Ibandronate polymorph b

FIELD: chemistry.

SUBSTANCE: invention relates to a new crystalline polymorph of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid monosodium salt monohydrate (Ibandronate) with formula I, which is characterised by x-ray powder diffraction pattern with characteristic peaks at angles 2-theta: 9.7°, 12.2°, 14.4°, 16.8° and 25.8°, IR-spectrum with characteristic peaks, cm^-1: 3679, 3164, 2955; 2854, 1377, 1290, 1157, 1093, 1068, 1035, 965, 951, 933, 905, 761 and 723, as well as a vibrational Raman spectrum with characteristic peaks, cm^-1: 2968, 2951, 2928, 2887, 2849, 1441, 1308, 1136, 1056, 1023, 954, 907, 839, 762 and 678. formula I.

EFFECT: obtaining a new crystalline ibandronate polymorph used for controlling hypercalcemia, having improved solubility.

13 cl, 6 dwg, 6 ex, 1 tbl

The present invention relates to a new polymorphic crystalline modification monohydrate, monosodium salt of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid (ibandronate) of the following formula:

and how it was received.

Ibandronate is one of the most effective drugs against bone resorption, which directly inhibits the activity of osteoclasts and is a powerful pharmacological tool to control hypercalcemia. Ibandronate is bound to hydroxyapatite in calcified bone tissue, giving it resistance to hydrolytic decomposition proceeding involving phosphates, and thus inhibits both normal and abnormal bone resorption. This drug increases bone mass, reduces the risk of fractures and, therefore, particularly suitable for the treatment of bone tissue diseases and disorders of calcium metabolism, such as osteoporosis or Paget's disease (deforming fibrosa) (EP-A 0252504).

It was found that ibandronate can exist in different polymorphic modifications.

One polymorphic modification ibandronate, which is hereinafter in this application referred to as polymorphs And was identificar the van as thermodynamically more stable while the second polymorphic modification ibandronate, which is hereinafter in this application referred to as polymorphs, easier allocated in the production process.

The ability of the compound to exist in more than one crystalline modification is called polymorphism, and such different crystal modifications known as "polymorphic modifications", or "polymorphs". Polymorphism affects many properties of the drug in the solid state. Various crystalline modifications connections may largely differ from each other on the different physical properties that can directly influence, for example, their solubility. The polymorphism found in some organic compounds.

A comprehensive analysis of polymorphism in molecular crystals, including those used in the pharmaceutical industry, see, for example, in H.G.Brittain, Polymorphism in Pharmaceutical Solids, H.G.Brittain'or, Marcel Dekker Inc., New York, 1999, and in Solid-State Chemistry of Drugs, SSCI Inc., West Lafayette; Indiana, 1999.

The aim of the present invention is specific selection and establishment characteristics polymorphic modifications In ibandronate and the development of a method of producing polymorphic modifications In ibandronate.

This goal is achieved through the identification of crystalline polymorphic modifications In ibandronate andwell as the development of the method of its receipt, what is presented in the claims.

Unless specifically stated otherwise, to determine the value and volume of various terms used in the text of this application use the terms listed below.

The term "polymorphic modification In ibandronate" refers to crystalline polymorphic modifications monohydrate, monosodium salt of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid, as defined in the claims and in the description of the present invention.

The term "crystalline polymorphic modification" refers to a crystalline modification, which can be characterized using analytical methods such as x-ray powder diffraction, infrared spectroscopy and Raman spectroscopy.

The term IR means infrared.

Description of the drawings

Figure 1 shows the x-ray powder diffraction pattern of crystalline polymorphic modifications In ibandronate thus obtained as described in example 1.

Figure 2 presents the IR spectrum of the crystalline polymorphic modifications In ibandronate.

3 shows the Raman spectrum of polymorphic modifications In ibandronate.

4 shows x-ray powder diffraction pattern of crystalline polymorphic modifications And ibandronate, obtained is thus as described in reference example 2.

Figure 5 presents the IR spectrum of the crystalline polymorphic modifications And ibandronate.

Figure 6 presents the Raman spectrum of crystalline polymorphic modifications And ibandronate.

Crystalline polymorphs In ibandronate according to the present invention may be characterized using x-ray powder diffraction pattern showing characteristic peaks at approximately the following angles 2-theta:

Angle 2-theta is specified with the error component ±0,2 (specified in degrees 2-theta represents the angle of reflection in accordance with the Bragg law. Reflection when the angle of slip (angle between the incident beam and the surface) θ leads to reflection at an angle 2θ with respect to the direction of the incident beam.

Crystalline polymorphic modify the tion In ibandronate, as described above, may be further characterized by x-ray powder diffraction pattern shown in figure 1.

Crystalline polymorphs In ibandronate may be further characterized by IR absorption spectrum, which has characteristic peaks at approximately the following values of wave numbers, cm^-1:

The term "approximately" in this context means that the values specified in cm^-1may vary by ±4 cm^-1.

Crystalline polymorphs In ibandronate may be, in addition, is characterized characterized by the IR absorption spectrum shown in figure 2.

Crystalline polymorphs In ibandronate, as described above, can be further characterized using Raman vibrational spectroscopy. Raman spectrum contains the following characteristic peaks at approximately the following values cm^-1:

The term "approximately" in this context means that the values specified in cm^-1may vary by ±8 cm^-1.

Crystalline polymorphs In ibandronate may be further characterized by a Raman spectrum shown in figure 3.

Crystalline polymorphs In ibandronate described above may be further characterized by solubility in water, which constitutes approximately 279 g/l at 25°C (partial conversion to crystalline polymorphic modification And ibandronate).

The method according to the present invention is characterized by the crystallization of monosodium salt, or the monohydrate of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic key is lots polymorphic modification or a mixture of polymorphic modifications in temperature of 10°C to 45°C in the polar solvent and adding a polar aprotic solvent to initiate crystallization.

As the polar solvent, preferably water use.

Suitable polar aprotic solvents are aliphatic ketones, such as acetone or methyl ethyl ketone, or cyclic ethers, such as tetrahydrofuran or dioxane. Preferred polar aprotic solvents are acetone and tetrahydrofuran and tetrahydrofuran is preferred.

Preferably, the crystallization occurs at a temperature of approximately 35°C.

It is advisable to maintain the temperature of crystallization for from 15 minutes to 120 minutes.

The original product for implementing the method according to the present invention can be monosodium salt of 3-(N-methyl-N-pentyl)amino-l-hydroxypropane-1,1-diphosphonic acid, for example, obtained in accordance with the method described in reference example 1 or crystalline polymorphs And ibandronate, for example, received in accordance with reference example 2, or a mixture of crystalline polymorphic modifications And ibandronate with crystalline polio pneu modification In ibandronate.

The initial product may be either dissolved in the polar solvent at about room temperature and then heated to the crystallization temperature or alternatively can be dissolved at a higher temperature and then cooled to the crystallization temperature, as described above.

Residual ethanol that may be present after the implementation of the method of receipt (in accordance with reference example 1), can be easily removed according to known methods, for example by distillation of the ethanol in the form of an azeotrope.

Crystallization usually occurs spontaneously, but can also be initiated by adding crystals of polymorphic modifications In ibandronate.

Thus obtained suspension of crystals, as a rule, is cooled under stirring until complete crystallization, and then filtered.

The whole process of crystallization can be controlled with respect to temperature, periods of heating and cooling using equipment known to a person skilled in the technical field.

The branch target polymorphic modifications can be carried out using filtration methods known from the prior art. Generally, the obtained residue was washed with a polar solvent, which is used for cu is stylizacji, preferably a mixture of water and acetone in a ratio of about 1:1 (vol./vol.).

Drying crystalline polymorphic modifications In ibandronate preferably carried out at a temperature from 30°C to 60°C for approximately 24 to 72 h under normal or reduced pressure.

Ibandronate can be obtained with a content of crystalline polymorphic modifications In ibandronate constituting at least 80%.

Crystalline polymorphs In ibandronate according to the present invention can be used as a pharmaceutically active compound that acts as an effective remedy against bone resorption, directly inhibits the activity of osteoclasts and thereby increases the mass of the bone. In accordance with that specified polymorphic modification can be used for the treatment and/or prevention of diseases associated with bone structure and calcium metabolism, such as osteoporosis or Paget's disease (deforming fibrosa).

In addition, the present invention relates to pharmaceutical compositions comprising crystalline polymorphic modification In ibandronate, as defined above, and a pharmaceutically acceptable carrier and/or adjuvant.

The present invention also regarding the Xia to crystalline polymorphic modifications In ibandronate, as described above for use as therapeutically active compounds.

The following examples serve to illustrate the present invention.

Examples

Measurement of powder x-ray diffraction

Powder x-ray diffraction pattern of the individual crystalline polymorphic modifications a and b ibandronate register on the diffractometer "Bruker D8 Advance AXS" (geometry: Bragg-Brentano; radiation: CuKα in the angle range 2θ from 2° to 40°; C - the second monochromator; a scanning step of constituting of 0.02°, and when the scan time of, for example, 4.0 with one step). Samples weighing approximately 500 mg are placed in the holder and exposed to CuKα radiation. Radiation after diffraction by a crystal lattice is transformed into electronic signals using a scintillation counter and the resulting data is processed using the software package "Diffrac plus". Powder x-ray diffraction pattern of the individual crystalline polymorphic modifications a and b ibandronate shown in figure 1 and 4.

Check the IR spectra

The IR spectra of the individual crystalline polymorphic modifications a and b ibandronate register for the sample in the form of a film suspension in nujol, consisting of approximately 15 mg of sample in approximately 15 mg of Noyola, between the two plates of calcium chloride. Measurements carried out on IR spectrometer with Fourier transform (IFS55 ("Bruker"), or similar device)log transmittance spectra (resolution 4 cm^-1detector: DTGS). The IR spectra of the individual crystalline polymorphic modifications a and b ibandronate shown in figure 2 and 5.

Check Raman spectra

Raman spectra of individual crystalline polymorphic modifications a and b ibandronate register for the sample in powder form by weight to about 20 mg, which is placed in a glass ampoule (shortened ampoules for NMR). The measurements were carried out using the equipment of the firm "Nicolet" for Raman spectrometry with Fourier transform in combination with a spectrometer Magna 860" ("Nicolet") with scattering at 90°, detector: InGaAs. Measurement parameters: resolution of 8 cm^-1; laser power 0.95 W, the number of scans - 300. Raman spectra with Fourier transform individual crystalline polymorphic modifications a and b ibandronate shown in figure 3 and 6.

Measurement of solubility

The solubility of individual crystalline polymorphic modifications a and b ibandronate measured for different solutions. Approximately 10 g of the corresponding polymorphic modifications And or suspended in three different buffer solutions at pH 2, pH 4 buffer Titrisol", citrate/HCl)at pH 7 (methenamine-buffer, Hcl) or in the water. The resulting suspension is stirred for 24 h at 25°C and then further incubated for 24 h without stirring at the same temperature. The solubility calculated by titration according to the following procedure.

The residue is filtered off, take 2 ml of the filtrate, add 5 ml of the solution "Titriplex III, and dilute with water to 100 ml and Then 2 ml of this solution add 0.1 ml of the indicator xrenovy orange and bring the pH to 6.5 by adding small portions metaraminol buffer solution or a 0.1 M solution of chloroethanol acid. The solution is immediately titrated using complex Th-DCTA - xrenovy orange, until the color will not change from orange to reddish-purple. The end point is fixed spectrophotometrically.

The results are shown in the following table.

Reference example 1

Getting monosodium salt of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid

250 g (1,19 mol) of the hydrochloride of N-methyl-N-pentyl-β-alanine, 233 g (2,84 mol) of phosphoric acid, 151 ml of 1.65 mol) of phosphorus oxychloride and 900 ml of diethylmalonate heated stepwise up to 80°C. After 2 h the reaction with continued heating the resulting mixture was cooled to 60°C and add 1733 ml demineralized water, and then carry out the azeotropic distillation of diethylmalonate/water at a temperature of from 90 to 101°C. Add 358 ml of demineralized water, the resulting mixture was refluxed and distilled water. Type 316 ml of demineralized water and the second time distilled water. Finally add 2040 ml of demineralized water and the resulting residue is cooled to 24°C. the pH Value was adjusted at 23°C with a solution of sodium hydroxide (50%) to the value of 4.4. After that add 1100 ml of ethanol of crystallization. The resulting suspension is stirred for 8 hours at a temperature of from 21 to 22°C. Then the solid substances is about to separate, washed using 344 ml of a cold mixture of ethanol/demineralized water (in the ratio of 7/5, vol./vol.), then 344 ml of a mixture of acetone/demineralized water (in the ratio of 5/2,./about.) and dried at 60°C. Receive 315,6 g (yield 73,7%) specified in the header of the product as colourless crystals.

Analysis (complexometric titration): 100,6% (calculated calculated on the anhydrous and solvent free basis).

Residual solvent: 2,3% ethanol (GC - gas chromatography), 3,9% water (KF - Fisher).

Reference example 2

Obtaining crystalline polymorphic modifications And ibandronate

Dissolve 150 g of monosodium salt of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid (produced according to reference example 1) in 390 ml of demineralized water at about 70-90°C. Distilled 205 ml of water. After filtration, the filtrate is cooled to 60°C. and stirred for 45 minutes initiate Crystallization using crystalline polymorphic modification A. After crystallization add a mixture of demineralized water/acetone (290 ml/518 ml), preheated to 50°C. with stirring. After that, the resulting suspension is cooled to a temperature of approximately 20-25°C. under stirring until complete crystallization. Separate the product and washed using a mixture (50 ml acetone/demineralized water in a ratio of 1:1 (vol./vol.). The product is dried for 48 h in a vacuum from 150 to 20 mbar at 60°C.

Yield: 85%.

According to powder x-ray diffraction of the product identified as crystalline polymorphs And ibandronate (figure 4).

Analysis (complexometric titration): 101,0% (calculated calculated on the anhydrous and solvent free basis).

Example 1

Obtaining crystalline polymorphic modifications In ibandronate

Dissolving 55 g of monosodium salt of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid (produced according to reference example 1) in 240 ml of demineralized water. Distilled 75 ml of water. After filtration, the remaining solution is heated to 35°C and add 190 ml of acetone for 20 minutes then the mixture is cooled to ≤25°C under stirring until complete crystallization. Separate the product and washed using a mixture of acetone/demineralized water in a ratio of 1:1 (vol./vol.). The product is dried in vacuum from 150 to 20 mbar for 12 h at 40°C and for 24 h at 60°C.

Yield: 81%.

According to powder x-ray diffraction of the product identified as crystalline polymorphs In ibandronate (figure 1).

Example 2

Obtaining crystalline polymorphic modifications In ibandronate

Dissolving 55 g of monosodium salt of 3-N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid (produced according to reference example 1) in 240 ml of demineralized water. Distilled 75 ml of water. After filtration, the remaining solution was adjusted to 35°C, then add 47 ml of acetone and initiate crystallization, using 0.5 g of crystalline polymorphic modifications In ibandronate, followed by the addition of 144 ml of acetone. The resulting mixture is cooled to ≤25°C under stirring to achieve complete crystallization. Separate the product and washed using a mixture of acetone/demineralized water in a ratio of 1:1 (vol./vol.). The product is dried in vacuum from 150 to 20 mbar at 40°C for 12 h and at 60°C for 24 hours

Yield: 82%.

According to powder x-ray diffraction of the product identified as crystalline polymorphs In ibandronate (figure 1).

Example 3

Obtaining crystalline polymorphic modifications In ibandronate

Dissolving 55 g of monosodium salt of 3-(N-methyl-N-pentyl)amino-l-hydroxypropane-1,1-diphosphonic acid (obtained according to reference example 1) in 240 ml of demineralized water. Distilled 75 ml of water. After filtration, the remaining solution is brought to a temperature of 35°C, add 382 ml of acetone for 20 min and simultaneously add 0.5 g of crystalline polymorphic modifications In ibandronate. The resulting mixture is cooled to ≤25°C under stirring to achieve complete crystallization. Separate polucen the th product and washed, using a mixture of acetone/demineralized water in a ratio of 1:1 (vol./vol.). The product is dried in vacuum from 150 to 20 mbar at 40°C for 12 h and then at 60°C for 24 hours

Yield: 88%.

According to powder x-ray diffraction of the product identified as crystalline polymorphs In ibandronate (figure 1).

Example 4

Obtaining crystalline polymorphic modifications In ibandronate

Monosodium salt of ibandronate (55 g are in accordance with the reference example 1) are dissolved in 240 ml of demineralized water. Distilled 75 ml of water. After filtration, the remaining solution is brought to a temperature of 35°C and add 190 ml of tetrahydrofuran (THF) 20 minutes After that, the mixture is cooled to ≤25°C under stirring until complete crystallization. Separate the product and washed using 20 ml of THF. The product is dried in vacuum from 150 to 10 mbar for 12 h at 40°C and for 24 h at 60°C.

Yield: 82%.

According to powder x-ray diffraction of the product identified as crystalline polymorphs In ibandronate (figure 1).

Example 5

Obtaining crystalline polymorphic modifications In ibandronate

Monosodium salt of ibandronate (55 g are in accordance with the reference example 1) are dissolved in 240 ml of demineralized water. Distilled 75 ml of water. P the following filtration, the remaining solution is brought to a temperature of 35°C, then add 47 ml of tetrahydrofuran (THF) and initiate the crystallization by the addition of 0.5 g of ibandronate in the form of crystalline modification V, and then adding 143 ml of THF. The resulting mixture is cooled to ≤25°C under stirring to achieve complete crystallization. Separate the product and washed using 20 ml of THF. The product is dried in vacuum from 150 to 10 mbar at 40°C for 12 h and then at 60°C for 24 hours

Yield: 79%.

According to powder x-ray diffraction of the product identified as crystalline polymorphs In ibandronate (figure 1).

Example 6

Getting monohydrate, monosodium salt ibandronate, polymorphic modification

Monosodium salt of ibandronate (55 g are in accordance with the reference example 1) are dissolved in 240 ml of demineralized water. Distilled 75 ml of water. After filtration, the remaining solution was adjusted to a temperature of 55°C, then add 190 ml of tetrahydrofuran (THF) for 1 hour. The resulting mixture is cooled to ≤25°C under stirring to achieve complete crystallization. Separate the product and washed using 20 ml of THF. The product is dried in vacuum from 150 to 10 mbar at 40°C for 12 h and then at 60°C for 24 hours

Yield: 78.5 per cent.

According to powder x-ray diffraction of the product identificare is an as crystalline polymorphs In ibandronate (figure 1).

1. Crystalline polymorphs of monohydrate, monosodium salt of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid (ibandronate), which is characterized by a powder x-ray diffraction pattern with characteristic peaks at about the following angles 2-theta:

2. Crystalline polymorphs according to claim 1, which is characterized by a powder x-ray diffraction pattern is shown in figure 1.

3. Crystalline polymorphs of ibandronate, which is characterized by the IR absorption spectrum, which contains characteristic peaks at about the following wave numbers, cm^-1: 3679 cm^-1, 3164 cm^-1, 2955 cm^-1; 2854 cm^-1, 1377 cm^-1, 1290 cm^-1, 1157 cm^-1, 1093 cm^-1, 1068 cm^-1, 1035 cm^-1, 965 cm^-1, 951 cm^-1, 933 cm^-1and 905 cm^-1, 71 cm ^-1and 723 cm^-1.

4. Crystalline polymorphs according to claim 3, characterized by the IR absorption spectrum shown in figure 2.

5. Crystalline polymorphs of ibandronate, which is characterized by a characteristic maximum in the vibrational Raman spectrum approximately at 2968 cm^-1.

6. Crystalline polymorphs according to claim 5, characterized by characteristic peaks in the vibrational Raman spectrum at approximately the following length of wave numbers, cm^-1: 2968 cm^-1, 2951 cm^-1, 2928 cm^-1, 2887 cm^-1, 2849 cm^-1, 1441 cm^-1, 1308 cm^-1, 1136 cm^-1, 1056 cm^-1, 1023 cm^-1, 954 cm^-1, 907 cm^-1, 839 cm^-1, 762 cm^-1and 678 cm^-1.

7. Crystalline polymorphic modification under subparagraph 5 and 6, characterized by the vibrational Raman spectrum shown in figure 3.

8. Ibandronate containing at least 80% crystalline polymorphic modifications described in claims 1 to 7.

9. A method of obtaining a crystalline polymorphic modification ibandronate according to claims 1-8, including the crystallization of monosodium salt of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid or its monohydrate, polymorphic modification or a mixture of polymorphic modifications in the temperature, costal is the fact that from 10 to 45°C, in polar solvent and adding a polar aprotic solvent to initiate crystallization.

10. The method according to claim 9, wherein the polar solvent is a water, the polar aprotic solvent is an aliphatic ketone or cyclic simple ether.

11. The method according to claim 10, characterized in that as the polar aprotic solvent used tetrahydrofuran.

12. Pharmaceutical compositions for the control of hypercalcemia, including crystalline polymorphic modification according to any one of claims 1 to 8 or crystalline polymorphic modification obtained by the method according to any of PP-11, and a pharmaceutically acceptable carrier and/or adjuvant.

13. Crystalline polymorphs according to any one of claims 1 to 8 or crystalline polymorphs obtained by the method according to any of PP-11, for use as therapeutically active compounds for controlling hypercalcemia.