Polymorphic modification of a ibandronate

FIELD: chemistry.

SUBSTANCE: invention relates to a new crystalline polymorphic modification of a monohydrate of mon-sodium salt of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid (ibandronate) of formula 1, used for controlling hypercalcemia. formula 1.

EFFECT: obtaining a new crystalline modification of biologically active compound.

14 cl, 6 dwg, 7 ex

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 degradation occurring with the participation of 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 of the polymorphic modifications of ibandronate, which is hereinafter in this application referred to as polymorphs And was broken arowana as thermodynamically more stable while the second polymorphic modification ibandronate, which is hereinafter 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 modification " 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 And ibandronate and the development of a method of producing polymorphic modifications And ibandronate.

This goal is achieved through the identification of crystalline polymorphic modifications And ibandronate and also the development that accounts for the th way it is received, 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 And ibandronate" refers to a polymorphic crystal modification 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 And ibandronate thus obtained as described in example 1.

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

3 shows the Raman spectrum of crystalline polymorphic modifications And ibandronate.

4 shows x-ray powder diffraction pattern of crystalline polymorphic modifications In the IBAN is Renata, thus obtained as described in example 2.

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

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

Crystalline polymorphs And ibandronate according to the present invention may be characterized using x-ray powder diffraction patterns, which are characteristic peaks at angles 2-theta, at approximately

Angle 2-theta is specified with an accuracy of ±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 modifications the Oia And ibandronate, as described above, may be further characterized by x-ray powder diffraction pattern shown in figure 1.

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

The term approximately in this context means that the values listed in the

cm^-1may vary by approximately ±4 cm^-1.

Crystalline polymorphs And ibandronate may be further characterized by an infrared absorption spectrum shown in figure 2.

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

The term approximately in this context means that the values listed in the

cm^-1may vary by ±8 cm^-1.

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

Crystalline polymorphs And ibandronate described above may be further characterized by the value of the solubility in water, which constitutes approximately 278 g/l at 25°C.

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 acids, polymorphic modification or a mixture of polymorphic modifications at the temperature of from 50°C to 70°C, dissolve in polar is barely.

As the polar solvent, preferably water use.

Preferably, the crystallization occurs in water at a temperature of approximately 60°C.

To initiate crystallization can be added polar aprotic solvent.

Suitable polar aprotic solvent is an acetone.

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 either monosodium salt of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid, for example, obtained in accordance with the method described in reference example 1 or crystalline polymorphic modification In ibandronate, which, for example, receive in accordance with reference example 2, or a mixture of crystalline polymorphic modifications In ibandronate with crystalline polymorphic modification And 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, to the which may be present after the implementation of the method of receipt (in accordance with reference example 1), can easily be 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 And 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 crystallization, preferably a mixture of water and acetone in a ratio of about 1:1 (vol./vol.).

Drying crystalline polymorphic modifications And ibandronate preferably carried out at a temperature from 40°C to 80°C for approximately 9 hours to 72 hours at normal or reduced pressure.

Crystalline polymorphs of ibandronate according to the present invention can be obtained with the content of Chris is aricescu polymorphic modifications And ibandronate, constituting at least 80%.

Alternatively, the crystalline polymorphs And ibandronate can be obtained using tempering (heat treatment) wet monosodium salt of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid, for example, obtained in accordance with the method described in reference example 1 or crystalline polymorphic modifications In ibandronate, for example, which is obtained in accordance with reference example 2, or of a mixture of crystalline polymorphic modifications In ibandronate with crystalline polymorphic modification And ibandronate at a temperature of from 30°to 90°C.

Residual ethanol that may remain after the implementation of the method (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.

The term "wet" in this context means that the original products contain some amount of water, typically about 10% water.

Crystalline polymorphs And ibandronate according to the present invention can be used as a pharmaceutically active compound that acts as an effective remedy against bone resorption, direct Inga the range of 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 And ibandronate, as defined above, and a pharmaceutically acceptable carrier and/or adjuvant.

The present invention also relates to crystalline polymorphic modifications And 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 - uα in the angle range 2θ = 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 is exposed to uα-radiation is possible. 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 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 detector 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 pre the education Fourier in combination with the spectrometer Magna 860" ("Nicolet") with scattering at 90°, the InGaAs detector. Measurement parameters: resolution of 8 cm^-1the 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 hours at 25°C and then further incubated for 24 hours 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, as long as the color does not change from Oran is eve 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 hours 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 is ethylcarbonate/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 21 to 22°C. Then the solid was separated, 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 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 in the water. After filtration, the remaining solution is heated to 35°C and add 190 ml of acetone for 20 minutes. The resulting 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 hours at 40°C and 24 hours at 60°C.

Yield: 81%.

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

Example 1

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. Crystallization initiate using crystalline polymorphic modification A. After crystallization, 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 of 50 ml of acetone/demineralized water in a ratio of 1:1 (vol./vol.). The dry product is jut for 48 hours in a vacuum of from 150 to 20 mbar at 60°C.

Yield: 75%.

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

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

Example 2

Obtaining crystalline polymorphic modifications And ibandronate

Dissolve 150 g of crystalline polymorphic modifications In ibandronate (receive, in accordance with reference example 2) in 185 ml of demineralized water at approximately 90°C. Then the solution is cooled to 60°C. and stirred for 30 minutes. Crystallization initiate using crystalline polymorphic modification And ibandronate. The resulting suspension is cooled to a temperature of approximately 20-25°C. until 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 hours in a vacuum of from 150 to 20 mbar at 60°C.

Yield: 80%.

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

Example 3

Obtaining crystalline polymorphic modifications And ibandronate

Dissolve 150 g of monosodium salt of 3-(N-methyl-N-pentyl)amino-1-hydroxyp is open-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 obtained filtrate is cooled to 60°C. and stirred for 45 minutes. Initiate crystallization by adding crystalline polymorphic modifications And ibandronate. 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 of 50 ml of acetone/demineralized water in a ratio of 1:1 (vol./vol.). The product is dried for 48 hours in a vacuum of 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 1).

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

Example 4

Obtaining crystalline polymorphic modifications And ibandronate

Dissolve 100 g of crystalline polymorphic modifications In ibandronate (receive, in accordance with reference example 2) in 304 ml of demineralized water heated to 60°C., and then filtered. To the obtained filtrate, maintaining a temperature of 55°C. is added dropwise ml acetone for 1 hour. Maintain the specified temperature of the mixture under stirring for 2 hours, then cooled to 15-20°C. the Product produce by filtration and washed using 120 ml of a solvent 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 14 hours and then at 60°C for 24 hours.

Yield: 88%.

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

Example 5

Obtaining crystalline polymorphic modifications And ibandronate

Dissolve 100 g of crystalline polymorphic modifications In ibandronate (receive, in accordance with reference example 2) in 304 ml of demineralized water heated to 60°C. and then the solution is filtered. To the obtained filtrate, maintaining a temperature of 55°C. is added dropwise 347 ml of acetone for 1 hour. In the process of adding acetone to initiate crystallization, add crystals of polymorphic modifications And ibandronate. Maintain the specified temperature of the mixture under stirring for 2 hours, then cooled to 15-20°C. the Product produce by filtration and washed using 120 ml of a solvent mixture of acetone/demineralized water (1:1 ratio). The product is dried in vacuum from 150 to 20 mbar at 40 the C for 14 hours and then at 60°C for 24 hours.

Yield: 90%.

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

Example 6

Obtaining crystalline polymorphic modifications And ibandronate (thermoregulation)

Get 30 grams just besieged ibandronate in accordance with reference example 2, but use directly after filtration without drying and confirm the structure as polymorphic modification (the moisture content is approximately 10%, the structure of the dried sample is confirmed as polymorphic modification), heated for 45 minutes at 60°C and 60 mbar, until the acetone has evaporated, followed by tempering (heat treatment) at 60°C and 900 mbar for 19 hours and drying at 60°C and 40 mbar for 9 hours in a rotary evaporator.

Yield: quantitative.

According to powder x-ray diffraction of the product identified as crystalline polymorphs And ibandronate (contents polymorphic modifications To 19%).

Example 7

Obtaining crystalline polymorphic modifications And ibandronate

Suspended 30 g of crystalline polymorphic modifications In ibandronate obtained in accordance with reference example 2, in a mixture of 95.4 ml of demineralized water and 103,4 ml of acetone at 20°C. is Obtained when spengiu heated to 60°C for 1 hour, stirred for 15 minutes, cooled to 20°C for 1 hour and stirred for 5 minutes at 20°C. This cycle was repeated twice. The resulting suspension is stirred for 17 hours. Separating the resulting product and dried for 18 hours in a vacuum of from 150 to 20 mbar at 60°C.

According to powder x-ray diffraction of the product identified as crystalline polymorphs And ibandronate (contents polymorphic modifications To 23%).

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 angles 2-theta at approximately

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

3. Crystalline polymorphs of ibandronate according to claim 1, characterized by the IR absorption spectrum, which contains characteristic peaks at about the following wave numbers, cm^-1: 3678 cm^-1, 3164 cm^-1, 2854 cm^-1, 1377 cm^-1, 1288 cm^-1, 1157 cm^-1, 1094 cm^-1, 1069 cm^-1, 1035 cm^-1, 966 cm^-1, 951 cm^-1, 933 cm^-1, 903 cm^-1, 760 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 according to claim 1, which is characterized by a characteristic maximum in the vibrational Raman spectrum at about 1460 cm^-1.

6. Crystalline polymorphs according to claim 5, characterized by characteristic peaks in the vibrational Raman spectrum approximately at the following wave numbers, cm^-1: 2950 cm^-1, 2927 cm^-1, 2889 cm^-1, 2851 cm^-1, 1460 cm^-1, 1443 cm^-1, 1308 cm^-1, 1137 cm^-1, 1056 cm^-1, 1024 cm^-1, 954 cm^-1, 904 cm^-1, 839 cm^-1, 761 cm^-1and 678 cm^-1.

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

8. Crystalline polymorphs according to any one of claims 1 to 7 or crystalline modification obtained by the method according to any of PP-13 intended for use as therapeutically active compounds for controlling hypercalcemia.

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

10. 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 at a temperature of from 50 to 70°C. in a polar solvent.

11. The method according to claim 10, wherein the polar solvent is a water.

12. The method according to claim 10 or 11, characterized in that the acetone as the polar aprotic solvent is added to initiate crystallization.

13. A method of obtaining a crystalline polymorphic modification ibandronate according to claims 1-8, including thermoregulation wet monosodium salt of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid or its monohydrate, polymorphic modifications or polymorphic modifications at the temperature of from 30 to 90°C.

14. Pharmaceutical composition having inhibitory activity against osteocel the ists, 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-13, and a pharmaceutically acceptable carrier and/or adjuvant.