail below.

Table 1 EXAMPLES Diffraction of X-ray powder X-ray powder diffraction data was obtained by methods known in the art using a SCINTAG X-ray powder X-ray diffractometer model X'TRA equipped with a solid state detector. Copper radiation of 1.548 A was used. A round aluminum sample holder with a zero round bottom quartz plate, with a cavity of 25 mm (diameter) * 0.5 mm (depth).

Scan parameters: Range: 2-40 degrees two theta (+ 0.2 degrees two theta) Scan mode: continuous scan Step size: 0.05 degrees Scan speed: 5 degrees / minute Thermal Gramimetric Analysis (TGA) The thermal gravimetric analysis (TGA) was performed at a heating rate of 10 ° C / minute using a Mettler instrument model TG50. The sample size was 7-15 mg.

In certain examples employing a reflux medium, this is a mixture of solvents. The composition of these reflux media of mixed solvents is expressed as a ratio on a volume by volume (v / v) basis. The amount of water that must be added to the reflux media is calculated according to the following formula: (10 volumes of alcohol per gram of IBD-Ac x 100) / X% alcohol = Y when Y is the total amount of alcohol and water together Y x (100-X)% water / 100 = Z When Z is the volume of water that must be added Differential scanning calorimetry The differential scanning calorimetric analysis (DSC) was performed with a Mettler Toledo DSC 821e calorimeter. Samples of 3 to 5 milligrams, held in a vented crucible (3 holes), were analyzed at a heating rate of 10 ° per minute.

Spray drying Spray drying was performed in a Buchi Mini B290 spray dryer with an evaporation capacity of 1 L / hour for water and higher for organic solvents. The maximum temperature input was 220 ° C, the air flow was at a maximum of 35 m2 / hour and the spray gas was compressed air or nitrogen at 200-800 L / hour and 5-8 bars. The diameter of the nozzle was 0.7 mm (standard) and the nozzle cover was 1.4 mm and 1.5 mm.

Form C of Ibandronate Sodium Example 1 Ibandronate sodium (3 g) was dissolved in dimethyl sulfoxide (DMSO) (20 ml) at 125 ° C. To the obtained solution, 2-butanol (40 ml) was added dropwise to obtain a white precipitate. The suspension was stirred at 125 ° C for 3 hours, then cooled to room temperature and stirred for 16 hours. The precipitate was isolated by vacuum filtration, washed with 2-butanol (2x5 ml) and dried in a vacuum oven at 50 ° C for 24 hours to obtain 3 g of the crystalline form C of ibandronate sodium. Form C can present a weight loss of 15% to 16% in TGA, performed as described above.

Example 2 The ibandronate sodium (3 g) was dissolved in DMSO (20 ml) at 120 ° C. To the obtained solution, 1-butanol (40 ml) was added dropwise to obtain a white precipitate. The suspension was stirred at 120 ° C for 3 hours, then cooled to room temperature and stirred for 16 hours. The precipitate was isolated by vacuum filtration, washed with 1-butanol (2x5 ml) and dried in a vacuum oven at 50 ° C for 24 hours to obtain 3 g of the crystalline form C of ibandronate sodium.

Form D sodium of Ibandronate Example 3 Ibandronate sodium (3 g) was dissolved in water (6 ml) at reflux temperature. To the obtained solution, acetone (50 ml) was added dropwise at reflux temperature to obtain a white precipitate. The suspension was stirred at reflux temperature for 4.5 hours, then cooled to room temperature. The precipitate was isolated by vacuum filtration, washed with acetone (3x13 ml) and dried in a vacuum oven at 50 ° C for 22 hours to obtain 3.3 g of the crystalline D-form of ibandronate sodium. Form D may present a 25% weight loss in the TGA.

E-Form of ibandronate sodium Example 4 Ibandronate sodium (3 g) was dissolved in water (6 ml) at reflux temperature. To the obtained solution, methanol (45 ml) was added dropwise at reflux temperature to obtain a white precipitate. The suspension was stirred at reflux temperature for 4.5 hours, then cooled to room temperature. The precipitate was isolated by vacuum filtration, washed with methanol (2x20 ml) and dried in a vacuum oven at 50 ° C for 26 hours to obtain 2.95 g of the crystalline E-form of ibandronate sodium. Form E can present a weight loss of 14% to 21% in the TGA.

Example 5 Ibandronate sodium (3 g) was dissolved in water (18 ml) at room temperature. To the obtained solution, 1-butanol (40 ml) was added to obtain a white precipitate. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with 1-butanol (2x16 ml) and dried in a vacuum oven at 50 ° C for 23 hours to obtain 2.3 g of the crystalline E-form of ibandronate sodium.

Example 6 Ibandronate sodium (3 g) was dissolved in water (6 ml) at reflux temperature. To the obtained solution, 1-butanol (50 ml) was added dropwise to obtain a white precipitate. The suspension was stirred at reflux temperature for 4 hours, then cooled to room temperature. The precipitate was isolated by vacuum filtration, washed with 1-butanol (2x20 ml) and dried in a vacuum oven at 50 ° C for 19 hours to obtain 2.8 g of the crystalline E-form of ibandronate sodium.

Form F sodium of ibandronate Example 7 Ibandronate sodium (3 g) was dissolved in water (6 ml) at reflux temperature. To the obtained solution, IPA (50 ml) was added dropwise to obtain a white precipitate. The suspension was stirred at reflux temperature for 4 hours, then cooled to room temperature and stirred for 16 hours. The precipitate was isolated by vacuum filtration, washed with IPA (2x20 ml) and dried in a vacuum oven at 50 ° C for 24 hours to obtain 3 g of the crystalline form I of ibandronate sodium. Form F can present a weight loss of 13% to 32% in the TGA.

Example 8 A solution of sodium hydroxide (0.63 g) in water: IPA (20:80 v / v, 9.5 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water: IPA (20:80 v / v, 53 ml) at reflux temperature. The reaction mixture was heated to reflux temperature for another 4 hours to obtain a pH of 3.93-4.01. Then the reaction mixture was cooled to room temperature and stirred for 72 hours. The new cooling was performed using an ice bath. The precipitate was filtered, washed with IPA (2x25 ml) and dried in a vacuum oven at 50 ° C for 24 hours to give 4.4 g of the crystalline form I of ibandronate sodium.

Example 9 A solution of sodium hydroxide (0.63 g) in water: IPA (40:60 v / v, 12 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water: IPA ( 40:60 v / v, 71 ml) at reflux temperature. The reaction mixture was heated to reflux temperature for another 4 hours to obtain a pH of 4.0-4.12. Then the reaction mixture was cooled to room temperature and stirred for 16 hours. The new cooling was performed using an ice bath. The precipitate was filtered, washed with IPA (2x25 ml) and dried in a vacuum oven at 50 ° C for 24 hours to give 4.3 g of the crystalline form I of ibandronate sodium.

Example 10 A solution of sodium hydroxide (0.63 g) in water: IPA (60:40 v / v, 19 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water: IPA (60:40 v / v, 106 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for another 30 minutes to obtain a pH of 4.14. Then the reaction mixture was cooled to room temperature and stirred for 16 hours. The new cooling was performed using an ice bath. The precipitate was filtered, washed with IPA (2x25 ml) and dried in a vacuum oven at 50 ° C for 23 hours to give 5.2 g of the crystalline form I of ibandronate sodium.

G form of ibandronate sodium Example 11 Ibandronate sodium (3 g) was dissolved in water (18 ml) at room temperature. To the obtained solution, DMSO (40 ml) was added in one portion to obtain a white precipitate. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with DMSO (2x17 ml) and dried in a vacuum oven at 50 ° C for 23 hours to obtain 2.5 g of the crystalline form of sodium ibandronate. Form G can present a weight loss of 22% to 25% in the TGA.

Example 12 Ibandronate sodium (3 g) was dissolved in DMSO (60 ml) at 120 ° C. The obtained solution was stirred at 120 ° C for 25 minutes. The solution was cooled to room temperature and stirred for 16 hours. Ethanol (250 ml) was added in one portion to obtain a precipitate. The suspension was stirred at room temperature for 2 hours. The precipitate was then isolated by filtration and dried in a vacuum oven at 50 ° C for 24 hours to obtain 3.3 g of the crystalline form of sodium ibandronate.

Form I of ibandronate sodium Example 13 Iodine of ibandronate (3 g) was dissolved in water (18 ml) at room temperature. To the obtained solution, ethanol (40 ml) was added in one portion to obtain a white precipitate. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with ethanol (2x20 ml) and dried in a vacuum oven at 50 ° C for 28 hours to obtain 2.5 g of the crystalline form H of ibandronate sodium. Form H can present a weight loss of 13% to 16% in the TGA.

Example 14 Ibandronate sodium (3 g) was dissolved in water (18 ml) at room temperature. To the obtained solution, IPA (40 ml) was added in one portion to obtain a white precipitate. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with IPA (2x20 ml) and dried in a vacuum oven at 50 ° C for 27 hours to obtain 2.2 g of the crystalline form H of ibandronate sodium.

Example 15 Ibandronate sodium (3 g) was dissolved in water (18 ml) at room temperature. To the obtained solution, methanol (40 ml) was added in one portion to obtain a white precipitate. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with methanol (2x30 ml) and dried in a vacuum oven at 50 ° C for 27 hours to obtain 2.5 g of the crystalline form H of ibandronate sodium.

Form I of ibandronate sodium Example 16 Ibandon of ibandronate (3 g) was dissolved in water (6 ml) at room temperature. To the solution obtained, DMSO (45 ml) was added dropwise to obtain a white precipitate. The suspension was stirred at reflux temperature for 6 hours, then cooled to room temperature and stirred for 16 hours. The precipitate was isolated by vacuum filtration, washed with DMSO (2x20 ml) and dried in a vacuum oven at 50 ° C for 25 hours to obtain 3.1 g of the crystalline form I of ibandronate sodium. Form J can present a weight loss of 22% to 23% in the TGA.

K-form of ibandronate sodium Example 17 A suspension of amorphous ibandronic acid (5 g) in IPA (50 ml) was heated to reflux temperature. Sodium hydroxide (0.63 g) was added and the reaction mixture was heated at reflux temperature for another 4 hours to obtain a pH of 4.19. Then the reaction mixture was cooled to room temperature. The new cooling was performed using an ice bath. The precipitate was filtered, washed with IPA (2x25 ml) and dried in a vacuum oven at 50 ° C for 24 hours to give 5.5 g of ibandronate crystalline sodium K-form. Form K may present a loss of. weight of 10% to 14% in the TGA.

Ibandronate sodium form K2 Example 18 Ibandronate sodium (3 g) was dissolved in water (6 ml) at reflux temperature. The solution was cooled to room temperature. The resulting precipitate was isolated by vacuum filtration, washed with water (1.5 ml) and dried in a vacuum oven at 50 ° C for 20 hours to obtain 0.4 g of the crystalline sodium K2 form of ibandronate . Form K2 can present a weight loss of 9% to 10% in the TGA.

Form I3 of ibandronate sodium Example 19 A solution of amorphous ibandronic acid (2.7 g) in water (25 ml) and sodium hydroxide (0.34 g, solid) was stirred at 70 ° C. The solution was poured into IPA (500 ml). The resulting precipitate was stirred at 0 ° C for 16 hours. The precipitate was isolated by vacuum filtration and dried in a vacuum oven at 50 ° C for 24 hours to yield 2.7 g of ibandronate crystalline sodium K3 form. Form K3 can present a weight loss of 7% to 8% in the TGA.

Form Q of ibandronate sodium Example 20 Ibandronate sodium (3 g) was dissolved in water (18 ml) at room temperature. To the obtained solution, acetone (72 ml) was added in one portion to obtain a white precipitate. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with acetone (2x20 ml) and dried in a vacuum oven at 50 ° C for 20 hours to obtain 2.8 g of the crystalline Q-form of ibandronate sodium. Form Q can present a weight loss of 5% to 25% in the TGA.

Example 21 Ibandon of ibandronate (3 g) was dissolved in water (18 ml) at room temperature. To the obtained solution, acetonitrile (70 ml) was added in one portion to obtain a white precipitate. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with acetonitrile (3x15 ml) and dried in a vacuum oven at 50 ° C for 24 hours to obtain 2.5 g of the crystalline Q-form of ibandronate sodium.

Example 22 Ibandonate sodium (3 g) was dissolved in water (6 ml) at reflux temperature. To the obtained solution, acetone (50 ml) was added dropwise at reflux temperature to obtain a white precipitate. The suspension was stirred at reflux temperature for 4.5 hours and then cooled to room temperature. The precipitate was isolated by vacuum filtration, washed with acetone (2x13 ml) to obtain 4.1 g of the crystalline Q-form of wet ibandronate sodium.

Example 23 A suspension of amorphous ibandronic acid (4.6 g) in acetone (96 ml) was heated to reflux temperature. Sodium hydroxide (0.58 g, solid) was added and the reaction mixture was stirred at reflux temperature for another 10 hours to obtain a pH of 3.35. Then the reaction mixture was cooled to room temperature. The new cooling was performed using an ice bath. The precipitate was filtered, washed with acetone (2x25 ml) and dried in a vacuum oven at 50 ° C for 21 hours to give 4.5 g of the crystalline Q-form of ibandronate sodium.

Example 24 A suspension of amorphous ibandronic acid (5 g) in ethanol (50 ml) was heated to reflux temperature. Sodium hydroxide (0.63 g, solid) was added and the reaction mixture was stirred at reflux temperature for another 4 hours to obtain a pH of 3.5. Then the reaction mixture was cooled to room temperature. The new cooling was performed using an ice bath. The precipitate was filtered, washed with ethanol (2x25 ml) and dried in a vacuum oven at 50 ° C for 20 hours to give 5.5 g of the crystalline Q-form of ibandronate sodium.

Example 25 A solution of amorphous ibandronic acid (4.5 g) in water (11 ml) and sodium hydroxide (0.56 g, solid) was stirred at room temperature. The solution was added dropwise to acetone (100 ml). The resulting precipitate was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with acetone (2x10 ml) and dried in a vacuum oven at 50 ° C for 24 hours to give 4.8 g of the ibandronate crystalline sodium Q-form.

Example 26 A solution of sodium hydroxide (0.63 g) in water: acetonitrile (20:80 v / v, 12.5 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water: acetonityl (20:80 v / v, 50 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for another 20 minutes to obtain a pH of 3.80. Then the reaction mixture was cooled to room temperature and stirred for 16 hours. The precipitate was filtered, washed with acetonitrile (2x10 ml) and dried in a vacuum oven at 50 ° C for 22.5 hours to give 4.0 g of the crystalline Q-form of ibandronate sodium.

Example 27 A solution of sodium hydroxide (0.63 g) in water: acetonitrile (60:40 v / v, 19 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water: acetonitrile (60: 40 v / v, 106 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 1 hour. Then the reaction mixture was cooled to room temperature. The new cooling was performed using an ice bath. The seeding was made, and the mixture, of the reaction was stirred at 10 ° C for 16 hours. The precipitate was isolated by vacuum filtration, washed with acetonitrile (2x10 ml) and dried in a vacuum oven at 50 ° C for 23 hours to give 1.0 g of the crystalline Q-form of ibandronate sodium.

Ql form of ibandronate sodium Example 28 Sodium of ibandronate (3 g) was dissolved in water (18 ml) at room temperature. To the obtained solution, 2-butanol (40 ml) was added in one portion to obtain a white precipitate. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with 2-butanol (2x16 ml) and dried in a vacuum oven at 50 ° C for 24 hours to obtain 2.2 g of the crystalline Ql form of ibandronate sodium. Form Ql can present a weight loss of 9% to 16% in the TGA.

Example 29 A solution of ibandronate sodium (1 g) in water (8 ml) was dripped into tetrahydrofuran (THF) while stirring at room temperature. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration and dried in a vacuum oven at 50 ° C for 22.5 hours to obtain 0.98 g of the ibandronate crystalline sodium Ql form.

Form Q2 of ibandronate sodium Example 30 Ibandronate sodium (3 g) was dissolved in water (6 ml) at reflux temperature. To the obtained solution, acetonitrile (50 ml) was added dropwise at reflux temperature to obtain a white precipitate. The suspension was stirred at reflux temperature for 4.5 hours. The precipitate was isolated by vacuum filtration, washed with acetonitrile (3x20 ml) and dried in a vacuum oven to obtain 3 g of the crystalline form Q2 of wet ibandronate sodium. Form Q2 can present a weight loss of 16% to 17% in the TGA.

Example 31 A solution of amorphous ibandronic acid (4.5 g) in water (20 ml) and 1 N sodium hydroxide (14 ml) was stirred at room temperature to obtain a pH of 3.5. The solution was added dropwise to 2-butanol (100 ml) while stirring. The precipitate obtained was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with 2-butanol (2x20 ml) and dried in a vacuum oven at 50 ° C for 24 hours to obtain 4.4 g of the crystalline form of sodium. ibandronate.

Form Q3 of ibandronate sodium Example 32 A solution of sodium hydroxide (0, 63 g) in aqueous methanol (60:40 v / v, 19 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water: methanol (60:40 v / v, 106 ml) at room temperature. of reflux. The reaction mixture was heated at reflux temperature for an additional 1.5 hours to obtain a pH of 4.01. Then the reaction mixture was cooled to room temperature. The new cooling was performed using an ice bath. The precipitate was filtered, washed with methanol (2x25 ml) and dried in a vacuum oven at 50 ° C for 19 hours to give 5.2 g of the crystalline form Q3 of ibandronate sodium. The Q3 form can present a weight loss of 7% to 9% in the TGA.

Example 33 A suspension of amorphous ibandronic acid (5 g) in ethanol (50 ml) was heated to reflux temperature. Sodium hydroxide (0.63 g, solid) was added and the reaction mixture was stirred at reflux temperature for another 4 hours to obtain a pH of 4.0. Then the reaction mixture was cooled to room temperature. The new cooling was performed using an ice bath. The white solid was filtered, washed with ethanol (2x25 ml) and dried in a vacuum oven at 50 ° C for 19 hours to give 4.7 g of ibandronate crystalline sodium form Q3.

Ibandronate Q4 form of ibandronate sodium Example 34 A solution of amorphous ibandronic acid (4.5 g) in water (9 ml) and sodium hydroxide (0.63 g, solid) was stirred at reflux temperature. The solution was poured into a cold acetone (100 ml). The resulting precipitate was stirred at 3 ° C for 2 hours. The precipitate was isolated by vacuum filtration, washed with acetone (2x15 ml) and dried in a vacuum oven at 50 ° C for 24 hours to obtain 5.0 g of the crystalline Q4 form of ibandronate sodium. Form Q4 can present a weight loss of 7% to 8% in the TGA.

Form I5 of ibandronate sodium Example 35 A solution of sodium hydroxide (0.63 g) in water: acetonitrile (40:60 v / v, 12.33 ml) was added dropwise to a solution of amorphous ibandronic acid ( 5 g) in water: acetonitrile (40:60 v / v, 71 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 1 hour to obtain a pH of 4.05. Then the reaction mixture was cooled to room temperature. The new cooling was performed using an ice bath. The precipitate was isolated by vacuum filtration, washed with acetonitrile (2x20 ml) and dried in a vacuum oven at 50 ° C for 20 hours to give 3.9 g of the crystalline Q5 form of ibandronate sodium. The Q5 form can have a weight loss of 5% to 11% in the TGA.

Example 36 A solution of amorphous ibandronic acid (5 g) in ethanol (50 ml) was stirred at room temperature. Aqueous sodium hydroxide (0.63 g, 12.5 ml) was added and the reaction mixture was stirred at room temperature for another 2 hours. The precipitate was isolated by filtration, washed with ethanol (50 ml) and dried in a vacuum oven at 50 ° C for 24 hours to give 5.5 g of ibandronate crystalline sodium form Q5.

Example 37 A solution of amorphous ibandronic acid (5 g) in methanol (100 ml) was stirred at room temperature. Solid sodium hydroxide (0.63 g) was added. The obtained precipitate was stirred at room temperature for another 22 hours. The precipitate was isolated by filtration, washed with methanol (30 ml) and dried in a vacuum oven at 50 ° C for 24 hours to give 5.4 g of ibandronate crystalline sodium form Q5.

Ibandronate Q6 form of ibandronate sodium Example 38 A solution of amorphous ibandronic acid (5 g) in 96% aqueous ethanol (70 ml) was stirred at reflux temperature. Solid sodium hydroxide (0.63 g) was added. The precipitate obtained was cooled to room temperature and stirred at room temperature for another 20 hours. The precipitate was isolated by filtration, washed with 96% aqueous ethanol (2x10 ml) and dried in a vacuum oven at 50 ° C for 24 hours to give 6.0 g of ibandronate crystalline sodium form Q6. Form Q6 can present a weight loss of 9% to 10% in the TGA.

Ibandronate sodium QQ form Example 39 Ibandronate sodium (3 g) was dissolved in water (18 ml) at room temperature. To the obtained solution, THF (40 ml) was added in one portion to obtain a white precipitate. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with THF (2x20 ml) and dried in a vacuum oven at 50 ° C for 18 hours to obtain 2.1 g of the crystalline QQ form of ibandronate sodium. Form QQ can present a weight loss of 5% to 12% in the TGA.

Example 40 A solution of sodium hydroxide (0, 57 g) in water acetone (40:60 v / v, 11.4 ml) was added dropwise to a solution of amorphous ibandronic acid (4.5 g) in water acetone (40:60 v / v, 64 g). , 4 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for a further 2 hours to obtain a pH of 4.5. Then the solution was cooled to room temperature. The new cooling was performed using an ice bath. The precipitate was isolated by vacuum filtration, washed with acetone (2x15 ml) and dried in a vacuum oven at 50 ° C for 21 hours to give 3.9 g of the crystalline sodium QQ form of ibandronate.

Example 41 Amorphous ibandronic acid (5 g) was added to a solution of solid sodium hydroxide (0.6 g) dissolved in 93% ethanol (100 μm) at 55 ° C. The obtained suspension was stirred at 55 ° C for 3 hours. Then the suspension was cooled to room temperature. The precipitate was isolated by vacuum filtration, washed with 93% ethanol (3x25 ml) and dried in a vacuum oven at 50 ° C for 24 hours to give 4.5 g of the crystalline QQ form of ibandronate sodium .

Example 41 A sodium solution of ibandronate (1.5 g) and water (9 ml) was stored under a saturated acetone atmosphere (9 ml) at room temperature for 2 weeks. Then the solution was decanted, and the product was dried in a vacuum oven at 50 ° C for 18 hours to give 0.9 g of the crystalline QQ form of ibandronate sodium.

Example 43 A solution of sodium hydroxide (0.63 g) in water (12.5 ml) was added dropwise to a suspension of amorphous ibandronic acid (5 g) in ethanol (70 ml) at reflux temperature. The solution was then cooled to room temperature and stirred for 72 hours to obtain a pH of 4.15. The precipitate was isolated by vacuum filtration, washed with ethanol (2x25 ml) and dried in a vacuum oven at 50 ° C for 23 hours to give 4.97 g of the crystalline QQ form of ibandronate sodium.

Example 44 A solution of sodium hydroxide (0.63 g) in ethanol (14 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water (50 ml) at room temperature. The suspension obtained was stirred for 3 hours to obtain a pH of 4.1. The precipitate was isolated by vacuum filtration, washed with ethanol (2x25 ml) and dried in a vacuum oven at 50 ° C for 22 hours to give 5.4 g of the crystalline QQ form of ibandronate sodium.

R-form of ibandronate sodium Example 45 Ibandon of ibandronate (3 g) was dissolved in water (18 ml) at room temperature. To the obtained solution, ethanol (40 ml) was added in one portion to obtain a white precipitate. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with ethanol (2x20 ml) to obtain 3.3 g of the crystalline form R of ibandronate sodium. Form R can present a weight loss of 10% to 16% in the TGA.

Example 46 A solution of sodium hydroxide (0.63 g) in water: ethanol (60:40 v / v, 19 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water: ethanol ( 60:40 v / v, 106 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 3.5 hours to obtain a pH of 4.03. Then the reaction mixture was cooled to room temperature. The new cooling was performed using an ice bath. The precipitate was filtered, washed with ethanol (2x25 ml) and dried in a vacuum oven at 50 ° C for 19 hours to give 4.7 g of the crystalline R-form of ibandronate sodium.

Example 47 A solution of sodium hydroxide (0.63 g) in water: methanol (20:80 v / v, 10 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water: methanol ( 20:80 v / v, 53 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 1.5 hours to obtain a pH of 4.15. Then the reaction mixture was cooled to room temperature. The new cooling was performed using an ice bath. The precipitate was filtered, washed with ethanol (2x25 ml) and dried in a vacuum oven at 50 ° C for 21 hours to give 5.2 g of the crystalline R-form of ibandronate sodium.

Example 48 A solution of sodium hydroxide (0.63 g) in water: methanol (40:60 v / v, 12 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water: methanol ( 40:60 v / v, 71 ml) at reflux temperature. The reaction mixture was heated to reflux temperature for an additional 1.5 hours to obtain a pH of 4.04. Then the reaction mixture was cooled to room temperature. The new cooling was performed using an ice bath. The precipitate was filtered, washed with ethanol (2x25 ml) and dried in a vacuum oven at 50 ° C for 21 hours to give 5.1 g of the crystalline R-form of ibandronate sodium.

Example 49 Sodium hydroxide (0.63 g, solid) was added to a solution of amorphous ibandronic acid (5 g) in water: methanol (60:40 v / v, 125 ml) at reflux temperature. The reaction mixture was heated to reflux temperature for an additional 25 minutes. Then the reaction mixture was cooled to room temperature to obtain a precipitate (pH = 4.10). The new cooling was performed using an ice bath. The precipitate was filtered, washed with ethanol (2x25 ml) and dried in a vacuum oven at 50 ° C for 21 hours to give 5.2 g of the crystalline R-form of ibandronate sodium.

Example 50 A solution of sodium hydroxide (0.63 g) in water: ethanol (60:40 v / v, 19 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water: ethanol ( 60:40 v / v, 106 ml) at room temperature. The reaction mixture was heated at room temperature for an additional 16 hours to obtain a pH of 4.11. The white solid was filtered, washed with ethanol (2x25 ml) and dried in a vacuum oven at 50 ° C for 21 hours to give 5.1 g of the crystalline R-form of ibandronate sodium.

Sodium form of ibandronate Example 51 A solution of sodium hydroxide (0.63 g) in water-methanol (40:60 v / v, 12 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water: ethanol (40:60 v / v, 71 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 3.5 hours to obtain a pH of 4.03. Then the reaction mixture was cooled to room temperature. The new cooling was performed using an ice bath. The precipitate was filtered, washed with ethanol (2x25 ml) and dried in a vacuum oven at 50 ° C for 18 hours to give 4.9 g of the crystalline S-form of ibandronate sodium. The S form can present a weight loss of 11% to 12% in the TGA.

T-form of ibandronate sodium Example 52 A solution of sodium hydroxide (0.58 g) in water: acetone. (20:80 v / v, 9 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water acetone (20:80 v / v, 49 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 1.5 hours to obtain a pH of 4.0. Then the reaction mixture was cooled to room temperature. The new cooling was performed using an ice bath. The precipitate was filtered, washed with acetone (1x50 ml) and dried in a vacuum oven at 50 ° C for 21 hours to give 3.8 g of the crystalline sodium T-form of ibandronate. The T-shape can have a weight loss of 5% to 7% in the TGA.

Amorphous Ibandronate Sodium Example 53 Ibandronate sodium (3 g) was dissolved in DMSO (10 ml) at 120 ° C. To the obtained solution, acetone (40 ml) was added dropwise to obtain a white precipitate. The suspension was stirred at reflux for 3.5 hours. The solution was cooled to room temperature and stirred for 16 hours. The gelatinous precipitate was isolated by vacuum filtration and dried in a vacuum oven at 50 ° C for 24 hours to obtain 2.7 g of amorphous ibandronate sodium. The amorphous ibandronate sodium may present a weight loss of 6.8% to 24.4% or less in the TGA.

Example 54 Ibandronate sodium (3 g) was dissolved in DMSO (10 ml) at 120 ° C. To the obtained solution, acetone (40 ml) was added dropwise to obtain a white precipitate. The suspension was stirred at reflux for 10 minutes. The solution was cooled to room temperature and stirred for 16 hours. The gelatinous precipitate was isolated by vacuum filtration and dried in a vacuum oven at 50 ° C for 24 hours to obtain 2 ', 2 g of amorphous ibandronate sodium.

Example 55 A solution of sodium hydroxide (0.63 g) in water-methanol (80:20 v / v, 38 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water: ethanol (80: 20 v / v, 212 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 3 hours to obtain a pH of 3.24. Then the reaction mixture was cooled to room temperature. The clear solution was evaporated until dried to obtain 5.7 g of amorphous ibandronate sodium.

Example 56 A solution of sodium hydroxide (0.63 g) in water: IPA (80:20 v / v, 38 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water: IPA ( 80:20 v / v, 212 ml) at reflux temperature. The reaction mixture was heated to reflux temperature for an additional 45 minutes. Then the reaction mixture was cooled to room temperature. The clear solution was evaporated until dried to obtain 5.9 g of amorphous ibandronate sodium.

Example 57 A suspension of amorphous ibandronic acid (5 g) in acetonitrile (50 ml) was heated to reflux temperature. Solid sodium hydroxide (0.63 g) was added. The reaction mixture was stirred at reflux temperature for another 6 hours. Then the reaction mixture was cooled to room temperature. The new cooling was performed using an ice bath to obtain a clear gel (pH = 4.05). The gelatinous product was dried in a vacuum oven at 50 ° C for 24 hours to give 2.6 g of amorphous ibandronate sodium.

Example 58 A solution of sodium hydroxide (0.63 g) in water: acetonitrile (60:40 v / v, 0.19 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water: acetonitrile (60:40 v / v, 106 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 1 hour. Then the reaction mixture was cooled to room temperature. The new cooling was performed using an ice bath. The clear solution was seeded with the ibandronate sodium Kl form and stirred for 16 hours. The mother liquor was evaporated to dryness to give 3.5 g of amorphous ibandronate sodium.

Example 59 A solution of sodium hydroxide (0.55 g) in water: acetonitrile (80:20 v / v, 33 ml) was added dropwise to a solution of amorphous ibandronic acid (4 g) in water: acetonitrile ( 80:20 v / v, 187 ml) at reflux temperature. Then the reaction mixture was cooled to room temperature. The clear solution was evaporated until dried to obtain 5.2 g of amorphous ibandronate sodium.

Example 60 A solution of amorphous ibandronic acid (5 g) in water (50 ml) was heated to reflux temperature. Solid sodium hydroxide (0.63 g) was added and the reaction mixture was stirred at reflux temperature for an additional 1 hour. Then the reaction mixture was cooled to room temperature. The clear solution was evaporated to give 5.6 g of amorphous ibandronate sodium.

Example 61 A suspension of amorphous ibandronic acid (5 g) in acetonitrile (50 ml) was stirred at room temperature. Solid sodium hydroxide (0.63 g) was added and the reaction mixture was stirred at room temperature for another 72 hours. The precipitate is. isolated by vacuum filtration and dried in a vacuum oven at 50 ° C for 20 hours to give 5.0 g of amorphous ibandronate sodium.

Example 62 A suspension of amorphous ibandronic acid (5 g) in acetonitrile (200 ml) was heated to reflux temperature. Solid sodium hydroxide (0.63 g) was added and the reaction mixture was stirred at reflux temperature for another 2 hours. Acetone (50 ml) was added dropwise. Then the reaction mixture was cooled to room temperature and stirred for 16 hours. The precipitate was isolated by vacuum filtration, washed with acetone (50 ml) and dried in a vacuum oven at 50 ° C for 22 hours to obtain 3.5 g of amorphous ibandronate sodium.

Example 63 A solution of amorphous ibandronic acid (5 g) in water (30 ml) was stirred at room temperature. Aqueous sodium hydroxide (0.63 g NaOH in 20 mL of water) was added and the reaction mixture was stirred at room temperature for an additional 1 hour. The solution was evaporated until dried. Hexanes (100 ml) were added to the residue and stirred for 16 hours at room temperature. The precipitate was isolated by vacuum filtration, washed with hexanes (1x50 ml) and dried in a vacuum oven at 50 ° C for 45 hours to obtain 5.1 g of amorphous ibandronate sodium.

Example 64 Ibandronate sodium (9 g) was dissolved in water (90 ml) at room temperature. The solution was divided into three portions and each portion was spray-dried using a Buchi Mini B-290 spray dryer using a standard 0.7 mm diameter nozzle with a nozzle cover of 1.4 or 1.5 mm . In each case, amorphous ibandronate sodium was obtained.

For portion 1, the nitrogen gas was at an inlet temperature of 50 ° C. The evaporated solvent and nitrogen came out of the spray dryer at a temperature of 41-34 ° C.

For portion 2, the nitrogen gas was at an inlet temperature of 100 ° C. The evaporated solvent and nitrogen came out of the spray dryer at a temperature of 77-62 ° C.

For portion 1, the nitrogen gas was at an inlet temperature of 150 ° C. The evaporated solvent and nitrogen came out of the spray dryer at a temperature of 96-109 ° C.

Table 2: Preparation of the monosodium salt of ibandronate Using amorphous IBD-Ac as the initial material Amorphous ibandronic acid Example 65 An aqueous solution (40% w / w) of ibandronic acid (150 ml) was evaporated under vacuum (20-30 mmHg) until it was dried while heating the flask in a water bath (up to 70 ° C) C) to obtain amorphous ibandronic acid (67 g).

Having described the invention with reference to particular preferred embodiments and illustrative examples, those skilled in the art will appreciate the modifications to the described and illustrated invention that do not depart from the spirit and scope of the invention disclosed in the specification. The Examples are set forth to help understand the invention but are not intended and should not be construed as limiting its scope in any way. The examples do not include detailed descriptions of conventional methods. These methods are known to those skilled in the art and are described in numerous publications. Polymorphism in Pharmaceutical Solids, Drugs and the Pharmaceutical Sciences, Volume 95 can be used as a guide. All references mentioned herein are incorporated in their entirety.

Claims (59)

1. Sodium of amorphous ibandronate.
2. A process for preparing amorphous ibandronate sodium comprising the step of spray drying an ibandronate sodium solution in water.
3. A crystalline form of ibandronate sodium selected from the group consisting of: a) the crystalline form of ibandronate sodium characterized by X-ray reflections at 4.7, 5.0, 17.2, 18.3 and 19.5 ± 0.2 ° 2T; b) the crystalline form of sodium of ibandronate characterized by X-ray reflections at 4.8, 9.3, 18.5, 23, 1 and 36, 1 ± 0.2 ° 2T; c) the crystalline form of sodium of ibandronate characterized by X-ray reflections at 4.6, 4.8, 5.3, 9.3 and 34.7 ± 0.2 ° 2T; d) the crystalline form of sodium of ibandronate characterized by X-ray reflections at 4.9, 5.1, 6.0, 20.0 and 36.4 ± 0.2 ° 2T; e) the crystalline form of sodium of ibandronate characterized by X-ray reflections at 4.7, 9.2, 17,, 18, 4 and 19.9 ± 0.2 ° 2T; f) the crystalline form of sodium of ibandronate characterized by X-ray reflections at 4.8, 5.7, 17, 3, 19.5 and 26, 9 ± 0.2 ° 2T; g) the crystalline form of sodium of ibandronate characterized by X-ray reflections at 4.6, 9.2, 18.3, 19.6 and 25.6 ± 0.2 ° 2T; h) the crystalline form of sodium of ibandronate characterized by X-ray reflections at 5.0, 5.9, 17. 2, 20.0 and 25, 9 ± 0.2 ° 2T; i) the crystalline form of sodium of ibandronate characterized by X-ray reflections at 5.1, 6.1, 17. 3, 20.1 and 21.5 ± 0.2 ° 2T; j) the crystalline form of sodium of ibandronate characterized by X-ray reflections at 5.1, 6.2, • 17, 3, 19.7 and 20, 1 ± 0.2 ° 2T; k) the crystalline form of sodium of ibandronate characterized by X-ray reflections at 5.0, 6.1, 17.2, 25.7 and 30.9 + 0.2 ° 2T; 1) the crystalline form of sodium of ibandronate characterized by X-ray reflections at 4.7, 6.0, 17.2, 26.2 and 31.0 ± 0.2 ° 2T; m) the crystalline form of sodium of ibandronate characterized by X-ray reflections at 4.9, 6.2, 25.9, 31, 0 and 37, 1 ± 0.2 ° 2T; n) the crystalline form of sodium of ibandronate characterized by X-ray reflections at 5.9, 17.1, 19, 6, 20.2 and 21, 3 ± 0.2 ° 2T; o) the crystalline form of sodium of ibandronate characterized by X-ray reflections at 6.1, 17.2, 19, 6, 20.3 and 21, 4 ± 0.2 ° 2T; p) the crystalline form of sodium of ibandronate characterized by X-ray reflections at 6.1, 17.2, 19. 6, 20.1 and 21.5 ± 0.2 ° 2T; q) the crystalline form of sodium of ibandronate characterized by X-ray reflections at 6.1, 17.3, 19, 6, 21.5 and 30, 8 ± 0.2 ° 2T; r) the crystalline form of sodium of ibandronate characterized by x-ray reflections at 6.2, 25.9, 26. 7, 31.1 and 37, 2 ± 0.2 ° 2T; s) the crystalline form of sodium of ibandronate characterized by X-ray reflections at 5.3, 6.0, 17. 2, 18.7 and 20.0 ± 0.2 ° 2T; t) the crystalline form of sodium of ibandronate characterized by X-ray reflections at 4.8, 5.1, 5.3, 5.4 and 6.1 ± 0.2 ° 2T; u) the crystalline form of · ibandronate sodium characterized by x-ray reflections at 6.2, 115.7, 26. 3, 32, 6 and 35, 6 ± 0.2 ° 2T.
4. 4. The crystalline form of ibandronate sodium according to claim 3, characterized by X-ray reflections at 4.7, 5.0, 17.2, 18.3 and 19.5 ± 0.2 ° 2T, designated Form C , and further characterized by X-ray reflections at 17.6, 19.7, 20, 2, 20, 6 and 23, 8 ± 0.2 ° 2T.
5. 5. The crystalline form of ibandronate sodium according to claim 4, which has a powder X-ray diffraction pattern that is substantially as shown in Figure 1.
6. 6. The crystalline form of sodium of ibandronate according to claim 4, wherein the crystalline form is a monoethanolate.
7. 7. The crystalline form of sodium of ibandronate according to claim 3, characterized by X-ray reflections at 4.8, 9.3, 18.5, 23.1 and 36.1 ± 0.2 ° 2T, denominated Form D , and further characterized by X-ray reflections at 15.3, 19.9, 26.3, 27.2 and 30.4 ± 0.2 ° 2T.
8. 8. The crystalline form of ibandronate sodium according to claim 7, which has a powder X-ray diffraction pattern that is substantially as shown in Figure 2.
9. 9. The crystalline form of sodium of ibandronate according to claim 3, characterized by X-ray reflections at 4.6, 4.8, 5.3, 9.3 and 34.7 ± 0.2 ° 2T, designated Form E , and further characterized by X-ray reflections at 18.6, 23.3, 24.5, 27, 1 and 30, 1 ± 0.2 ° 2T.
10. 10. The crystalline form of ibandronate sodium according to claim 9, which has a powder X-ray diffraction pattern that is substantially as shown in Figure 3.
11. 11. The crystalline form of ibandronate sodium according to claim 9, wherein the crystalline form is a hemibutanolate.
12. 12. The crystalline form of sodium of ibandronate according to claim 3, characterized by X-ray reflections at 4.9, 5.1, 6.0, 20.0 and 36.4 + 0.2 ° 2T, designated Form F , and further characterized by X-ray reflections at 18.6, 26.0, 28.5, 30.4 and 31.3 ± 0.2 ° 2T.
13. 13. The crystalline form of ibandronate sodium according to claim 12, which has a diffraction pattern that is substantially that shown in Figure 4.
14. 14. The crystalline form of sodium of ibandronate according to claim 3, characterized by X-ray reflections at 4.7, 9.2, 17.4, 18.4 and 19.9 ± 0.2 ° 2T, designated Form G , and further characterized by X-ray reflections at 10.1, 15.2, 18, 7, 26.3 and 27.1 ± 0.2 ° 2T.
15. 15. The crystalline form of ibandronate sodium according to claim 14, which has a powder X-ray diffraction pattern that is substantially as shown in Figure 5.
16. 16. The crystalline form of sodium of ibandronate according to claim 3, characterized by X-ray reflections at 4.8, 5.7, 17.3, 19.5 and 26.0 ± 0.2 ° 2T, designated Form H , and further characterized by X-ray reflections at 18.5, 20.1, 23.8, 31, 1 and 37, 1 ± 0.2 ° 2T.
17. 17. The crystalline form of ibandronate sodium according to claim 16, which has a powder X-ray diffraction pattern that is substantially as shown in Figure 6.
18. 18. The crystalline sodium form of ibandronate according to claim 3, characterized by X-ray reflections at 4.6, 9.2, 18.3, 19.6 and 25.6 ± 0.2 ° 2T, designated Form J , and further characterized by X-ray reflections at 17.5, 18.9, 21.7, 22, 9 and 29.5 ± 0.2 ° 2T.
19. 19. The crystalline form of ibandronate sodium according to claim 18, which has a powder X-ray diffraction pattern that is substantially as shown in Figure 7.
20. 20. The crystalline form of sodium of ibandronate according to claim 3, characterized by X-ray reflections a 5. 0, 5.9, 17.2, 20.0 and 25.9 + 0.2 ° 2T, designated Form K, and further characterized by X-ray reflections at 118.5, 19.7, 21.4, 26 , 5 and 31, 1 ± 0.2 ° 2T.
21. 21. The crystalline form of ibandronate sodium according to claim 20, which has a powder X-ray diffraction pattern that is substantially as shown in Figure 8.
22. 22. The crystalline sodium form of ibandronate according to claim 3, characterized by 'X-ray reflections a 5. 1, 6.1, 17.3, 20.1 and 21.5 ± 0.2 ° 2T, designated Form K2, and further characterized by X-ray reflections at 18.6, 19.6, 26.1, 26, 8 and 31, 1 ± 0.2 ° 2T.
23. 23. The crystalline form of ibandronate sodium according to claim 22, which has a powder X-ray diffraction pattern that is substantially as shown in Figure 9.
24. 24. The crystalline form of sodium of ibandronate according to claim 3, characterized by X-ray reflections at 5.1, 6.2, 17.3, 19.7 and 20.1 ± 0.2 ° 2T, designated Form K3 , and further characterized by X-ray reflections at 18.5, 21.5, 23.8, 25.8 and 31.1 + 0.2 ° 2T.
25. 25. The crystalline form of ibandronate sodium according to claim 24, which has a powder X-ray diffraction pattern that is substantially as shown in Figure 10.
26. 26. The crystalline form of sodium of ibandronate according to claim 3, characterized by X-ray reflections at 5.0, 6.1, 17.2, 25.7 and 30.9 ± 0.2 ° 2T, called Form Q , and further characterized by X-ray reflections at 16.8, 21.4, 26, 7, 29, 1 and 36.9 ± 0.2 ° 2T.
27. 27. The crystalline form of ibandronate sodium according to claim 26, which has a powder X-ray diffraction pattern which is substantially that shown in Figure 11.
28. 28. The crystalline form of sodium of ibandronate according to claim 3, characterized by X-ray reflections at 4.7, 6.0, 17.2, 26.2 and 31.0 ± 0.2 ° 2T, denominated Ql Form , and further characterized by X-ray reflections at 19.5, 21.4, 25, 8, 29, 1 and 37, 1 ± 0.2 ° 2T.
29. 29. The crystalline form of ibandronate sodium according to claim 28, which has a powder X-ray diffraction pattern that is substantially that shown in Figure 12 or Figure 12a.
30. 30. The crystalline sodium form of ibandronate according to claim 3, characterized by X-ray reflections at 4.9, 6.2, 25.9, 31.0 and 37.1 ± 0.2 ° 2T, designated Form Q2 , and also characterized by reflections of rays? to 16.9, 17.3, 19.0, 26.6 and 29.2 ± 0.2 ° 2T.
31. 31. The crystalline form of ibandronate sodium according to claim 30, which has a diffraction pattern that is substantially that shown in Figure 13 or Figure 13a.
32. 32. The crystalline form of sodium of ibandronate according to claim 3, characterized by X-ray reflections at 5.9, 17.1, 19.6, 20.0 and 21.3 ± 0.2 ° 2T, designated Form Q3 , and further characterized by X-ray reflections at 18.0, 18.5, 23, 6, 24, 7 and 30.8 ± 0.2 ° 2T.
33. 33. The crystalline form of ibandronate sodium according to claim 32, which is a powder X-ray diffraction diagram that is substantially as shown in Figure 14.
34. 34. The crystalline form of sodium of ibandronate according to claim 3, characterized by X-ray reflections at 6.1, 17.2, 19.6, 20.3 and 21.4 ± 0.2 ° 2T, designated Form Q4 , and further characterized by X-ray reflections at 16.9, 18.1, 18.5 and 23.7 ± 0.2 ° 2T.
35. 35. The crystalline form of ibandronate sodium according to claim 34, which has a powder X-ray diffraction pattern that is substantially as shown in Figure 15.
36. 36. The crystalline sodium form of ibandronate according to claim 3, characterized by X-ray reflections at 6.1 / 17.2, 19.6, 20.1 and 21.5 ± 0.2 ° 2T, designated Form Q5 , and characterized further by X-ray reflections at 16.8, 24.7, 25.7, 29, 0 and 30, 9 ± 0.2 ° 2T.
37. 37. The crystalline form of ibandronate sodium according to claim 36, which has a powder X-ray diffraction pattern that is substantially as shown in Figure 16.
38. 38. The crystalline form of sodium of ibandronate according to claim 3, characterized by X-ray reflections at 6.1, 17.3, 19.6, 21.5 and 30.8 ± 0.2 ° 2T, denominated Form Q6 , and further characterized by X-ray reflections at 16.9, 20.2, 25, 6, 26, 9 and 29.1 ± 0.2 ° 2T.
39. 39. The crystalline form of ibandronate sodium according to claim 38, which has a powder X-ray diffraction pattern that is substantially as shown in Figure 17. 1
40. 40. The crystalline form of sodium of ibandronate according to claim 3, characterized by X-ray reflections a 6. 2, 25.9, 26.7, 31, 1 and 37.2 ± 0.2 ° 2T, called the QQ Form and further characterized by X-ray reflections at 16.9, 17.3, 21.5, 24, 7 and 29.2 ± 0.2 ° 2T.
41. 41. The crystalline form of ibandronate sodium according to claim 40, which has a powder X-ray diffraction pattern that is substantially as shown in Figure 18.
42. 42. The crystalline sodium form of ibandronate according to claim 40, which has a particle size distribution of not more than 100 μ.
43. 43. The crystalline sodium form of ibandronate according to claim 42, which has a particle size distribution of not more than 60 μ.
44. 44. The crystalline form of sodium of ibandronate according to claim 3, characterized by X-ray reflections a 5. 3, 6.0, 17.2, 18.7 and 20.0 ± 0.2 ° 2T, designated Form R, and further characterized by X-ray reflections at 20.5, 25.0, 26.5, 29 , 1 and 31, 0 + 0.2 ° 2T.
45. 45. The crystalline form of ibandronate sodium according to the claim. 44, which has a powder X-ray diffraction diagram that is substantially the one shown in Figure 19.
46. 46. The crystalline form of ibandronate sodium according to claim 44, wherein the crystalline form is a hemiethanolate.
47. 47. The crystalline form of sodium of ibandronate according to claim 3, characterized by X-ray reflections at 4.8, 5.1, 5.3, 5.4, and 6.1 ± 0.2 ° 2T, called Form S, and characterized further by X-ray reflections at 10.5, 21.0, 26.3, 33.0 and 38.2 ± 0.2 ° 2T.
48. 48. The crystalline form of ibandronate sodium according to claim 47, which has a powder X-ray diffraction pattern that is substantially that shown in Figure 20 or Figure 20a.
49. 49. The crystalline form of ibandronate sodium according to claim 47, wherein the crystalline form is a hemiethanolate.
50. 50. The crystalline form of sodium of ibandronate according to claim 3, characterized by X-ray reflections at 6.2, 15.7, 26.3, 32.6 and 35.6 ± 0.2 ° 2T, denominated Form T , and further characterized by X-ray reflections at 117.6, 19.4, 26.9, 31.7 and 38.7 ± 0.2 ° 2T.
51. 51. The crystalline sodium form of ibandronate according to claim 50, which has a powder X-ray diffraction pattern that is substantially as shown in Figure 21.
52. 52. Crystalline ibandronate sodium solvate.
53. 53. Crystalline ibandronate sodium alcoholate.
54. 54. Sodium ethanolate of crystalline ibandronate.
55. 55. The crystalline form of ibandronate sodium according to claim 52, wherein the ethanolate is monoethanolate.
56. 56. The crystalline sodium form of ibandronate according to claim 52, wherein the ethanolate is hemiethanolate.
57. 57. Crystalline ibandronate sodium butanolate.
58. 58. The crystalline form of sodium of ibandronate according to claim 57, wherein the butanolate is hemibutanolate.
59. 59. A pharmaceutical composition comprising the ibandronate sodium according to claim 1 or 58 and a pharmaceutically acceptable carrier.