KR20090052750A - Valsartan di-potassium salt hydrate and preparation method thereof - Google Patents

Abstract

The present invention relates to a novel crystalline valsartan dipotassium salt monohydrate and a method for preparing the same.

Description

Valsartan dipotassium salt monohydrate and its preparation {{Valsartan di-potassium salt hydrate and preparation method}

(S) -N- (1-carboxy-2-methylprop-1-yl) -N-pentanoyl-N- [2 '-(1H-), which is an AT ₁ receptor antagonist of formula (I) A novel crystalline dipotassium salt hydrate of tetrazol-5-yl) -biphenyl-4-yl-methyl] -amine (valsartan) and a process for preparing the same.

(I)

(I)

Valsartan, marketed under the trade name DIOVAN in many countries, is an oral antihypertensive drug with very good antagonism against angiotensin II receptors. Valsartan and its salts are disclosed in European Patent 02443938 but do not disclose specific salts. Meanwhile, US Patent 6869970 discloses valsartan calcium salts and magnesium salts, and Korean Patent 0529658 discloses valsartan calcium salts and magnesium salts, as well as monosodium salts, disodium salts, monopotassium salts, dipotassium salts, and bis-diethylammonium salts. , Bis-dipropylammonium salts, bis-dibutylammonium salts, mono-L-arginine salts, bis-L-arginine salts, mono-L-lysine salts and bis-L-lysine salts are disclosed.

In particular, the method for preparing valsartan dipotassium salt hydrate (3.5 hydrate) disclosed in Example 3 of Korean Patent 0529658 is added dropwise 2N potassium hydroxide to valsartan acetonitrile solution, heating the mixed solution, followed by 3 days at room temperature. Seeding and solidification at 0 ° C. for 24 hours. The process involves four days of process steps, the addition of potassium hydroxide dropwise, followed by unnecessary heating in the manufacturing process.

The method for preparing valsartan dipotassium salt hydrate disclosed in Example 4 (3.96 hydrate) of the patent is adding dropwise 2N potassium hydroxide to valsartan ethanol solution at 0 ° C., concentrating the mixed solution together with toluene and acetonitrile, respectively. Removing residual water and further vacuum drying through aziotropic distillation, dissolving the resulting solid in an acetonitrile solution containing water and solidifying for 4 days at room temperature after low temperature seeding. . The method is not suitable for practical processing because it requires four days and additional concentration and drying steps that are unnecessary in the process to remove residual moisture. In addition, XRD information of the valsartan dipotassium salt by the method described in Example 4 was not mentioned.

That is, the method described in this patent may be easy to handle on a small scale (laboratory) or medium scale on a manufacturing scale, but the additional treatment described above is problematic in terms of production process and is not desirable in view of manufacturing yield and potential product quality. not.

The present inventors have intensively researched to develop new crystalline hydrates and new preparation methods of valsartan dipotassium salt.As a result of the production process and novel crystalline forms, which result in an improved yield of valsartan dipotassium salt hydrate through surprisingly efficient process steps. Valsartan dipotassium salt hydrate was discovered and the present invention was completed.

The present invention provides an AT ₁ receptor antagonist (S) -N- (1-carboxy-2-methylprop-1-yl) -N-pentanoyl-N- [2 '-(1H-tetrazol-5-yl A novel crystalline dipotassium salt of) -biphenyl-4-yl-methyl] -amine and a method for preparing the same are provided.

The present invention provides a hydrate of a novel crystalline dipotassium salt of valsartan and a process for preparing the same.

In general, an efficient process step means that the type and amount of solvent used are small, the time for heating or seeding the reaction solution is low, and the step or time for concentrating the reaction solution is low. In general, when preparing a salt hydrate, the reaction solution containing water is concentrated, and then water removal through ageotropic distillation is an unnecessary step in the process, and a method of solidifying by adding an appropriate solvent to the residue containing the water obtained by first concentration. This is efficient.

In particular, the method for preparing valsartan dipotassium salt hydrate (3.5 hydrate) disclosed in Example 3 of Patent 0529658 is added dropwise 2N potassium hydroxide to valsartan acetonitrile solution, heating the mixed solution, followed by 3 days at room temperature. Seeding and solidification at 0 ° C. for 24 hours. The process involves four days of process steps, the addition of potassium hydroxide dropwise, followed by unnecessary heating in the manufacturing process.

The method for preparing valsartan dipotassium salt hydrate (3.96 hydrate) disclosed in Example 4 of the patent is adding dropwise 2N potassium hydroxide to valsartan ethanol solution at 0 ° C., and concentrating the mixed solution together with toluene and acetonitrile, respectively. Removing residual water and further vacuum drying through aziotropic distillation, dissolving the resulting solid in an acetonitrile solution containing water and solidifying for 4 days at room temperature after low temperature seeding. . The method is not suitable for practical processing because it requires four days and additional concentration and drying steps that are unnecessary in the process to remove residual moisture. In addition, no XRD information of the valsartan dipotassium salt by the method described in Example 4 was also mentioned.

That is, the method described in this patent may be easy to handle on a small scale (laboratory) or medium scale on a manufacturing scale, but the additional processing described above is problematic in terms of production process and is undesirable in view of manufacturing yield and potential product quality. not.

The inventors of the present invention, the step of heating the reaction solution unnecessary in the manufacturing process (the patent 0529658, Example 3) and the step of removing the water remaining through the geothermal distillation of the solution containing water and further vacuum drying (the patent 0529658, practice) Example 4) A method for preparing valsartan dipotassium salt hydrate was developed. In addition, a process step requires four days, and has been developed a manufacturing method that does not go through the step of solidifying by seeding (Patent 0529658, Examples 3 to 4). That is, the present invention provides an efficient and improved method for preparing valsartan dipotassium salt hydrate, which eliminates unnecessary process steps, and a preferred embodiment thereof is specified in Example 1 below.

Thus, the process of the present invention is also consequently understood to obtain significant manufacturing advantages, for example increased production yields through efficient process steps.

In addition, a compound having a polymorphic polymorphic polymorphic polymorphism has a variety of properties, especially in medicine, it is known that there is a large difference in solubility, dissolution rate, stability and the like. Therefore, when using a compound having a polymorphic form as a medicine, it is necessary to be able to stably provide a compound having a constant crystallinity in order to secure uniform quality and a constant action effect required as a medicine. Also in the phase, a stable crystal polymorph capable of maintaining the same quality is required.

Thus, one aspect of the present invention provides novel crystalline forms.

The crystalline form according to the present invention is very important from the viewpoint of improving the solubility of the drug because the degree of water dissociation is higher than that of the free acid. This property is advantageous on the one hand because the dissolution process is faster and on the other hand the amount of water required for such a solution is smaller. This advantage also leads to an increase in bioavailability and is therefore advantageous for patients.

The crystalline form according to the invention is a crystalline form with a pronounced melting point associated with significant endothermic melt enthalpy compared to the free acid. In addition, the crystalline form of the dipotassium salt hydrate according to the present invention not only has a better quality than valsartan, which is stable and stable during storage and distribution, but also simplifies the last step in the manufacturing process by such stability, thereby providing a manufacturing and economic advantage.

In the hydrates according to the invention, for example, water molecules are intercalated into the crystal lattice of the compound to become hydrates, and the extent to which the selected solvent or water reaches the solvate or hydrate in the reaction and crystallization stages is generally unpredictable, process It is determined by several interactions between the conditions, valsartan and the solvent.

Thus, one aspect of the present invention provides a novel crystalline form of valsartan dipotassium salt hydrate.

According to the invention (S) -N- (1-carboxy-2-methylprop-1-yl) -N-pentanoyl-N- [2 '-(1H) comprising the following steps a) to d) Also provided is an improved process for the preparation of a novel crystalline dipotassium salt hydrate of -tetrazol-5-yl) -biphenyl-4-yl-methyl] -amine (valsartan). In particular the hydrate is a monohydrate.

a) (S) -N- (1-carboxy-2-methylprop-1-yl) -N-pentanoyl-N- [2 '-(1H-tetrazol-5-yl) -biphenyl-4 Titrating a potassium hydroxide aqueous solution to a polar solvent comprising -yl-methyl] -amine, preferably with a solution temperature not exceeding 40 ° C;

b) optionally stirring the neutral reaction solution, and optionally concentrating the reaction solution;

c) adding a water-insoluble solvent to the residue; And

d) optionally solidifying by stirring the mixture and liberating the resulting valsartan dipotassium salt hydrate.

Step a)

Preferred polar solvents for step a) are generally any water miscible organic solvents such as acetonitrile, acetone or tetrahydrofuran. Preferred solvent is tetrahydrofuran. Preferred aqueous potassium hydroxide solution is 1M to 4M, more preferably 2M. Preferably, the reaction of the mixture with potassium hydroxide is carried out at a temperature of 20 to 50 ° C, more preferably 40 ° C or less.

Step b)

The agitation of step b) can be carried out at a pH of 6-9. Preferably at neutral pH 7.0. More preferably, the mixture is stirred for 1 hour at neutral pH 7.0.

Also in water-miscible organic solvents containing water, the organic solvent and water can generally be removed by distillation. The LOD measurement (satorius, model name MA45, 105 degrees, 30 minutes) of the residue comprising water concentrated by distillation in Example 1 specified below is 5 to 20%, more preferably 8 to 9%.

Step c)

Preferred insoluble solvents for step c) are generally any organic solvents, such as acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, ethyl acetate, methyl acetate, diethyl ether, diiso Propyl ether, tertiary butyl methyl ether and mixed solvents thereof. Preferably it is a mixed solution of ethyl acetate and diethyl ether, More preferably, it is a 1: 1 mixed solution of ethyl acetate and diethyl ether. Preferably, step c) may be carried out by adding a 1: 1 mixed solution of diethyl ether and ethyl acetate at a temperature in the range of 25-30 ° C., followed by further stirring.

Step d)

After the glass of the salt according to step d) is solidified by a mechanical stirrer, the washing solution in the step of releasing the resulting valsartan dipotassium salt hydrate is preferably any organic solvent as in step c) above. Preferably it is a 1: 1 mixed solution of ethyl acetate and diethyl ether. Preferably, step d) may filter the solid obtained by stirring the mixture, wash with a 1: 1 mixed solution of diethyl ether and ethyl acetate, and then vacuum dry to obtain valsartan dipotassium salt monohydrate. .

Nuclear magnetic resonance spectra of the valsartan dipotassium salt monohydrate according to the present invention were measured at 300 MHz in a CD ₃ OD solution using a JNM-EX300 device manufactured by Jeol (see FIG. 2). ¹ H NMR (300 MHz, CD ₃ OD) δ: 7.53 7.38 (m, 4H), 7.17 7.01 (m, 4H), 4.82 (dd, 1H), 4.55 (dd, 1H), 3.91 (d, 1H), 2.71 2.47 (m, 1H), 2.31 2.00 (m, 2H), 1.63 (m, 1H), 1.54 1.33 (m, 2H), 1.21 (m, 1H), 1.00 0.92 (m, 3H), 0.82 (d, 3H), 0.69 (d, 3H). The splitting of the peaks is expressed as follows (d) = doublet; (dd) = doublet of doublet; (m) = multiplet.

Infrared spectrum of valsartan dipotassium salt monohydrate according to the present invention was measured by ATR-IR (damped total reflection-infrared spectroscopy) spectroscopy using a TENSOR 27 device from Brucker, and valsartan dipotassium salt monohydrate was absorbed as follows. (See FIG. 3) (represented by the reciprocal of the wavelength number in cm ⁻¹ ): 3341 (br w); 2959 (w); 2932 (w); 2872 (w); 1740 (w); 1634 (m); 1583 (st); 1507 (w); 1458 (m); 1395 (m); 1363 (m); 1317 (w); 1302 (w); 1228 (w); 1208 (w); 1176 (w); 1136 (w); 1106 (w); 1011 (w); 976 (w); 942 (w); 840 (w); 788 (w); 762 (m); 742 (m); 669 (w). The strength of the absorption band is expressed as follows (br w) = wide and weak strength (w) = weak strength (m) = medium strength (st) = strong strength.

The strongest absorption bands by ATR-IR spectroscopy were as follows (inverse of wavelength number (cm ⁻¹ )): 3341 (br w); 2959 (w); 2932 (w); 1740 (w); 1634 (m); 1583 (st); 1458 (m); 1395 (m); 1363 (m); 1228 (w); 1208 (w); 762 (m); 742 (m). The margin of error for the absorption band of the ATR-IR is ± 2 cm ^-1 .

The optical rotation of the valsartan dipotassium salt monohydrate according to the present invention is [α] ²⁰ _D =-(47 ± 2) ° in methanol as a 1% solution at 20 ° C.

Mass measurement of valsartan dipotassium salt monohydrate according to the present invention was carried out by ionizing in FAB low mode (fast atom bombarding) using Jeol's JMS-700 FAB-MS: m / e = 512 (M + 1) ⁺ ; Valsartan free acid mass 435; Valsartan Dipotassium Mass 511. Those skilled in the art will readily appreciate that mass spectrometry excludes solvates, particularly hydrates, of compounds.

The water content of the monohydrate of the valsartan dipotassium salt according to the invention is theoretically 3.4%. Moisture measurement by Karl Fisher titrator (Metrohm, 799 GPT Titrino) results in water content of 3.8% and water content measurement using Pyris 1 TGA (Perkin-Elmer) 3.7 Was%. From this, the total equation is calculated as follows (C ₂₄ H ₂₇ N ₅ O ₃ ) ₂ ^- K ₂ ^{2 +} · (1.1 ± 0.1) H ₂ O.

In addition, weight loss was measured using a thermogravimetric method of 2.406 mg of valsartan dipotassium salt hydrate under N ₂ condition without water. Water loss for monohydrate at a heating rate of T _r = 10 K · min ⁻¹ was measured as a function of temperature, and the results are shown in Table 1 below (see FIG. 4).

Temperature (℃) Weight loss or water loss (%) 25 0 50 0 75 0.9 100 2.4 125 2.6 150 3.3 175 3.5 200 3.7 225 4.0 250 4.4 275 4.5

The melting point of the valsartan dipotassium salt monohydrate according to the present invention was measured using Diamond DSC (Perkin-Elmer) to measure 2.967 mg of the sample in a sealed aluminum pan at a heating rate T _r = 20 K · min ⁻¹ . 117 ° C ± 2 ° C (see Figure 5).

The X-ray powder pattern of the valsartan dipotassium salt monohydrate according to the present invention was measured by a Guinier camera (D8 Discover by Bruker) on an X-ray film under a floodlight using Cu-Kα ₁ irradiation at room temperature, The interplanar spacing d and intensity of its most important lines are shown in Table 2 below (see FIG. 1); The relative intensity of the strongest peak was set at 100% and the relative intensity was expressed as follows. 40-100% (vst) = very strong; 20-40% (st) = strong; 10-20% (m) = medium; 5-10% (w) = weak; <5% (vw) = very weak.

2θ [°] burglar 4.6 vst 4.9 vst 5.2 st 8.8 w 9.2 vst 10.7 vw 11.2 vw 12.6 vw 13.8 vw 14.8 m 15.3 vw 16.4 w 17.8 vw 18.4 w 18.9 vw 21.3 vw 21.9 vw 22.5 w 23.2 vw 23.5 vw 24.0 w 25.5 vw 26.6 vw 27.0 vw 29.4 vw 31.2 w 31.6 w 32.6 w 33.7 w 34.8 w 36.0 w 37.2 w 37.9 w 39.4 w 40.6 w 42.5 w 43.3 w 44.1 w 45.0 w 47.3 w

The X-ray powder pattern of valsartan dipotassium salt monohydrate according to the present invention and Example 3 (3.5 hydrate, Comparative Example 1) and Example 12 (3.4 hydrate, Comparative Example 2) of Patent 0529658 are compared to Table 3 below. It is apparent that the valsartan dipotassium monohydrate according to the present invention has a novel crystalline form; The relative intensity of the strongest peak was set at 100% and the relative intensity was expressed as follows. 40-100% (vst) = very strong; 20-40% (st) = strong; 10-20% (m) = medium; 5-10% (w) = weak; <5% (vw) = very weak.

Comparative Example 1 Valsartan dipotassium salt monohydrate according to the present invention Comparative Example 2 Valsartan dipotassium salt monohydrate according to the present invention 2θ [°] burglar burglar 2θ [°] burglar burglar 4.6 River vst 4.9 River vst 8.8 medium w 9.4 River vst 9.2 River vst 11.4 about No peak 11.1 about vw 12.8 about No peak 12.5 about vw 14.0 about No peak 14.8 River m 15.0 about No peak 15.3 about vw 15.6 about vw 16.4 medium w 16.6 medium w 17.8 River w 18.0 about vw 18.2 medium w 18.5 about vw 18.4 medium w 18.9 about vw 18.9 medium vw 20.7 about No peak 20.4 medium No peak 21.5 about vw 21.1 about vw 22.0 about vw 21.3 medium w 22.7 medium w 22.3 about w 23.3 about vw 22.5 about w 24.1 medium w 23.1 River vw 25.6 about vw 23.9 medium w 25.8 about No peak 25.6 River vw 27.1 medium vw 26.6 River vw 29.4 about vw 26.9 medium vw 28.1 medium No peak

Example

The present invention is explained in more detail by the following examples. However, the scope of protection of the present invention is not intended to be limited to the following examples.

Example  One

Valsartan (100 g) was dissolved in THF (500 mL) at room temperature and titrated with 2N KOH (208 mL) for 2 h while stirring with a magnetic stirrer not to exceed the solution temperature of 40 ° C. The neutral solution (pH 7.0) was stirred for 1 hour and distilled under reduced pressure at 37 ℃ to concentrate the reaction solvent to about 10% volume. Diethyl ether and ethyl acetate 1: 1 mixed solvent (1000 mL) were added to the residue containing water at room temperature at a time and stirred for 10 hours. The resulting white crystalline was separated using a Buechner filter and the wet filter cake was washed with diethyl ether and ethyl acetate 1: 1 mixed solvent (100 mL). The resultant was dried in a vacuum oven at 35 ° C. for 3 days until the weight loss reached a certain weight, to obtain 113 g of white crystalline. The yield was 92% based on free acid valsartan. ¹ H NMR (300 MHz, CD ₃ OD) δ: 7.53 7.38 (m, 4H), 7.17 7.01 (m, 4H), 4.82 (dd, 1H), 4.55 (dd, 1H), 3.91 (d, 1H), 2.71 2.47 (m, 1H), 2.31 2.00 ( m, 2H), 1.63 (m, 1H), 1.54 1.33 (m, 2H), 1.21 (m, 1H), 1.00 0.92 (m, 3H), 0.82 (d, 3H), 0.69 (d, 3H).

The X-ray powder diffraction spectrum (XRD) for the crystalline form according to the present invention is shown in FIG. 1, with the ten most significant peaks on the XRD being about 2θ = 4.6 °, 4.9 °, 5.2 °, 8.8 °, 9.2 °, It occurs at 14.8 °, 16.4 °, 17.8 °, 22.5 ° and 24.0 °.

The infrared spectrum of the crystalline form according to the present invention is shown in Fig. 3, and the strongest absorption band is as follows (inverse of wavelength number (cm ⁻¹ )): 3341 (br w); 2959 (w); 2932 (w); 1740 (w); 1634 (m); 1583 (st); 1458 (m); 1395 (m); 1363 (m); 1228 (w); 1208 (w); 762 (m); 742 (m). The margin of error for the absorption band of the ATR-IR is ± 2 cm ^-1 .

The optical rotation of the crystalline form according to the present invention is [α] ²⁰ _D =-(47 ± 2) ° in methanol as a 1% solution at 20 ° C.

The mass value of the crystalline form according to the present invention is FAB-MS: m / e = 512 (M + 1) ⁺ .

Mass loss or water loss by thermogravimetric analysis of the crystalline form according to the present invention is shown in FIG. 4, and the measured value is 3.7%.

The melting point by the differential differential calorimeter of the crystalline form according to the present invention is shown in Fig. 5, and the measured value is about 117 ° C.

Example  2

ingredient Prescription 1 Prescription 2 Valsartan 2K · 1H ₂ O of Example 1 80 g 97 g Avicel PH101 54 g 50 g Crospovidone - 15 g L-HPC 20 g - SIO ₂ 1.5 g 1.5 g Mg-s 4.5 g 4.5 g EtOH 6 g -

The tablets were prepared by mixing the above components and tableting according to a conventional method for producing tablets. A dissolution test was performed to evaluate the solubility of the tablets prepared above.

Dissolution Test

The dissolution test was conducted in accordance with the Dissolution Test Method 2 of the Pharmacopoeia General Test Methods. The tablets (prescription 1 and prescription 2) prepared in Example 2 and the reference drug (dioban tablet, 80 mg) were used as an eluent for 900 mL of water, and were carried out for 120 minutes under conditions of 100 revolutions / minute.

Elution test start The eluate was taken at 0, 10, 15, 30, 45, 60, 90, 120 minutes, filtered, and the filtrate was analyzed by HPLC method as a sample solution.

The results are shown in graphs showing the elution concentrations with time in FIGS. 6 (prescription 1) and 7 (prescription 2). According to the results, it can be seen that the tablet prepared in Example 2 was significantly higher than the reference drug (dioban tablet, 80 mg) in the dissolution rate and dissolution amount.

1 is an XRD of valsartan dipotassium salt monohydrate;

2 is a ¹ H NMR of valsartan dipotassium salt monohydrate;

3 is ATR-IR of valsartan dipotassium salt monohydrate;

4 is the TGA of monohydrate of valsartan dipotassium salt;

5 is DSC of monohydrate of valsartan dipotassium salt;

Figure 6 is a dissolution test results of the prescription 1 and Comparative Example Dioban of the present invention;

7 is a dissolution test results of Dioban of the second formulation and Comparative Example of the present invention

Claims (15)

Valsartan dipotassium salt monohydrate in crystalline form. Crystalline form with an X-ray powder diffraction pattern having specific peaks substantially at 4.6 °, 4.9 °, 5.2 °, 8.8 °, 9.2 °, 14.8 °, 16.4 °, 17.8 °, 22.5 ° and 24.0 °, converted to 2θ Valsartan dipotassium salt monohydrate. The valsartan dipotassium salt monohydrate according to claim 1 or 2, characterized by substantially the following X-ray powder diffractogram:

The valsartan dipotassium salt form of crystalline form according to claim 1 or 2, having a main absorbance peak at 3341, 2959, 2932, 1740, 1634, 1583, 1458, 1395, 1363, 1228, 1208, 762 and 742 cm ⁻¹ . Luggage. The valsartan dipotassium salt monohydrate according to claim 1 or 2, characterized by substantially the following IR spectrum:

3. The valsartan dipotassium salt monohydrate of claim 1 or 2, characterized by substantially the following TGA spectrum:

The valsartan dipotassium salt monohydrate of claim 1, wherein the valsartan dipotassium salt monohydrate has a melting point of about 117 ° C. ± 2 ° C. 4. The valsartan dipotassium salt monohydrate according to claim 1 or 2, characterized by substantially the following DSC spectrum:

. a) titrating an aqueous potassium hydroxide solution with a polar solvent comprising valsartan; b) optionally stirring the mixture and then concentrating; c) solidifying by adding water-insoluble solvent to the residue; And d) valsartan dipotassium salt hydrate comprising the step of liberating valsartan dipotassium salt hydrate. 10. The method of claim 9, wherein the polar solvent is at least one selected from the group consisting of acetonitrile, acetone and tetrahydrofuran. The process according to claim 9, wherein step a) is carried out at a temperature of the mixture at 40 ° C. or less. The water-insoluble solvent of claim 9, wherein the water-insoluble solvent is acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, ethyl acetate, methyl acetate, diethyl ether, diisopropyl ether, tert-butyl Characterized in that it is selected from methyl ether and mixed solvents thereof. 13. The method of claim 12, wherein the water-insoluble solvent is a 1: 1 mixed solution of diethyl ether and ethyl acetate. The process according to claim 9, wherein step c) adds a 1: 1 mixed solution of diethyl ether and ethyl acetate at a temperature in the range of 25-30 ° C. and then further stirs. The method according to claim 9, wherein step d) comprises filtering the solid obtained by stirring the mixture, washing with a 1: 1 mixed solution of diethyl ether and ethyl acetate, and then vacuum drying to obtain valsartan dipotassium salt. Obtaining a luggage.

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