ES2368663T3 - CRYSTAL FORM OF THE SOUND IBANDRONATE. - Google Patents

Abstract

Crystalline form of ibandronate sodium, characterized in that it has X-ray reflections in 6.2, 15.7, 26.3, 32.6 and 35.6 ± 0.2 ° 2θ.

Description

Crystalline form of ibandronate sodium. 5 Field of the invention The present invention relates to the solid state chemistry of ibandronate sodium.

Background of the invention

10 The empirical formula of ibandronate sodium is C9H22NO7P2Na · H2O. The chemical name of ibandronate sodium is monosodium salt of (1-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:

20 Ibandronate sodium is a third generation bisphosphonate that contains nitrogen characterized in that it has an aliphatic tertiary amine side chain. Ibandronate sodium is a white powder.

US Patent No. 4,972,814 discloses diphosphonic acid derivatives, the processes for their preparation 25 and the pharmaceutical compositions containing them.

Boniva® (ibandronate sodium) has been developed by Hoffmann-La Roche for the treatment of bone disorders such as hypercalcemia of malignancy, osteolysis, Paget's disease, osteoporosis and metastatic bone disease. It is available in the form of an intravenous injection that is administered every 2-3 months and in the form of

30 oral formulation.

Boniva® is also marketed in Europe under the name Bondronat® for the treatment of bone complications related to cancer. Bondronat®, available in 1 ml ampoules of concentrate for solution for infusion, contains 1,125 mg of ibandronate monosodium salt monohydrate, corresponding to 1 mg of acid

35 ibandronic.

The present invention relates to the solid state physical properties of ibandronate sodium. These properties can be modified by controlling the conditions under which the ibandronate sodium is obtained as a solid. Physical properties of the solid state include, for example, the fluidity of the ground solid. Bliss

Fluency affects the ease with which the material is handled during its transformation into a pharmaceutical product. When the particles of the powdered compound do not flow easily with respect to each other, the formulation specialist requires the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.

Another important solid state property of a pharmaceutical compound is its dissolution rate in an aqueous fluid. The dissolution rate of an active substance in the patient's stomach fluid may have therapeutic consequences, since it imposes a limit higher than the speed with which said active substance administered orally can reach the patient's bloodstream. The dissolution rate is also taken into account in the formulation of syrups, elixirs and other liquid medications. The solid state form of a compound can also affect its behavior during compaction 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. Said polymorphic form may give rise to a thermal behavior different from that of the amorphous material or other polymorphic form. 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 particular spectroscopic properties that can be detected by powder X-ray crystallography, solid state 13C NMR spectrometry and infrared spectrometry.

Generally, the crystalline solid exhibits greater chemical and physical stability than the amorphous form and forms with low crystallinity. It can also have a better solubility, hygroscopicity, volumetric 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. This expands the repertoire of materials available to the formulation specialist to design, for example, a pharmaceutical dosage form of a drug with a controlled release profile or other desired characteristic. There is a need in the art for additional polymorphic forms of ibandronate sodium.

Characteristics of the invention.

In one aspect, the present invention discloses a new crystalline form of ibandronate sodium and a pharmaceutical composition comprising it.

The present invention discloses a crystalline solid ibandronate crystalline sodium called T-shape, characterized by powder X-ray diffraction reflections at 6.2, 15.7, 26.3, 32.6 and 35.6 ± 0.2 degrees two theta.

Brief description of the figures

Figure 1 is an X-ray powder diffractogram of ibandronate sodium of 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 of form F. Figure 5 is an X-ray powder diffractogram of ibandronate sodium of 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 of form J. Figure 8 is an X-ray powder diffractogram of ibandronate sodium of form K. Figure 9 is an X-ray diffractogram of ibandronate sodium powder of form K2. Figure 10 is an X-ray diffractogram of ibandronate sodium powder of form K3. Figure 11 is an X-ray powder diffractogram of ibandronate sodium of form Q. Figure 12 is an X-ray diffractogram of ibandronate sodium powder of form Q1. Figure 12a is an X-ray diffractogram of ibandronate sodium powder of form Q1. Figure 13 is an X-ray diffractogram of ibandronate sodium powder of form Q2.

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

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

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

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

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

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

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

Figure 20 is an X-ray powder diffractogram of ibandronate sodium form S.

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

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

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

Detailed description of the invention

The present invention discloses new crystalline forms of ibandronate sodium, as well as an amorphous form thereof. In one embodiment, the present invention discloses each crystalline form essentially devoid of other crystalline forms, that is, with a content of other crystalline forms not exceeding 5%.

Ibandronate can also occur in solvate forms of ibandronate sodium. The range of solvent content for said solvates is defined below:

Solvate form Solvent content range (by weight) 1/3 ethanolate: 4-5% monoethanolate: 8-12% hemibutanolate 8-10%

The solvate forms of ibandronate sodium include crystalline solid alcoholates of ibandronate sodium, such as crystalline solid ethanolate of ibandronate sodium, monoethanolate and crystalline solid hemietanolate of ibandronate sodium, crystalline solid butanolate of sodium ibandronate and solid hemibutanoate.

The crystalline solid form of ibandronate sodium called form C is characterized in that it has powder X-ray diffraction reflections at 4.7, 5.0, 17.2, 18.3 and 19.5 ± 0.2 degrees two theta. Furthermore, said form C can 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 representative diagram of powder X-ray diffraction of the form

C. Said form C may be a monohydrate and / or a monoethanolate. In addition, form C can be characterized by TGA, showing a weight loss of between about 15 and about 16%.

The crystalline solid form of ibandronate sodium called form D is characterized in that it has powder X-ray diffraction reflections at 4.8, 9.3, 18.5, 23.1 and 36.1 ± 0.2 degrees two theta. Furthermore, said form D can be characterized by powder X-ray diffraction reflections at 15.3, 19.9, 26.3, 27.2 and 30.4 ± 0.2 degrees two theta. Figure 2 shows a representative powder X-ray diffraction diagram for form D. Form D may be a hexahydrate. In addition, form D can be characterized by TGA, showing a weight loss of between about 24 and about 26%.

The crystalline solid form of ibandronate sodium called form E is characterized in that it has powder X-ray diffraction reflections at 4.6, 4.8, 5.3, 9.3 and 34.7 ± 0.2 degrees two theta. In addition, said form E can be characterized by powder X-ray diffraction reflections at 18.6, 23.3, 24.5, 27.1 and 30.1 ± 0.2 degrees two theta. Figure 3 shows a representative diagram of powder X-ray diffraction for form E. Said form E may be a hemibutanolate and / or a sesquihydrate. In addition, form E can be characterized by TGA, showing a weight loss of between about 14 and about 21%.

The crystalline solid form of ibandronate sodium called form F is characterized in that it has reflections of powder X-ray diffraction at 4.9, 5.1, 6.0, 20.0 and 36.4 ± 0.2 degrees two theta. In addition, said form F can be characterized by powder X-ray diffraction reflections at 18.6, 26.0, 28.5, 30.4 and 31.3 ± 0.2 degrees two theta. Figure 4 shows a representative diagram of powder X-ray diffraction for form F.

In addition, the F form can be characterized by TGA, showing a weight loss of between about 10 and about 32%.

The crystalline solid form of ibandronate sodium form G is characterized in that it has reflections of powder X-ray diffraction at 4.7, 9.2, 17.4, 18.4 and 19.9 ± 0.2 degrees two theta. In addition, said G-shape can be characterized by powder X-ray diffraction reflections at 10.1, 15.2, 18.7, 26.3 and 27.1 ± 0.2 degrees two theta. Figure 5 shows a representative powder X-ray diffraction diagram for form G. Form G may be a hexahydrate. In addition, the G form can be characterized by TGA, showing a weight loss of between about 22 and about 25%.

The crystalline solid form of ibandronate sodium called form H is characterized in that it has powder X-ray diffraction reflections at 4.8, 5.7, 17.3, 19.5 and 26.0 ± 0.2 degrees two theta. In addition, said form H can 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 representative powder X-ray diffraction diagram for the H form. In addition, the H form can be characterized by TGA, showing a weight loss of between about 13 and about 16%.

The crystalline solid form of ibandronate sodium called form J is characterized in that it has powder X-ray diffraction reflections at 4.6, 9.2, 18.3, 19.6 and 25.6 ± 0.2 degrees two theta. In addition, said form J can 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 representative powder X-ray diffraction diagram for form J. Form J may be a hexahydrate. In addition, the J form can be characterized by TGA, showing a weight loss of between about 22 and about 23%.

The crystalline solid form of ibandronate sodium form K is characterized in that it has reflections of powder X-ray diffraction at 5.0, 5.9, 17.2, 20.0 and 25.9 ± 0.2 degrees two theta. In addition, said K shape can be characterized by powder X-ray diffraction reflections at 18.5, 19.7, 21.4, 26.5 and 31.1 ± 0.2 degrees two theta. Figure 8 shows a representative powder X-ray diffraction diagram for form K. Form K may be a sesquihydrate. In addition, the K form can be characterized by TGA, showing a weight loss of between about 10 and about 15%.

The crystalline solid form of ibandronate sodium called form K2 is characterized in that it has reflections of powder X-ray diffraction in 5.1, 6.1, 17.3, 20.1 and 21.5 ± 0.2 degrees two theta. Furthermore, said K2 form can be characterized by powder X-ray diffraction reflections at 18.6, 19.6, 26.1, 26.8 and 31.1 ± 0.2 degrees two theta. Figure 9 shows a representative diagram of powder X-ray diffraction for form K2. In addition, the K2 form can be characterized by TGA, showing a weight loss of between about 9 and about 10%.

The crystalline solid form of ibandronate sodium called form K3 is characterized in that it has reflections of powder X-ray diffraction at 5.1, 6.2, 17.3, 19.7 and 20.1 ± 0.2 degrees two theta. In addition, said K3 form can 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 representative diagram of powder X-ray diffraction for form K3. In addition, the K3 form can be characterized by TGA, showing a weight loss of between about 7 and about 8%.

The crystalline solid form of ibandronate sodium called form Q is characterized in that it has powder X-ray diffraction reflections at 5.0, 6.1, 17.2, 25.7 and 30.9 ± 0.2 degrees two theta. In addition, said Q form can be characterized by powder X-ray diffraction reflections at 16.8, 21.4, 26.7, 29.1 and 36.9 ± 0.2 degrees two theta. Figure 11 shows a representative powder X-ray diffraction diagram for the Q form. The Q form can be presented within a range between a monohydrate and a hexahydrate. In addition, the Q form can be characterized by TGA, showing a weight loss of between about 5 and about 25%.

The crystalline solid form of ibandronate sodium called form Q1 is characterized in that it has powder X-ray diffraction reflections at 4.7, 6.0, 17.2, 26.2 and 31.0 ± 0.2 degrees two theta. In addition, said Q1 form can be characterized by powder X-ray diffraction reflections at 19.5, 21.4, 25.8, 29.1 and 37.1 ± 0.2 degrees two theta. Figures 12 and 12a show a representative diagram of powder X-ray diffraction for form Q1. The Q1 form may be presented within a range between a dihydrate and a trihydrate. In addition, the Q1 form can be characterized by TGA, showing a weight loss of between about 9 and about 16%.

The crystalline solid form of ibandronate sodium called form Q2 is characterized in that it has powder X-ray diffraction reflections at 4.9, 6.2, 25.9, 31.0 and 37.1 ± 0.2 degrees two theta. In addition, said Q2 form can be characterized by powder X-ray diffraction reflections at 16.9, 17.3, 19.0, 26.6 and 29.2 ± 0.2 degrees two theta. Figures 13 and 13a show a representative diagram of powder X-ray diffraction for form Q2. The Q2 form can be presented within a range between a dihydrate and a tetrahydrate. In addition, the Q2 form can be characterized by TGA, showing a weight loss of between about 8 and about 17%.

The crystalline solid form of ibandronate sodium called form Q3 is characterized in that it has powder X-ray diffraction reflections at 5.9, 17.1, 19.6, 20.2 and 21.3 ± 0.2 degrees two theta. In addition, said Q3 form can be characterized by powder X-ray diffraction reflections at 18.0, 18.5, 23.6, 24.7 and 30.8 ± 0.2 degrees two theta. Figure 14 shows a representative powder X-ray diffraction diagram for form Q3. In addition, the Q3 form can be characterized by TGA, showing a weight loss of between about 7 and about 9%.

The crystalline solid form of ibandronate sodium called form Q4 is characterized in that it has reflections of powder X-ray diffraction at 6.1, 17.2, 19.6, 20.3 and 21.4 ± 0.2 degrees two theta. In addition, said Q4 form can be characterized by powder X-ray diffraction reflections at 16.9, 18.1, 18.5, 23.7 and 24.8 ± 0.2 degrees two theta. Figure 15 shows a representative powder X-ray diffraction diagram for form Q4. In addition, the Q4 form can be characterized by TGA, showing a weight loss of between about 7 and about 8%.

The crystalline solid form of ibandronate sodium called form Q5 is characterized in that it presents reflections of powder X-ray diffraction in 6.1, 17.2, 19.6, 20.1 and 21.5 ± 0.2 degrees two theta. In addition, said Q5 form can be characterized by powder X-ray diffraction reflections at 16.8, 24.7, 25.7, 29.0 and 30.9 ± 0.2 degrees two theta. Figure 16 shows a representative powder X-ray diffraction diagram for form Q5. In addition, the Q5 form can be characterized by TGA, showing a weight loss of between about 5 and about 11%.

The crystalline solid form of ibandronate sodium form Q6 is characterized in that it has reflections of powder X-ray diffraction in 6.1, 17.3, 19.6, 21.5 and 30.8 ± 0.2 degrees two theta. In addition, said Q6 form can be characterized by powder X-ray diffraction reflections at 16.9, 20.2, 25.6, 26.9 and 29.1 ± 0.2 degrees two theta. Figure 17 shows a representative powder X-ray diffraction diagram for form Q6. In addition, the Q6 form can be characterized by TGA, showing a weight loss of between about 9 and about 10%.

The crystalline solid form of ibandronate sodium called the QQ form is characterized in that it has powder X-ray diffraction reflections at 6.2, 25.9, 26.7, 31.1 and 37.2 ± 0.2 degrees two theta. In addition, said QQ form can be characterized by powder X-ray diffraction reflections at 16.9, 17.3, 21.5, 24.7 and 29.2 ± 0.2 degrees two theta. Figure 18 shows a representative powder X-ray diffraction diagram for the QQ form. This crystalline form does not transform into other polymorphic forms by more than 5% when stored, for example, at a relative humidity of 100% and at 40 ° C for 3 days. In addition, the QQ form has a particle size distribution of not more than 100 μ, preferably not more than 60 μ. The Q2 form can be presented within a range between a monohydrate and a trihydrate. In addition, the QQ form can be characterized by TGA, showing a weight loss of between about 5 and about 12%.

An optical microscope can be used for direct observation and evaluation of the maximum size and shape of the particles. A suspension of material (such as a sample in fluid silicone) can be placed on a slide and viewed using different lenses in the microscope. The particle size can be estimated using an internal calibrated ruler.

The crystalline solid form of ibandronate sodium called form R is characterized in that it has powder X-ray diffraction reflections at 5.3, 6.0, 17.2, 18.7 and 20.0 ± 0.2 degrees two theta. In addition, said R form can be characterized by powder X-ray diffraction reflections at 20.5, 25.0, 26.5, 29.1 and 31.0 ± 0.2 degrees two theta. Figure 19 shows a representative powder X-ray diffraction diagram for the R form. The R form can be a hemietanolate and / or a monohydrate. In addition, the R form can be characterized by TGA, showing a weight loss of between about 10 and about 11%.

The crystalline solid form of ibandronate sodium form S is characterized in that it has reflections of powder X-ray diffraction at 4.8, 5.1, 5.3, 5.4 and 6.1 ± 0.2 degrees two theta. In addition, said S form can be characterized by powder X-ray diffraction reflections at 10.5, 21.0, 26.3, 33.0 and 38.2 ± 0.2 degrees two theta. Figures 20 and 20a show a representative powder X-ray diffraction diagram for the S form. The S form may be a hemietanolate and / or a hemihydrate. In addition, the S form can be characterized by TGA, showing a weight loss of between about 11 and about 12%.

The present invention discloses a crystalline solid form of ibandronate sodium called form T. Said form T is characterized in that it has powder X-ray diffraction reflections in 6.2, 15.7, 26.3, 32.6 and 35 , 6 ± 0.2 degrees two theta. In addition, said T-shape can be characterized by powder X-ray diffraction reflections at 17.6, 19.4, 26.9, 31.7 and 38.7 ± 0.2 degrees two theta. Figure 21 shows a representative powder X-ray diffraction diagram for the T form. In addition, the T form can be characterized by TGA, showing a weight loss of between about 5 and about 7%.

Figure 22 shows a representative X-ray diffraction diagram for amorphous ibandronate sodium. In addition, the amorphous form can be characterized by TGA, showing a weight loss of between about 6.8 and about 24.4%.

Methods for the preparation of crystalline forms of ibandronate sodium include the steps of dissolving ibandronate sodium in a solvent and isolating the crystalline form of ibandronate sodium from the reaction mixture.

Methods for the preparation of crystalline forms of ibandronate sodium 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 said combination. The solvent may be an organic solvent, such as a ketone or a C3-C7 ester, a C1-C3 alcohol or acetonitrile; Water; or a mixture thereof. Among the preferred solvents are acetone, methanol, ethanol, isopropanol, acetonitrile, water and mixtures thereof. Sodium hydroxide can be solid, aqueous or, preferably, sodium hydroxide is in solution in the solvent in which sodium hydroxide and ibandronic acid are combined. The crystalline ibandronate sodium is preferably precipitated from a solution with a pH between about 3 and about 5, preferably about 4.

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

The methods may further comprise heating the combination (which may be a solution) and / or cooling it. For example, the combination can be heated at a temperature above room temperature to a temperature between about 50 ° C and 130 ° C, preferably at the approximate reflux temperature. The combination can be cooled to a temperature of about room temperature to a temperature of about 0 ° C, preferably at about room temperature. The solution can be cooled at once or in stages. When a cooling step is carried out in the process that is started with ibandronic acid and NaOH, the solution is preferably cooled in stages, still more preferably by first cooling to room temperature and then further cooling with an ice bath.

Preferably, the combination is a solution and it is stirred during one or more stages in order to facilitate complete precipitation. Preferably, the solution is stirred during one or more stages for a period between about 10 minutes and about 72 hours, preferably between about 1 hour and about 20 hours, still more preferably for about 16 hours.

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 procedures 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 dissolution. Also, it can be dried in a vacuum oven at about 50 ° C for about 24 hours, or it can be dried by evaporation.

A process for preparing ibandronate sodium of form C includes the steps of dissolving ibandronate sodium in dimethylsulfoxide (DMSO) to form a solution, combining the solution with butanol to form a suspension and isolation of ibandronate sodium of form C from said suspension. Preferably, the solution is heated to a temperature between about 120 ° C and about 125 ° C. Preferably, the suspension is stirred at the heating temperature for a period between about 1 and about 5 hours, more preferably for about 3 hours. Preferably, the process further includes cooling the suspension at approximately room temperature.

A process for preparing ibandronate sodium form D includes the steps of dissolving ibandronate sodium in water to form a solution, combining the solution with acetone to form a suspension and isolating crystalline ibandronate from said suspension. Preferably, the process includes heating the solution to approximately reflux temperature. Preferably, the suspension is stirred at approximately reflux temperature for a period between about 1 and about 5 hours, preferably for about 4.5 hours. Preferably, the process further includes cooling the suspension at approximately room temperature.

A method for preparing ibandronate sodium form E 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 isolating sodium ibandronate crystalline form E from said suspension. Said process may also include heating and cooling the solution. When the process includes heating the solution, it is preferably heated to approximately reflux temperature. When the solution is heated, the suspension is preferably stirred at about reflux temperature for a period between about 1 and about 5 hours, more preferably between about 4 and about 4.5 hours. Subsequently, the heated suspension can be cooled to approximately room temperature. Optionally, when 1-butanol is used, the process is carried out at approximately room temperature.

A process for preparing ibandronate sodium form F 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 ibandronate sodium form F from said suspension. Preferably, the process includes heating the solution to approximately reflux temperature. Preferably, the suspension is stirred at about reflux for a period between about 1 and about 5 hours, more preferably for about 4 hours. Preferably, the process further includes cooling the suspension at approximately room temperature.

A process for preparing ibandronate sodium of form F includes the steps of combining sodium hydroxide with ibandronic acid in a mixture of water and isopropanol with a proportion of water with respect to isopropanol between 20:80 and 60:40 and the isolation of the ibandronate sodium form F from the reaction mixture. Preferably, the process includes heating the reaction mixture to approximately reflux temperature. Preferably, the reaction mixture is stirred at about reflux for a period between about 0.5 and about 5 hours. Preferably, the process further includes cooling the suspension at approximately room temperature.

A process for preparing ibandronate sodium form G includes the steps of dissolving ibandronate sodium in water to form a solution, combining the solution with DMSO to form a suspension and isolation of ibandronate sodium form G from said suspension. Preferably, the solution is approximately at room temperature. Preferably, the suspension is stirred at approximately room temperature for approximately 16 hours.

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

A process for preparing ibandronate sodium form H 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 isolation of ibandronate sodium form H from said solution. suspension.

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

A process for preparing ibandronate sodium form J includes the steps of dissolving ibandronate sodium in water to form a solution, combining the solution with DMSO to form a suspension and isolation of ibandronate sodium form J from said suspension. Preferably, the process includes heating the solution to approximately reflux temperature. Preferably, the suspension is stirred at approximately reflux temperature for a period between about 1 and about 10 hours, more preferably for about 6 hours. Preferably, the process further includes cooling the suspension at approximately room temperature.

A process for preparing ibandronate sodium form K includes the dissolution steps of combining sodium hydroxide with ibandronic acid in isopropanol and isolation of ibandronate sodium form K from the solution. Preferably, the process includes heating the reaction mixture to approximately reflux temperature. Preferably, the reaction mixture is stirred at about reflux for a period between about 1 and about 5 hours, more preferably for about 4 hours. Preferably, the process further includes cooling the suspension at approximately room temperature.

A process for the preparation of ibandronate sodium form K2 includes the steps of dissolving ibandronate sodium in water and isolation of ibandronate sodium form K2 from the reaction mixture. Preferably, the process includes heating the reaction mixture to approximately reflux temperature. Preferably, the process further includes cooling the reaction mixture at approximately room temperature.

A process for preparing ibandronate sodium in the form of K3 includes the steps of combining sodium hydroxide with ibandronic acid in water to form a solution, combining said solution with isopropanol to form a suspension and isolation of the ibandronate of sodium in form K3 from said solution. suspension. Preferably, the process includes heating the solution of ibandronic acid in water at approximately 70 ° C. Preferably, the isopropanol is cold and the suspension is further cooled, preferably at about 0 ° C. Preferably, the suspension is stirred at about 0 ° C for about 16 hours.

A process for preparing ibandronate sodium of form Q 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 isolation of ibandronate sodium of form Q from said solution. Preferably, the solution is approximately at room temperature. Preferably, the suspension is stirred at approximately room temperature for approximately 16 hours. Optionally, when the solvent is acetone, the solution is heated to approximately reflux temperature and the suspension is stirred at approximately reflux temperature for a period between about 4 and about 5 hours. Preferably, when the suspension is at approximately reflux temperature, the process further includes cooling the suspension at approximately room temperature.

A process for preparing ibandronate sodium of form Q includes the steps of combining sodium hydroxide with ibandronic acid in acetone, ethanol, water, or a mixture of water and acetonitrile with a proportion of water with respect to acetonitrile of approximately 20:80 or about 60:40 and the isolation of ibandronate sodium form Q 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 with a proportion of water with respect to acetonitrile of approximately

20:80 or about 60:40, the reaction mixture is preferably at reflux temperature and then it is cooled to approximately room temperature.

A process for preparing ibandronate sodium form Q1 includes 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 isolation of ibandronate sodium form Q1 from said solution. suspension. Preferably, the solution is approximately at room temperature. Preferably, the suspension is stirred at approximately room temperature for approximately 16 hours.

A process for preparing ibandronate sodium in form Q2 includes the steps of dissolving ibandronate sodium in water to form a solution, combining the solution with acetonitrile to form a suspension and isolation of ibandronate sodium in form Q2 from said suspension. Preferably, the process includes heating the reaction mixture to approximately reflux temperature. Preferably, the process includes stirring the suspension at approximately reflux temperature for a period between about 1 and about 5 hours, preferably for 4.5 hours. Preferably, the process further includes cooling the suspension at approximately room temperature.

A process for preparing ibandronate sodium of form Q2 includes the steps of combining sodium hydroxide with ibandronic acid in water to form a solution, combining said solution with 2-butanol and isolation of ibandronate sodium of form Q2 from the mixture of reaction. Preferably, the solution is approximately at room temperature. Preferably, the reaction mixture is stirred at approximately room temperature for approximately 16 hours.

A process for preparing ibandronate sodium in Q3 form includes the steps of combining sodium hydroxide with ibandronic acid in methanol or a mixture of water and methanol with a proportion of water with respect to methanol of approximately 60:40 and the isolation of ibandronate sodium Q3 from the reaction mixture. Preferably, the reaction mixture is heated to approximately reflux temperature. Preferably, the process includes stirring the reaction mixture at approximately reflux temperature for a period between about 1 and about 5 hours. Preferably, the process further includes cooling the reaction mixture at approximately room temperature.

A process for preparing ibandronate sodium in Q4 form includes the steps of combining sodium hydroxide with ibandronic acid in water to form a solution, combining said solution with acetone and isolating ibandronate sodium in Q4 form from the reaction mixture. Preferably, the solution is heated at approximately reflux temperature. Preferably, acetone is a cold acetone. Preferably, when the acetone is added, the reaction mixture is stirred at a temperature between about 0 ° C and about 5 ° C, more preferably at about 3 ° C, for a period between about 1 and about 5 hours, more preferably for about 2 hours.

A process for preparing ibandronate sodium in a Q5 form includes the steps of combining sodium hydroxide with ibandronic acid in a mixture of water and acetonitrile with a proportion of water with respect to acetonitrile of approximately 40:60, ethanol or methanol and the isolation of ibandronate sodium form Q5 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 approximately at room temperature. Preferably, when the solvent is water and acetonitrile with a ratio of water to acetonitrile of about 40:60, the reaction mixture is preferably heated to about reflux temperature and then it is cooled to about room temperature. .

A process for preparing ibandronate sodium in form Q6 includes the steps of combining sodium hydroxide with ibandronic acid in approximately 96% ethanol and isolation of ibandronate sodium in form Q6 from the reaction mixture. Preferably, sodium hydroxide is added to a solution of ibandronic acid and 96% ethanol at approximately reflux temperature. Preferably, the process includes stirring the reaction mixture at about room temperature for a period between about 10 and about 30 hours, preferably for about 20 hours.

A process for preparing ibandronate sodium in QQ form includes the steps of dissolving ibandronate sodium in water to form a solution, combining the solution with THF to form a suspension and isolation of ibandronate sodium in QQ form from said suspension. Preferably, the suspension is stirred at approximately room temperature for approximately 16 hours.

A process for preparing ibandronate sodium in a QQ form includes the steps of combining sodium hydroxide with ibandronic acid in a mixture of water and acetone with a water to acetone ratio of approximately 40:60, ethanol or water to form a solution and isolation of ibandronate sodium in QQ form from said solution. When the solvent is ethanol, it is preferably about 93% ethanol. Alternatively, the solvent may be ethanol and ibandronic acid is added in a solution with water. When the solvent is water, ibandronic acid is added in a suspension with ethanol.

A process for preparing ibandronate sodium in QQ form includes the steps of dissolving ibandronate sodium in water to form a solution, maintaining said solution in a saturated acetone environment and decanting it to obtain sodium ibandronate in QQ form.

A process for preparing ibandronate sodium form R includes the steps of dissolving ibandronate sodium in water to form a solution, combining the solution with ethanol to form a suspension and isolation of ibandronate sodium form R from said suspension. Preferably, the suspension is stirred at room temperature for approximately 16 hours.

A process for preparing ibandronate sodium form R includes the steps of combining sodium hydroxide with ibandronic acid in a mixture of water and ethanol with a proportion of ethanol water of about 60:40 or a mixture of water and methanol with a proportion of water with respect to methanol between about 20:80 and about 40:60 and isolation of the ibandronate sodium form R from the reaction mixture. Preferably, the reaction mixture is approximately at reflux temperature. Preferably, the process further includes cooling the reaction mixture at approximately room temperature.

A process for preparing ibandronate sodium form S includes the steps of combining sodium hydroxide with ibandronic acid in a mixture of water and ethanol with a proportion of ethanol water of approximately 40:60 and isolation of sodium ibandronate form S from the reaction mixture. Preferably, the process includes stirring the reaction mixture at approximately reflux temperature for a period between about 1 and about 5 hours, even more preferably for about 3.5 hours.

In another embodiment, the present invention discloses a method for preparing ibandronate sodium form T that includes the steps of combining sodium hydroxide with ibandronic acid in a mixture of water and acetone with a proportion of water with respect to acetone of approximately 20:80 and isolation of ibandronate sodium form T from the reaction mixture. Preferably, the process includes stirring the reaction mixture at approximately reflux temperature for a period between about 1 and about 5 hours, even more preferably for about 1.5 hours. Preferably, the process further includes cooling the reaction mixture at approximately room temperature.

A process for preparing amorphous ibandronate sodium includes the steps of dissolving ibandronate sodium in DMSO to form a solution, combining the solution with acetone to form a suspension and isolating amorphous ibandronate sodium from said suspension. Preferably, the process includes heating the solution to a temperature of approximately 120 ° C. Preferably, the suspension is stirred at about reflux for a period between about 10 minutes and about 5 hours, more preferably between about 10 minutes and about 3.5 hours. Preferably, the process further includes cooling the solution at approximately room temperature.

A process for preparing amorphous ibandronate sodium includes the steps of combining sodium hydroxide with ibandronic acid in a mixture of water and ethanol with an ethanol water ratio of approximately 80:20, a mixture of water and isopropanol with a proportion of water with respect to isopropanol of about 80:20, acetonitrile, a mixture of water and acetonitrile with a proportion of water with respect to acetonitrile between about 60:40 and about 80:20, or water, and isolation of amorphous sodium ibandronate from the reaction mixture. The process may further comprise the combination of the solution with an anti-solvent. For example, when the solvent is acetonitrile, acetone can be combined with the reaction mixture. When the solvent is water, hexanes can be combined with the solution.

Amorphous ibandronate sodium can be obtained by spray drying a solution of ibandronate sodium. The term " spray drying " It refers broadly to procedures that involve the breaking of liquid mixtures into small droplets (atomization) and the rapid removal of the solvent from said mixtures. In a typical spray drying apparatus, an intense drag force evaporates the solvent from the droplets, which can be achieved by a drying gas. Spray drying can be carried out in a conventional manner in the processes according to the present invention, see Remington: The Science and Practice of Pharmacy 681 (20th ed., 2000). The drying gas used in the present invention may be any suitable gas, although inert gases such as nitrogen, nitrogen enriched air or argon are preferred. Gas nitrogen is a particularly preferred drying gas for use in the process according to the present invention. The product of ibandronate sodium obtained by spray drying can be recovered by techniques commonly used in the art, such as the use of a cyclone or a filter. Preferably, amorphous ibandronate sodium is obtained by spray drying a solution of ibandronate sodium in water.

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

The diluents increase the volume of the solid pharmaceutical composition and can result in a pharmaceutical dosage form that contains the easiest composition for the patient and the person in charge of care. Among the diluents for solid compositions are, for example, microcrystalline cellulose (eg, Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar , dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (for example, Eudragit® ), potassium chloride, cellulose powder, 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 agglutinate the active substance and other excipients together after compression. Among the binders for solid pharmaceutical compositions are acacia, alginic acid, carbomers (for example, carbopol), sodium carboxymethylcellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), hydroxypropylmethylcellulose (e.g., Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., Kollidon® , Plasdone®), pregelatinized starch, sodium alginate and starch.

The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition. Among such disintegrants are alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose (for example, Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (for example, Kollidon ®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, potassium polacrilin, cellulose powder, pregelatinized starch, sodium alginate, sodium starch glycolate example, Explotab®) and starch.

Slides may be added to improve the fluidity of the solid, non-compacted composition and to improve the dosing accuracy. Among the excipients that can act as glidants are colloidal silicon dioxide, magnesium trisilicate, cellulose powder, starch, talc and tribasic calcium phosphate.

When a dosage form, such as a tablet, is prepared by compacting a powder composition, said composition is subjected to pressure by means of a punch and a die. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and die, which can cause pitting and other surface irregularities in the product. A lubricant can be added to the composition to reduce adhesion and facilitate release of the product from the matrix. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, lauryl sodium sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.

Flavors and flavor enhancers make the dosage form more pleasant for the patient. Among the flavorings and flavor enhancers customary in pharmaceutical products that can be included in the composition according to the present invention are maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and Tartaric acid

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

In the liquid pharmaceutical compositions according to the present invention, ibandronate sodium and all other solid excipients are dissolved or suspended in a liquid vehicle, such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.

The liquid pharmaceutical compositions may contain emulsifying agents for homogeneously dispersing throughout the composition an active ingredient or insoluble excipient in the liquid carrier. Among the emulsifying agents that may be useful in the liquid compositions according to the present invention are, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, Chondrus, pectin, methylcellulose , carbomers, ketostearyl alcohol and cetyl alcohol.

The liquid pharmaceutical compositions according to the present invention may also contain a viscosity enhancing agent in order to improve the mouthfeel of the product and / or coat the gastrointestinal tract. These agents include acacia, alginic acid, bentonite, carbomers, calcium or sodium carboxymethylcellulose, ketostearyl alcohol, methylcellulose, ethylcellulose, gelatin, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose , maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.

Sweeteners such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar can be added in order to improve the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid can be added in amounts safe for ingestion to improve storage stability.

According to 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 person skilled in the art can easily carry out the selection of the excipients and the quantities used on the basis of his experience and the consideration of the standard procedures and reference works of this field.

Solid compositions according to the present invention include powders, granules, aggregates and compacted compositions. Doses include doses suitable for oral, oral, rectal, parenteral administration (including subcutaneous, intramuscular and intravenous routes), by inhalation and ophthalmic. Although the most appropriate administration in each case will depend on the nature and severity of the disease to be treated, the preferred route of administration according to the present invention is oral. The doses can be suitably presented in unit dose form and can be prepared by any of the methods well known in the pharmaceutical art.

Among the dosage forms are solid dosage forms such as tablets, powders, capsules, suppositories, sachets, pills or tablets, as well as syrups, suspensions and liquid elixirs.

The dosage form according to the present invention may be a capsule containing the composition, preferably a solid powder or granulated composition according to the present invention, within a hard or soft shell. Said shell may consist of gelatin and may optionally contain a plasticizer such as glycerin and sorbitol, in addition to an opacifying or coloring agent.

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

A composition can be prepared for making tablets or filling capsules by wet granulation. In said wet granulation, all or some of the active ingredients and excipients in the form of powders are combined and then mixed in the presence of a liquid, generally water, which causes the powders to be added forming granules. The granulate is sieved and / or crushed, dried and then sieved and / or crushed until the desired particle size is obtained. Then, with the granulate, tablets can be formed or other excipients, such as a slider and / or a lubricant, can be added before forming them.

A tablet composition can be prepared in the conventional manner by dry mixing. For example, the mixed composition of active ingredients and excipients can be compacted to a block or sheet and then crushed to obtain compacted granules. Then, said compacted granules can be compressed until a tablet is obtained.

Alternatively to dry granulation, the mixed composition can be compressed directly into a compacted dosage form by direct compression techniques. Direct compression results in a more uniform tablet without granules. Among the excipients particularly suitable for direct compression of tablets are microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in the direct compression of tablets is known to those skilled in the art with experience and knowledge about the particular difficulties of tablet formation by direct compression.

A capsule filling according to the present invention may comprise any of the mixtures and granules mentioned above with reference to the formation of tablets, although they do not undergo any final stage of tablet formation.

A pharmaceutical formulation of ibandronate sodium can be administered. Preferably, ibandronate sodium is formulated for administration to a mammal, preferably a human being, 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 taking into account its physical and chemical stability at various pH values, viscosity (which results in its ability to be injected), fluidity, boiling point, miscibility and purity. Suitable solvents include USP alcohol, NF benzyl alcohol, USP benzyl benzoate and USP castor oil. Additional substances, such as buffers, solubilizers and antioxidants, among others, can be added to the formulation. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

Boniva® and / or Bondronat® can be used as a formulation guide. Boniva® is available as an intravenous injection administered every 2-3 months and as an oral formulation. Bondronat®, available in 1 ml ampoules of concentrate for solution for infusion, contains 1,125 mg of ibandronate monosodium salt monohydrate, corresponding to 1 mg of ibandronic acid.

The invention having been described, the same is illustrated below by the following non-limiting examples. Table 1 presents a summary of the examples described in greater detail below.

Table 1

Shape

Example Residual solvent Dry loss due to TGA [%] DSC Solvate / Hydrate

pT

dH

C

one 11.1% 15.0% 183.1 197.8 -105.8 -32.2 monoethanolate

C

2 16.0% 118.7 183.7 -3.6 -129.3

D

3 25.0% 102.1 130.4 164.5 -4.7 -1.9 -123.2

AND

4 14.4% 79.6 126.9 144.9 190.5 205.8 -3.0 -1.1 -9.1 -74.4 -41.5

AND

5 9.1% 15.8% 126.9 192.0 204.8 -5.0 -114.0 -33.7 hemibutanolate

AND

6 20.7% 191.9 -13.0

F

7 14.8% 101.7 142.3 181.2 193.9 -1.5 -7.9 -55.0 -34.3

F

8 13.6% 142.9 193.0 198.6 -1.1 -97.2 -57.9

F

9 16.4% 143.2 203.9 -1.2 -177.1

F

10 31.4% 149.4 177.9 188.7 196.5 -3.2 -24.8 -31.2 -54.4

(continuation)

Shape

Example Residual solvent Dry loss due to TGA [%] DSC Solvate / Hydrate

G

eleven 0.0% 22.4% 151.5 -173.7

G

12 25.0% 75,9148.4 -9.9 -165.8

H

13 15.6% 141,1183,9204.8 -44.7-120.9-35.0

H

14 14.5% 187.0 202.2 -90.2 -19.9

H

fifteen 13.8% 191.7 203.8 -81.4 -55.8

J

16 0.1% 22.8% 151,1188.6 -254.1-17.5

K

17 14.0% 70.2167.7183.2194.4 -8.0-13.0-73.5– 54.2

K2

18 9.3% 164.4 192.1 -95.5 -41.9

K3

19 7.6% 154.8 201.2 -43.7 -38.5

Q

twenty 0.6% 9.3% 153.5 179.1 -99.8 -73.2

Q

twenty-one 15.9% 149.6177.3190.3 -4.9-79.1-36.5

Q

22 0.0% 24.1% 102.1130.4164.5 -4.7-1.9 -123.2

Q

2. 3 8.2% 73.3154.1184.2 -0.9-135.6-1.4

(continuation)

Shape

Example Residual solvent Dry loss due to TGA [%] DSC Solvate / Hydrate

Q

24 10.1% 80.3159.1 -2.7 -142.1

Q

25 6.7% 163.8171.0 -66.6-78.2

Q

26 5.9% 156,0175.3 -97.1-80.4

Q

27 , 5.8% 178.0 -143.5

Q1

0.9% 15.9% 145.1180.0190.5 -5.2-76.0-33.0

Q1

29 9.3% 163,1189,7197.9 -32.3-122.7-88.4

Q2

30 0.9% 8.8% 156.3176.7191.0 -12.1-53.3-34.6

Q2

31 16.9% 131,1184,1192.5 -20.4-76.9-56.2

Q3

32 8.4% 127.3178.4201.1 + 24.2-87.3 + 5.4

Q3

33 7.7% 177.6196.8 -61.3-39.1

Q4

3. 4 7.7% 162.6 -103.1

Q5

35 5.7% 166,1173.4 -78.1-71.3

Q5

36 10.9% 86,7166,8193.1 -1.6-136.8-41.1

(continuation)

Shape

Example Residual solvent Dry loss due to TGA [%] DSC Solvate / Hydrate

Q5

37 7.3% 159.8 -127.6

Q6

38 9.3% 165.9 192.2 -83.7 -4.6

QQ

39 5.6% 143.8175.6 -128.0-29.0

QQ

40 6.1% 133,1173.9 -7.9-149.3

QQ

6.0% 160.5176.4 -96.6-97.0

QQ

41 8.8% 131.6173.0193.1 -14.1-98.5-39.4

QQ

42 6.3% 163.6 180.4 -70.9 -94.5

QQ

43 9.6% 153.2167.2178.0 -123.4-46.5-20.4

QQ

44 11.4% 141.6167.0192.3200.2 -21.0-23.5-72.9-65.4

R

Four. Five 10.5% 15.6% 141,1183,9204.8 -44.7-120.9-35.0 monoethanolate

R

46 4.6% 10.3% 165.9 196.5 -54.9 -52.9 1/3 ethanolate

R

47 10.4% 171.6195.7 -75.4-23.2

R

48 10.5% 161.5174.5183.4 -30.0-39.1-63.6

(continuation)

Shape

Example Residual solvent Dry loss due to TGA [%] DSC Solvate / Hydrate

R

49 10.5% 158.3177.2197.9 -12.1-83.2-24.5

R

fifty 10.3% 133,1173.9 -7.9 -149.3

S

51 8.6% 11.4% 150.4 200.9 -0.9 -188.4 monoethanolate

T

52 6.0% 174.0 -149.2

Amorphous

53 24.4% 54,688,5145.4 + 28.6-143.6-133.2

Amorphous

54 16.2% 66,792,5150.0 + 26.3-94.6-92.8

Amorphous

55 7.8% 56,688,2177.5 -21.1-84.6-31.7

Amorphous

56 8.4% 60,581,2133.3 -32.0-63.9-2.9

Amorphous

57 10.0% 80.7152.7 -95.2-2.0

Amorphous

58 8.4% 56,0105.2 -11.3-66.4

Amorphous

59 8.0% 51.5105.4163.5 -6.9-9.0-55.1

Amorphous

60 7.3% 83.3 -268.1

Amorphous

61 7.2% 56.0 96.2 -2.5 -88.8

Amorphous

62 9.1% 100.8 180.9 214.8 -321.0 +180.9 -5.0

Amorphous

63 6.8% 47.4 99.1 -3.1 -112.0

Examples

X-ray powder diffraction:

X-ray powder diffraction data was obtained by methods known in the art using a SCINTAG model X’TRA powder X-ray diffractometer provided with a solid state detector. Copper irradiation of 1.5418 Å was used. A round aluminum sample holder with a zero-bottom round quartz plate, with a cavity of 25 (diameter) x 0.5 (depth) mm.

Scanning Parameters: Range: 2-40 degrees two theta (+ 0.2 degrees two theta) Sweep mode: Continuous sweep. Step size: 0.05 degrees. Scanning speed: 5 degrees / min.

Thermal Gravimetric Analysis (TGA):

A thermogravimetric analysis (TGA) was carried out at a heating rate of 10 ° C / min. using a Mettler TG50 model instrument. The sample size was 7-15 mg.

In some examples using a reflux medium, said reflux medium is a mixture of solvents. The composition of said solvent mixture reflux means is expressed as a volume to volume ratio (v / v). The amount of water to be added to the reflux media is calculated according to the following formula:

(10 volumes of alcohol per grams 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 to be added.

Differential scanning calorimetry

A differential scanning calorimetry (DSC) analysis was performed with a Mettler Toledo DSC 821e calorimeter. Samples of between 3 and 5 milligrams collected in a crucible with valves (3 holes) at a heating rate of 10 ° per minute were analyzed.

Spray drying

Spray drying was carried out in a Buchi Mini Spray B-290 dryer with an evaporation capacity of 1 l / h for water and greater for organic solvents. The maximum temperature input was 220ºC, the air flow was a maximum of 35 m2 / h and the spray gas was compressed air or nitrogen at 200-800 l / h and 5-8 bar. The diameter of the nozzle measured 0.7 mm (standard) and the cap 1.4 mm and 1.5 mm.

Ibandronate sodium form C (reference)

Example 1

Sodium ibandronate (3 g) was dissolved in dimethylsulfoxide (DMSO) (20 ml) at 125 ° C. To the solution obtained was added 2-butanol (40 ml) 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 (2 x 5 ml) and dried in a vacuum oven at 50 ° C for 24 hours, obtaining 3 g of crystalline form ibandronate sodium C. Such form C can show a weight loss between about 15% and about 16% per TGA carried out as described above.

Example 2

Ibandronate sodium (3 g) was dissolved in DMSO (20 ml) at 120 ° C. To the solution obtained was added 1-butanol (40 ml) 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 (2 x 5 ml) and dried in a vacuum oven at 50 ° C for 24 hours, obtaining 3 g of crystalline form ibandronate sodium C.

Ibandronate sodium form D (reference)

Example 3

Ibandronate sodium (3 g) was dissolved in water (6 ml) at reflux temperature. To the solution obtained was added acetone (50 ml) dropwise at reflux temperature, obtaining 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 (3 x 13 ml) and dried in a vacuum oven at 50 ° C for 22 hours, obtaining 3.3 g of ibandronate sodium in crystalline form D. Form D can be show a weight loss of approximately 25% by TGA.

Ibandronate sodium form E (reference)

Example 4

Ibandronate sodium (3 g) was dissolved in water (6 ml) at reflux temperature. To the solution obtained methanol (45 ml) was added dropwise at reflux temperature, obtaining 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 methanol (2 x 20 ml) and dried in a vacuum oven at 50 ° C for 26 hours, obtaining 2.95 g of ibandronate sodium of crystalline form E. Form E can show a weight loss between approximately 14% and approximately 21% by TGA.

Example 5

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

Example 6

Ibandronate sodium (3 g) was dissolved in water (6 ml) at reflux temperature. To the solution obtained was added 1butanol (50 ml) dropwise, obtaining a white precipitate. The suspension was stirred at reflux temperature for 4 hours and then cooled to room temperature. The precipitate was isolated by vacuum filtration, washed with 1-butanol (2 x 16 ml) and dried in a vacuum oven at 50 ° C for 19 hours, obtaining 2.8 g of crystalline form ibandronate sodium E.

Ibandronate sodium form F (reference)

Example 7

Ibandronate sodium (3 g) was dissolved in water (6 ml) at reflux temperature. Isopropanol (IPA) (50 ml) was added dropwise to the solution obtained, obtaining 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 (2 x 20 ml) and dried in a vacuum oven at 50 ° C for 24 hours, obtaining 3 g of crystalline form ibandronate sodium F. Form F may show a weight loss between approximately 13% and approximately 32% by 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 at reflux temperature for an additional 4 hours in order to obtain a pH of 3.93-4.01. Then, the reaction mixture was cooled to room temperature and stirred for 72 hours. Additional cooling was carried out by an ice bath. The precipitate was filtered, washed with IPA (2 x 25 ml) and dried in a vacuum oven at 50 ° C for 24 hours, obtaining 4.4 g of crystalline form ibandronate sodium F.

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 at reflux temperature for an additional 4 hours in order to obtain a pH of 4.0-4.12. Then, the reaction mixture was cooled to room temperature and stirred for 16 hours. Additional cooling was carried out by an ice bath. The precipitate was filtered, washed with IPA (2 x 25 ml) and dried in a vacuum oven at 50 ° C for 24 hours, obtaining 4.3 g of crystalline form ibandronate sodium F.

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 an additional 30 minutes in order to obtain a pH of 4.14. Then, the reaction mixture was cooled to room temperature and stirred for 16 hours. Additional cooling was carried out by an ice bath. The precipitate was filtered, washed with IPA (2 x 25 ml) and dried in a vacuum oven at 50 ° C for 23 hours, obtaining 5.2 g of crystalline form ibandronate sodium F.

Ibandronate sodium form G (reference)

Example 11

Ibandronate sodium (3 g) was dissolved in water (18 ml) at room temperature. To the solution obtained was added DMSO (40 ml) at once, obtaining a white precipitate. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with DMSO (2 x 17 ml) and dried in a vacuum oven at 50 ° C for 23 hours, obtaining 2.5 g of ibandronate crystalline form G. Form G can show a weight loss between approximately 22% and approximately 25% by TGA.

Example 12

Ibandronate sodium (3 g) was dissolved in DMSO (60 ml) at 120 ° C. The solution obtained 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 at one time, obtaining a precipitate. The suspension was stirred at room temperature for 2 hours. Then, the precipitate was isolated by vacuum filtration and dried in a vacuum oven at 50 ° C for 24 hours, obtaining 3.3 g of ibandronate sodium crystalline G.

Ibandronate sodium form H (reference)

Example 13

Ibandronate sodium (3 g) was dissolved in water (18 ml) at room temperature. To the solution obtained was added ethanol (40 ml) at once, obtaining a white precipitate. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with ethanol (2 x 20 ml) and dried in a vacuum oven at 50 ° C for 28 hours, obtaining 2.5 g of ibandronate sodium in crystalline form H. Form H can show a weight loss between approximately 13% and approximately 16% by TGA.

Example 14

Ibandronate sodium (3 g) was dissolved in water (18 ml) at room temperature. IPA (40 ml) was added at once to the solution obtained, obtaining a white precipitate. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with IPA (2 x 20 ml) and dried in a vacuum oven at 50 ° C for 27 hours, obtaining 2.2 g of ibandronate sodium in crystalline form H.

Example 15

Ibandronate sodium (3 g) was dissolved in water (18 ml) at room temperature. To the solution obtained was added ethanol (40 ml) at once, obtaining a white precipitate. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with ethanol (2 x 30 ml) and dried in a vacuum oven at 50 ° C for 27 hours, obtaining 2.5 g of ibandronate sodium in crystalline form H.

Ibandronate sodium form J (reference)

Example 16

Ibandronate sodium (3 g) was dissolved in water (6 ml) at reflux temperature. DMSO (45 ml) was added dropwise to the solution obtained 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 (2 x 20 ml) and dried in a vacuum oven at 50 ° C for 25 hours, obtaining 3.1 g of sodium ibandronate in crystalline form J. Form J can show a weight loss between approximately 22% and approximately 23% by TGA.

Ibandronate sodium form K (reference)

Example 17

A suspension of amorphous ibandronic acid (5 g) in IPA (50 ml) was heated at reflux temperature. Sodium hydroxide (0.63 g, solid) was added and the reaction mixture was heated at reflux temperature for an additional 4 hours in order to obtain a pH of 4.19. Then, the reaction mixture was cooled to room temperature. Additional cooling was carried out by an ice bath. The precipitate was filtered, washed with IPA (2 x 25 ml) and dried in a vacuum oven at 50 ° C for 24 hours, obtaining 5.5 g of crystalline form ibandronate sodium K. Form K may show a loss of weight between approximately 10% and approximately 14% per TGA.

Ibandronate sodium form K2 (reference)

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, obtaining 0.4 g of ibandronate sodium in crystalline form K2. The K2 form may show a weight loss between about 9% and about 10% by TGA.

Ibandronate sodium form K3 (reference)

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. Said solution was poured into cold IPA (500 ml). The resulting precipitate was stirred at 0 ° C for 16 hours. Then, the precipitate was isolated by vacuum filtration and dried in a vacuum oven at 50 ° C for 24 hours, obtaining 2.7 g of ibandronate sodium in crystalline form K3. The K3 form may show a weight loss between about 7% and about 8% by TGA.

Ibandronate sodium form Q (reference)

Example 20

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

Example 21

Ibandronate sodium (3 g) was dissolved in water (18 ml) at room temperature. To the solution obtained was added acetonitrile (70 ml) at one time, obtaining a white precipitate. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with acetonitrile (3 x 15 ml) and dried in a vacuum oven at 50 ° C for 24 hours, obtaining 2.5 g of crystalline form ibandronate sodium Q.

Example 22

Ibandronate sodium (3 g) was dissolved in water (6 ml) at reflux temperature. To the solution obtained was added acetone (50 ml) dropwise at reflux temperature, obtaining 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 and washed with acetone (3 x 13 ml), obtaining 4.1 g of wet sodium ibandronate crystalline Q.

Example 23

A suspension of amorphous ibandronic acid (4.6 g) in acetone (96 ml) was heated at reflux temperature. Sodium hydroxide (0.58 g, solid) was added and the reaction mixture was stirred at reflux temperature for an additional 10 hours in order to obtain a pH of 3.35. Then, the reaction mixture was cooled to room temperature. Additional cooling was carried out by an ice bath. The white precipitate was filtered, washed with acetone (2 x 25 ml) and dried in a vacuum oven at 50 ° C for 21 hours, obtaining 4.5 g of crystalline form ibandronate sodium Q.

Example 24

A suspension of amorphous ibandronic acid (5 g) in ethanol (50 ml) was heated at reflux temperature. Sodium hydroxide (0.63 g, solid) was added and the reaction mixture was stirred at reflux temperature for an additional 4 hours in order to obtain a pH of 3.5. Then, the reaction mixture was cooled to room temperature. Additional cooling was carried out by an ice bath. The white solid was filtered, washed with ethanol (2 x 25 ml) and dried in a vacuum oven at 50 ° C for 20 hours, obtaining 5.5 g of crystalline form ibandronate sodium Q.

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 (2 x 10 ml) and dried in a vacuum oven at 50 ° C for 24 hours, obtaining 4.8 g of crystalline form ibandronate sodium Q.

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: acetonitrile ( 20:80 v / v, 50 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 20 minutes in order to obtain a pH of 3.80. Then, the reaction mixture was cooled to room temperature and stirred for 16 hours. The precipitate was isolated by vacuum filtration, washed with acetonitrile (2 x 10 ml) and dried in a vacuum oven at 50 ° C for 22.5 hours, obtaining 4.0 g of crystalline form ibandronate sodium Q.

Example 27

A solution of sodium hydroxide (0.63 g) in a mixture of 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 solution was heated at reflux temperature for an additional 1 hour. Then, the reaction mixture was cooled to room temperature. Additional cooling was carried out by an ice bath. An inoculation was carried out and the reaction mixture was stirred at 10 ° C for 16 hours. The precipitate was isolated by vacuum filtration, washed with acetonitrile (2 x 10 ml) and dried in a vacuum oven at 50 ° C for 23 hours, obtaining 1.0 g of crystalline form ibandronate sodium Q.

Ibandronate sodium form Q1 (reference)

Example 28

Ibandronate sodium (3 g) was dissolved in water (18 ml) at room temperature. To the solution obtained was added 2butanol (40 ml) at once, obtaining a white precipitate. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with 2-butanol (2 x 16 ml) and dried in a vacuum oven at 50 ° C for 24 hours, obtaining 2.2 g of crystalline form ibandronate sodium Q1. The Q1 form may show a weight loss between about 9% and about 16% by TGA.

Example 29

A solution of ibandronate sodium (1 g) was poured into water (8 ml) dropwise in tetrahydrofuran (THF) with 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, obtaining 0.98 g of ibandronate sodium in crystalline form Q1.

Ibandronate sodium form Q2 (reference)

Example 30

Ibandronate sodium (3 g) was dissolved in water (6 ml) at reflux temperature. To the solution obtained was added acetonitrile (50 ml) dropwise at reflux temperature, obtaining a white precipitate. The suspension was stirred at reflux temperature for 4.5 hours. The suspension was cooled to room temperature and stirred for 16 hours. The precipitate was isolated by vacuum filtration, washed with acetonitrile (3 x 20 ml) and dried in a vacuum oven at 50 ° C for 24 hours, obtaining 3 g of crystalline sodium ibandronate Q2. The Q2 form may show a weight loss between about 16% and about 17% by TGA.

Example 31

A solution of amorphous ibandronic acid (4.5 g) in water (20 ml) and 1 N aqueous sodium hydroxide (14 ml) was stirred at room temperature until a pH of 3.5 was obtained. The solution was added dropwise to 2-butanol (100 ml) with stirring. The precipitate obtained was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with 2-butanol (2 x 20 ml) and dried in a vacuum oven at 50 ° C for 24 hours, obtaining 4.4 g of crystalline form ibandronate sodium Q2.

Ibandronate sodium form Q3 (reference)

Example 32

A solution of sodium hydroxide (0.63 g) in water: 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 reflux temperature. The reaction mixture was heated at reflux temperature for an additional 1.5 hours in order to obtain a pH of 4.01. Then, the reaction mixture was cooled to room temperature. Additional cooling was carried out by an ice bath. The precipitate was filtered, washed with methanol (2 x 25 ml) and dried in a vacuum oven at 50 ° C for 19 hours, obtaining 5.2 g of crystalline form ibandronate sodium Q3. The Q3 form can show a weight loss between about 7% and about 9% by TGA.

Example 33

A suspension of amorphous ibandronic acid (5 g) in methanol (50 ml) was heated at reflux temperature. Sodium hydroxide (0.63 g, solid) was added and the reaction mixture was stirred at reflux temperature for an additional 4 hours in order to obtain a pH of 4.0. Then, the reaction mixture was cooled to room temperature. Additional cooling was carried out by an ice bath. The white solid was filtered, washed with methanol (2 x 25 ml) and dried in a vacuum oven at 50 ° C for 19 hours, obtaining 4.7 g of crystalline form ibandronate sodium Q3.

Ibandronate sodium form Q4 (reference)

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. Said solution was poured into cold acetone (100 ml). The resulting precipitate was stirred at 3 ° C for 2 hours. The precipitate was isolated by vacuum filtration, washed with cold acetone (2 x 15 ml) and dried in a vacuum oven at 50 ° C for 24 hours, obtaining 5.0 g of crystalline form ibandronate sodium Q4. The Q4 form can show a weight loss between about 7% and about 8% by TGA.

Ibandronate sodium form Q5 (reference)

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 in order to obtain a pH of 4.05. Then, the reaction mixture was cooled to room temperature. Additional cooling was carried out by an ice bath. The precipitate was isolated by vacuum filtration, washed with acetonitrile (2 x 20 ml) and dried in a vacuum oven at 50 ° C for 20 hours, obtaining 3.9 g of crystalline form ibandronate sodium Q5. The Q5 form can show a weight loss between about 5% and about 11% by 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 an additional 2 hours. The precipitate was isolated by vacuum filtration, washed with ethanol (50 ml) and dried in a vacuum oven at 50 ° C for 24 hours, obtaining 5.5 g of ibandronate sodium in crystalline 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 precipitate obtained was stirred at room temperature for an additional 22 hours. The precipitate was isolated by vacuum filtration, washed with methanol (30 ml) and dried in a vacuum oven at 50 ° C for 24 hours, obtaining 5.4 g of ibandronate sodium in crystalline form Q5.

Ibandronate sodium form Q6 (reference)

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 for an additional 20 hours. The precipitate was isolated by vacuum filtration, washed with 96% aqueous ethanol (2 x 10 ml) and dried in a vacuum oven at 50 ° C for 24 hours, obtaining 6.0 g of crystalline form ibandronate sodium Q6. The Q6 form can show a weight loss between about 9% and about 10% by TGA.

Ibandronate sodium QQ form (reference)

Example 39

Ibandronate sodium (3 g) was dissolved in water (18 ml) at room temperature. THF (40 ml) was added at once to the solution obtained, obtaining a white precipitate. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with THF (2 x 20 ml) and dried in a vacuum oven at 50 ° C for 18 hours, obtaining 2.1 g of ibandronate sodium in crystalline form QQ. The QQ form can show a weight loss between about 5% and about 12% by 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, 64.4 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 2 hours in order to obtain a pH of 4.5. Then, the solution was cooled to room temperature. Additional cooling was carried out by an ice bath. The precipitate was isolated by vacuum filtration, washed with acetone (2 x 15 ml) and dried in a vacuum oven at 50 ° C for 21 hours, obtaining 3.9 g of crystalline sodium ibandronate QQ.

Example 41

Amorphous ibandronic acid (5 g) was added to a solution of solid sodium hydroxide (0.6 g) dissolved in 93% ethanol (100 ml) at 55 ° C. The suspension obtained 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 (3 x 25 ml) and dried in a vacuum oven at 50 ° C for 24 hours, obtaining 4.5 g of ibandronate crystalline QQ crystalline.

Example 42

A solution of ibandronate sodium (1.5 g) and water (9 ml) was maintained in a saturated atmosphere of acetone (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, obtaining 0.9 g of crystalline ibandronate sodium QQ.

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. Then, the solution was cooled to room temperature and stirred for 72 hours in order to obtain a pH of 4.15. The precipitate was isolated by vacuum filtration, washed with ethanol (2 x 25 ml) and dried in a vacuum oven at 50 ° C for 23 hours, obtaining 4.97 g of crystalline sodium ibandronate QQ.

Example 44

A solution of sodium hydroxide (0.63 g) in ethanol (14 ml) was added dropwise to a solution of 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 (2 x 25 ml) and dried in a vacuum oven at 50 ° C for 22 hours, obtaining 5.4 g of ibandronate sodium in crystalline form QQ.

Ibandronate sodium form R (reference)

Example 45

Ibandronate sodium (3 g) was dissolved in water (18 ml) at room temperature. To the solution obtained was added ethanol (40 ml) at once, obtaining a white precipitate. The suspension was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration and washed with ethanol (2 x 20 ml), obtaining 3.3 g of wet sodium ibandronate in crystalline form R. The R form can show a weight loss between approximately 10% and approximately 16% by 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 in order to obtain a pH of 4.03. Then, the reaction mixture was cooled to room temperature. Additional cooling was carried out by an ice bath. The precipitate was filtered, washed with ethanol (2 x 25 ml) and dried in a vacuum oven at 50 ° C for 19 hours, obtaining 4.7 g of sodium crystalline ibandronate R.

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 in order to obtain a pH of 4.15. Then, the reaction mixture was cooled to room temperature. Additional cooling was carried out by an ice bath. The precipitate was filtered, washed with methanol (2 x 25 ml) and dried in a vacuum oven at 50 ° C for 21 hours, obtaining 5.2 g of ibandronate sodium crystalline R.

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 at reflux temperature for an additional 1.5 hours in order to obtain a pH of 4.04. Then, the reaction mixture was cooled to room temperature. Additional cooling was carried out by an ice bath. The precipitate was filtered, washed with methanol (2 x 25 ml) and dried in a vacuum oven at 50 ° C for 21 hours, obtaining 5.1 g of crystalline R. ibandronate sodium.

Example 49

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

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 stirred at room temperature for an additional 16 hours in order to obtain a pH of 4.11. The white solid was filtered, washed with ethanol (2 x 25 ml) and dried in a vacuum oven at 50 ° C for 21 hours, obtaining 5.1 g of crystalline R. ibandronate sodium.

Ibandronate sodium form S (reference)

Example 51

A solution of sodium hydroxide (0.63 g) in water: ethanol (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 in order to obtain a pH of 4.03. Then, the reaction mixture was cooled to room temperature. Additional cooling was carried out by an ice bath. The precipitate was filtered, washed with ethanol (2 x 25 ml) and dried in a vacuum oven at 50 ° C for 18 hours, obtaining 4.9 g of sodium crystalline ibandronate S. Form S may show a loss of weight between approximately 11% and approximately 12% per TGA.

Ibandronate sodium form T

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 in order to obtain a pH of 4.0. Then, the reaction mixture was cooled to room temperature. Additional cooling was carried out by an ice bath. The precipitate was filtered, washed with acetone (1 x 50 ml) and dried in a vacuum oven at 50 ° C for 21 hours, obtaining 3.8 g of sodium crystalline ibandronate T. Form T may show a loss of weight between approximately 5% and approximately 7% per TGA.

Amorphous Sodium Ibandronate (reference)

Example 53

Ibandronate sodium (3 g) was dissolved in DMSO (10 ml) at 120 ° C. To the solution obtained was added acetone (40 ml) dropwise, obtaining 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, obtaining 2.7 g of amorphous ibandronate sodium. Amorphous ibandronate sodium may show a weight loss between approximately 6.8% and 24.4%, or less, by TGA.

Example 54

Ibandronate sodium (3 g) was dissolved in DMSO (10 ml) at 120 ° C. To the solution obtained was added acetone (40 ml) dropwise, obtaining 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, obtaining 2.2 g of amorphous ibandronate sodium.

Example 55

A solution of sodium hydroxide (0.63 g) in water: ethanol (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 in order to obtain a pH of 3.24. Then, the reaction mixture was cooled to room temperature. The clear solution was evaporated to dryness, obtaining 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 at reflux temperature for an additional 45 minutes. Then, the reaction mixture was cooled to room temperature. The clear solution was evaporated to dryness, obtaining 5.9 g of amorphous ibandronate sodium.

Example 57

A suspension of amorphous ibandronic acid (5 g) in acetonitrile (50 ml) was heated at reflux temperature. Solid sodium hydroxide (0.63 g) was added. The reaction mixture was stirred at reflux temperature for an additional 6 minutes. Then, the reaction mixture was cooled to room temperature. Additional cooling was carried out using an ice bath in order to obtain a transparent gel (pH = 4.05). The gelatinous product was dried in a vacuum oven at 50 ° C for 24 hours, obtaining 2.6 g of amorphous ibandronate sodium.

Example 58

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. Additional cooling was carried out by an ice bath. The clear solution was inoculated with ibandronate sodium in a K1 form and stirred for 16 hours. The stock solution was evaporated to dryness, obtaining 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 to dryness, obtaining 5.2 g of amorphous ibandronate sodium.

Example 60

A suspension of amorphous ibandronic acid (5 g) in water (50 ml) was heated at reflux temperature. 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 until

5 dryness, obtaining 5.6 g of amorphous ibandronate sodium.

Example 61

A suspension of amorphous ibandronic acid (5 g) in acetonitrile (50 ml) was heated at reflux temperature. Be

10 added sodium hydroxide (0.63 g) and the reaction mixture was stirred at reflux temperature for an additional 72 hours. The precipitate was isolated by vacuum filtration and dried in a vacuum oven at 50 ° C for 20 hours, obtaining 5.0 g of amorphous ibandronate sodium.

Example 62

A suspension of amorphous ibandronic acid (5 g) in acetonitrile (200 ml) was heated at reflux temperature. Sodium hydroxide (0.63 g) was added and the reaction mixture was stirred at reflux temperature for an additional 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

20 dried in a vacuum oven at 50 ° C for 22 hours, obtaining 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. Was added

Aqueous sodium hydroxide (0.63 g of NaOH in 20 ml of water) and the reaction mixture was stirred at room temperature for an additional 1 hour. The solution was evaporated to dryness. 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 (1 x 50 ml) and dried in a vacuum oven at 50 ° C for 45 hours, obtaining 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 parts and each was spray dried using a Buchi B-290 mini-spray dryer with a

35 standard 0.7 mm diameter nozzle and 1.4 or 1.5 mm nozzle cap. In each case, amorphous ibandronate sodium was obtained.

For part 1, the gaseous nitrogen was at an inlet temperature of 50 ° C. The evaporated solvent and nitrogen left the dryer by spraying at a temperature of 41-34 ° C.

40 For part 2, the nitrogen gas was at an inlet temperature of 100 ° C. The evaporated solvent and nitrogen left the dryer by spraying at a temperature of 77-62 ° C.

For part 3, the gaseous nitrogen was at an inlet temperature of 150 ° C. The evaporated solvent and nitrogen left the spray dryer at a temperature of 96-109 ° C.

Table 2: Preparation of ibandronate monosodium salt:

EtOH

MeOH IPA ACN Acetone

0% v / v H2O

Q Q3 K Amorphous Q

20% v / v H2O

R + Q R F Q T

40% v / v H2O

S R F Q5 QQ

60% v / v H2O

R Q3 F Q -

80% v / v H2O

Amorphous Amorphous + T Amorphous Amorphous Amorphous> T

Using amorphous IBD-Ac as starting material

Ibandronic amorphous acid (reference)

Example 65

An aqueous solution (40% w / w) of ibandronic acid (150 ml) was evaporated in vacuo (20-30 mmHg) to dryness 5 while the flask was heated in a water bath (up to 70 ° C) to obtain amorphous ibandronic acid (67 g).

Having described the invention with reference to certain preferred embodiments and

certain illustrative examples, those skilled in the art will appreciate the possible modifications of the

The present invention as described and illustrated does not depart from the scope of application thereof as disclosed herein. The examples are presented in order to facilitate the understanding of the

present invention, but they are not intended to limit the scope thereof in any way and should not be understood as

this way. These examples do not include detailed descriptions of conventional methods. Such methods

They are well known to those skilled in the art and are described in numerous publications. You can use the

publication Polymorphism in Pharmaceutical Solids, Drugs and the Pharmaceutical Sciences, volume 95, as a guide.

Claims (4)

1. Crystalline form of ibandronate sodium, characterized in that it has X-ray reflections in 6.2, 15.7, 26.3, 32.6 and 35.6 ± 0.2 ° 2θ. 5 2. Crystalline form of ibandronate sodium according to claim 1, characterized in that it has other X-ray reflections in 17.6, 19.4, 26.9, 31.7 and 38.7 ± 0.2 ° 2θ.

3.

Crystalline form of ibandronate sodium according to claim 2, presenting the powder X-ray diffraction diagram shown below:

Four.

Pharmaceutical composition comprising ibandronate sodium according to any one of the preceding claims.