Amorphous allisartan medoxomil and preparation method thereof

Abstract

The present invention relates to an amorphous allisartan medoxomil and a preparation method thereof, wherein no X-ray diffraction peak appears in the amorphous X-ray diffraction pattern; the present invention also provides a preparation method of the amorphous allisartan medoxomil. The amorphous allisartan medoxomil prepared by the present invention has good fluidity, significantly improved stability, low organic solvent residual value, and is more in line with the medicinal needs of the preparation.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and specifically relates to an amorphous allisartan medoxomil and a preparation method thereof. Background Art

[0002] Alisartan medoxomil is a selective angiotensin II-1 receptor blocker developed and launched by Shenzhen Xinlitai Pharmaceuticals under the license of Allist Pharmaceuticals Inc. After oral administration, it is hydrolyzed by esterase to 5-carboxylic acid losartan (EXP3174) to exert its efficacy. The 80 and 240 mg specifications were approved for marketing in China in December 2014 for the oral treatment of mild to moderate essential hypertension.

[0003]

[0004] CN200710094131.0, CN201510271632.6 disclose a kind of Allisartan ester crystal form and preparation method. The Allisartan ester crystal prepared according to the method has the characteristics of high stability, but the bulk density of the crystal is relatively small, the fluidity is not good enough and there is obvious static electricity phenomenon after drying, and it is easy to produce dust when crushing, packaging and using, which brings inconvenience to the cleaning and labor protection of the operation site. CN104610232A, CN109320501A, CN111018841A disclose the amorphous form of Allisartan ester and its preparation method, but these amorphous fluidities are difficult to meet the subsequent production requirements, the bulk density is relatively small, the fluidity stability is not good enough, and the organic solvent residual amount is relatively high and affects the product quality, which is not suitable for the medicinal demand of preparation. Therefore, it is urgent to develop a kind of amorphous form of Allisartan ester, which has good fluidity, stability, and few residual solvents, and is more suitable for the medicinal demand of preparation. Summary of the invention

[0005] The purpose of the present invention is to overcome the deficiencies of the prior art and provide amorphous olmesartan medoxomil with good fluidity and stability. What is more surprising is that the amorphous material prepared by the present invention can solve the problem of solvent residue existing in the crystallization of ordinary solvents and avoid a series of subsequent product quality problems caused thereby. The method is safe and reliable, and the post-processing is simple and easy, which can effectively improve the quality of the product and provide safety guarantee for the industrial production of olmesartan medoxomil medicines.

[0006] The amorphous solid of the present invention has no obvious and sharp diffraction peaks in the X-ray powder diffraction (XRD) spectrum. Specifically, the XRD spectrum of the amorphous allisartan medoxomil of the present invention does not show obvious and sharp diffraction peaks, which is consistent with the characteristics of amorphous. More specifically, the XRD spectrum of the amorphous allisartan medoxomil of the present invention shows non-sharp diffraction peaks. Figure 1The amorphous allisartan medoxomil shown in the figure has two broad and weak non-sharp diffraction peaks in its XRD spectrum, which are two broad and weak diffraction peaks with 2θ between 0 and 30°.

[0007] Furthermore, for Figure 1 The XRD spectrum has a broad and weak diffraction peak between 2θ of 0-10° and 10-30°, respectively, and the peak intensity of the diffraction peak between 10-30° is higher than that of the diffraction peak between 0-10°. Figure 1 This indicates that the allisartan medoxomil provided by the present invention exists in an amorphous form.

[0008] The technical solution adopted by the present invention to solve the technical problem is as follows:

[0009] On one hand, the present invention provides an amorphous olmesartan medoxomil, characterized in that the amorphous XRD spectrum has a broad and weak diffraction peak at 2θ between 0 and 10° and between 10 and 30°, and the peak intensity of the diffraction peak between 10 and 30° is higher than that of the diffraction peak between 0 and 10°.

[0010] As a preferred technical solution, the amorphous has the following Figure 1 XRD spectrum shown.

[0011] As a preferred technical solution, the amorphous DSC spectrum has an endothermic peak at 57±5°C and an endothermic peak at 156±5°C.

[0012] As a preferred technical solution, the amorphous has the following Figure 2 DSC spectrum shown.

[0013] As a preferred technical solution, the amorphous has the following Figure 3 DSC spectrum shown.

[0014] As a preferred technical solution, the amorphous has the following Figure 4 DSC spectrum shown.

[0015] The present invention also provides a method for preparing amorphous allisartan medoxomil, the method comprising the following steps:

[0016] 1) Dissolve allisartan medoxomil in an organic solvent at room temperature or under heating;

[0017] 2) The obtained solution is concentrated to dryness under reduced pressure, dried in vacuum to constant weight, and then cooled to room temperature to obtain amorphous olisartan medoxomil;

[0018] Wherein, the organic solvent in step 1) is solvent A and / or solvent B, and V 溶剂A :V 溶剂B=100:1-5, the solvent A is one of dichloromethane and acetone, the solvent B is one of ethanol, ethyl acetate, n-heptane, n-hexane, and methyl tert-butyl ether, and the volume-mass ratio of the organic solvent to olmesartan medoxomil is controlled at 1.5-5 mL / g;

[0019] The relative pressure of the concentration pressure in step 2) is ≤ minus 0.08 MPa, and the temperature is 30-40°C; the relative pressure of the vacuum drying is ≤ minus 0.1 MPa, and the temperature is 40-50°C.

[0020] As a preferred technical solution, the relative pressure of the reduced pressure concentration is negative 0.09 MPa or negative 0.1 MPa.

[0021] As a preferred technical solution, the temperature of the reduced pressure concentration is 40°C.

[0022] As a preferred technical solution, the relative pressure of the vacuum drying is negative 0.1 MPa.

[0023] As a preferred technical solution, the vacuum drying temperature is 50°C.

[0024] Finally, the present invention also provides an allisartan medoxomil pharmaceutical composition, wherein the allisartan medoxomil pharmaceutical composition contains the amorphous allisartan medoxomil described above.

[0025] The pharmaceutical composition is composed of the amorphous ollisartan medoxomil described in the present invention and a pharmaceutically acceptable carrier or excipient. Specifically, the pharmaceutically acceptable carrier or excipient includes but is not limited to a filler, a binder, a disintegrant, a lubricant, and the like.

[0026] The pharmaceutical composition can be prepared into preparations including but not limited to tablets, capsules, granules, powders, suppositories and the like. Preferably, the pharmaceutical composition can be prepared into tablets.

[0027] The excipients are commonly used auxiliary materials in the field. Specifically, the fillers include but are not limited to starch, lactose, mannitol, sucrose, microcrystalline cellulose, etc.; the binders include but are not limited to hydroxymethyl cellulose, sodium carboxymethyl cellulose, starch slurry, gelatin, etc.; the disintegrants include but are not limited to sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, dry starch, cross-linked sodium carboxymethyl cellulose, etc.; the lubricants include but are not limited to micro-powdered silica gel, talc, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc., and the pharmaceutical composition can be further coated with commonly used coating materials as needed.

[0028] The "X-ray powder diffraction pattern or "XRPD" described in the present invention refers to the Bragg formula 2d sinθ=nλ (wherein λ is the wavelength of the X-ray, λ=1.54056Å, the diffraction order n is any positive integer, generally the first-order diffraction peak is taken, n=1), when the X-ray is incident on a certain atomic plane with d lattice plane spacing of a crystal or a partial crystal sample at a grazing angle θ (the complementary angle of the incident angle, also known as the Bragg angle), the Bragg equation can be satisfied, thereby measuring this set of X-ray powder diffraction patterns. The XRD spectrum of the amorphous olmesartan medoxomil described in the present invention does not show obvious and sharp diffraction peaks, which is consistent with the characteristics of amorphous. Figure 1 The amorphous allisartan medoxomil shown has two broad and weak non-sharp diffraction peaks in its X-ray powder diffraction (XRD) spectrum, which are two broad and weak diffraction peaks with 2θ between 0 and 30°.

[0029] The "differential scanning calorimetry or "DSC" mentioned in the present invention refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining a constant temperature of the sample, so as to characterize all physical and chemical changes related to thermal effects and obtain the phase change information of the sample.

[0030] The amorphous olmesartan medoxomil described in the present invention can be stably present in the pharmaceutical composition. Specifically, the tablets prepared by the conventional method in the art are still present in an amorphous form under the experimental conditions of high temperature, high humidity and light influence factors, and XRD detection shows that the tablets still exist in an amorphous form, and the content and purity remain basically unchanged, which can effectively ensure the quality of the drug.

[0031] Through the above technical solution, compared with the prior art, the present invention has the following beneficial effects:

[0032] 1. The amorphous allisartan medoxomil prepared by the present invention has a smaller angle of repose and a larger bulk density. It can be seen that the amorphous allisartan medoxomil obtained by the present invention has better fluidity and is more in line with the pharmaceutical requirements of the preparation.

[0033] 2. The amorphous olmesartan medoxomil prepared by the present invention has good stability under conditions of illumination, heating and high humidity, and the purity does not change significantly. Compared with the amorphous disclosed in CN104610232A, the stability is significantly improved.

[0034] 3. The amorphous olmesartan medoxomil prepared by the present invention has a low residual organic solvent content, which can solve the problem of solvent residue in the crystallization of ordinary solvents and avoid a series of subsequent product quality problems caused by it. The method is safe and reliable, and the post-processing is simple and easy. It can effectively improve the quality of the product and provide safety protection for the clinical application of olmesartan medoxomil drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1It is the XRD pattern of the amorphous olmesartan medoxomil described in Examples 1 to 10 of the present invention.

[0036] Figure 2 It is the DSC spectrum of the amorphous olisartan medoxomil described in Examples 1 and 4 to 10 of the present invention.

[0037] Figure 3 It is the DSC spectrum of the amorphous olisartan medoxomil described in Example 2 of the present invention.

[0038] Figure 4 This is the DSC spectrum of the amorphous allisartan medoxomil described in Example 3 of the present invention. DETAILED DESCRIPTION

[0039] The present invention will be explained in more detail below in conjunction with embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention, and are not intended to limit the essence and scope of the present invention.

[0040] In the following examples, the experimental methods are generally carried out according to conventional conditions or conditions recommended by the manufacturer.

[0041] Test instruments used in the experiment: 1. Differential Scanning Calorimeter (DSC)

[0042] Instrument model: Mettler Toledo DSC 3+STARe System

[0043] Purge gas: Nitrogen

[0044] Heating rate: 10.0℃ / min

[0045] Temperature range: 25~350℃.

[0046] 2. X-ray Powder Diffraction (XRPD)

[0047] Instrument model: Bruker D8 Discover A25 X-ray powder diffractometer

[0048] Ray: Monochromatic Cu-Kα ray (λ=1.5406)

[0049] Scanning mode: θ / 2θ, scanning range: 10~48°

[0050] Voltage: 40KV, Current: 40mA.

[0051] The starting material of the embodiment of the present invention, allisartan medoxomil, was prepared according to the method disclosed in patent CN200680000397.8. Example 1

[0052] 10.00 g of allisartan medoxomil and 50 mL of acetone were added to a flask and heated to 40°C to dissolve. Then, the solvent was removed by vacuum concentration at a relative pressure of minus 0.09 MPa and 40°C. The obtained solid was vacuum dried at a relative pressure of minus 0.1 MPa and 50°C to constant weight to obtain amorphous allisartan medoxomil. The XRD spectrum is shown in the attached figure. Figure 1 As shown in the DSC spectrum Figure 2 shown. Example 2

[0053] 10.00 g of allisartan medoxomil and 30 mL of a mixed solvent (V 二氯甲烷 :V 正庚烷 =20:1) was added to a flask and heated to 35°C to dissolve. Then, the solvent was removed by vacuum concentration at a relative pressure of -0.09MPa and 40°C. The obtained solid was vacuum dried at a relative pressure of -0.1MPa and 50°C to constant weight to obtain amorphous olisartan medoxomil. The XRD spectrum is shown in the attached figure. Figure 1 As shown in the DSC spectrum Figure 3 shown. Example 3

[0054] 10.00 g of allisartan medoxomil and 20 mL of a mixed solvent (V 二氯甲烷 :V 乙酸乙酯 =20:1) was added to a flask and heated to 35°C to dissolve. Then, the solvent was removed by vacuum concentration at a relative pressure of -0.09MPa and 40°C. The obtained solid was vacuum dried at a relative pressure of -0.1MPa and 50°C to constant weight to obtain amorphous olisartan medoxomil. The XRD spectrum is shown in the attached figure. Figure 1 As shown in the DSC spectrum Figure 4 shown. Example 4

[0055] 100.00 g of allisartan medoxomil and 210 mL of a mixed solvent (V 二氯甲烷 :V 甲基叔丁基醚 =20:1) was added to a flask and heated to 35°C to dissolve. Then, the solvent was removed by vacuum concentration at a relative pressure of -0.1MPa and 40°C. The obtained solid was vacuum dried at a relative pressure of -0.1MPa and 50°C to constant weight to obtain amorphous olisartan ester. The XRD spectrum is shown in the attached figure Figure 1 As shown in the DSC spectrum Figure 2 shown. Example 5

[0056] 10.00 g of allisartan medoxomil and 20 mL of a mixed solvent (V 二氯甲烷 :V 正己烷=20:1) was added to a flask, heated to 35°C to dissolve, and concentrated under reduced pressure at 40°C to remove the solvent at a relative pressure of -0.1MPa. The obtained solid was vacuum dried at 50°C at a relative pressure of -0.1MPa to constant weight to obtain amorphous olisartan medoxomil. The XRD spectrum is shown in the attached figure Figure 1 As shown in the DSC spectrum Figure 2 shown. Example 6

[0057] 110.00 g of allisartan medoxomil and 550 mL of a mixed solvent (V 丙酮 :V 正己烷 =20:1) was added to a flask, the temperature was raised to reflux and the solvent was removed at a relative pressure of -0.1 MPa. The obtained solid was vacuum dried at a relative pressure of -0.1 MPa and 50°C to constant weight to obtain amorphous olisartan medoxomil. The XRD spectrum is shown in the attached figure Figure 1 As shown in the DSC spectrum Figure 2 shown. Example 7

[0058] 120.00 g of allisartan medoxomil and 550 mL of a mixed solvent (V 丙酮 :V 正庚烷 =20:1) was added to a flask, the temperature was raised to reflux and the solvent was removed at a relative pressure of -0.1 MPa. The obtained solid was vacuum dried at a relative pressure of -0.1 MPa and 50°C to constant weight to obtain amorphous olisartan medoxomil. The XRD spectrum is shown in the attached figure Figure 1 As shown in the DSC spectrum Figure 2 shown. Example 8

[0059] 1.0 kg of allisartan medoxomil and 1.5 L of a mixed solvent of acetone and ethyl acetate (V acetone:V 乙酸乙酯 =30:1) was added to a flask, the temperature was raised to reflux and the solvent was removed at a relative pressure of -0.1 MPa. The obtained solid was vacuum dried at a relative pressure of -0.1 MPa and 50°C to constant weight to obtain amorphous olisartan ester. The XRD spectrum is shown in the attached figure Figure 1 As shown in the DSC spectrum Figure 2 shown. Example 9

[0060] 10.00 g of allisartan medoxomil and 30 mL of a mixed solvent (V 丙酮 :V 甲基叔丁基醚=30:1) was added to a flask, the temperature was raised to reflux and the solvent was removed at a relative pressure of -0.1 MPa. The obtained solid was vacuum dried at a relative pressure of -0.1 MPa and 50°C to constant weight to obtain amorphous olisartan ester. The XRD spectrum is shown in the attached figure Figure 1 As shown in the DSC spectrum Figure 2 shown.

[0061] Example 10

[0062] 10.00 g of Alisartan medoxomil and 45 mL of a mixed solvent (V 丙酮 :V 乙醇 =30:1) was added to a flask, the temperature was raised to reflux and the solvent was removed at a relative pressure of -0.1 MPa. The obtained solid was vacuum dried at a relative pressure of -0.1 MPa and 50°C to constant weight to obtain amorphous olisartan ester. The XRD spectrum is shown in the attached figure Figure 1 As shown in the DSC spectrum Figure 2 shown.

[0063] Experimental Example 1: Powder bulk density test

[0064] According to the method of Example 1 and Example 3 disclosed in patent CN104610232A, amorphous olmesartan medoxomil (referred to as "amorphous in patent Example 1 or 3") was obtained; the powders prepared in Examples 1 to 10 of the present invention were crushed and sieved through a 100 mesh sieve to obtain powders with a particle size similar to that of the patent amorphous, and the angle of repose of the powders was measured by the fixed funnel method; the bulk density of the powders was measured by the graduated cylinder tapping method, and the results are shown in Table 1 below:

[0065] Table 1

[0066]

[0067] From the above data, it can be seen that compared with the amorphous form obtained by patent CN104610232A, the amorphous olmesartan medoxomil prepared by the present invention has a smaller angle of repose and a larger bulk density. It can be seen that the amorphous olmesartan medoxomil obtained by the present invention has better fluidity.

[0068] Experimental Example 2: Influencing Factors Experiment

[0069] The amorphous obtained in Examples 1 to 10 and the "amorphous in Patent Example 1 or 3" were laid out in an open position to examine the stability of the samples under conditions of illumination (4500 Lux), heating (60° C.) and high humidity (RH90%). The sampling time was 5 days and 10 days, and the purity results detected by gas chromatography are shown in Table 2 below:

[0070] Table 2

[0071]

[0072] From the above data, it can be seen that the amorphous prepared by the present invention has good stability under conditions of light, heating and high humidity, and the purity does not change significantly. Compared with the amorphous disclosed in CN104610232A, the stability is significantly improved.

[0073] Experimental Example 3: Investigation of organic solvent residues

[0074] The amorphous forms obtained in Examples 1 to 10 and the amorphous forms of Patent Examples 1 or 3 were simultaneously vacuum dried at a relative pressure of -0.1 MPa and 50°C for 17 h and then the residual organic solvent was detected. The results obtained by gas chromatography are shown in Table 3 below:

[0075] Table 3

[0076]

[0077] It can be surprisingly seen from the above data that the amorphous prepared by the present invention has lower organic solvent residue than the amorphous disclosed in CN104610232A, which can better ensure the quality of the drug and is conducive to safe clinical application.

[0078] It will be understood by those skilled in the art that, unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as those generally understood by those skilled in the art to which this application belongs. It should also be understood that terms such as those defined in common dictionaries should be understood to have meanings consistent with the meanings in the context of the prior art, and will not be interpreted with idealized or overly formal meanings unless defined as herein.

[0079] The meaning of "and / or" described in this application means that the situations where each exists alone or both exist at the same time are included.

[0080] Based on the above ideal embodiments of the present invention, the relevant staff can make various changes and modifications without departing from the technical concept of the present invention through the above description. The technical scope of the present invention is not limited to the contents of the specification, and its technical scope must be determined according to the scope of the claims.

Claims

1. An amorphous allisartan medoxomil, characterized in that: The XRD spectrum of the amorphous form has a broad and weak diffraction peak between 0 and 10° and between 10 and 30°, respectively, and the peak intensity of the diffraction peak between 10 and 30° is higher than that of the diffraction peak between 0 and 10°. The amorphous form has an XRD spectrum as shown in Figure 1, and its DSC spectrum has an endothermic peak at 57±5°C and an endothermic peak at 156±5°C.

2. The amorphous allisartan medoxomil according to claim 1, characterized in that The amorphous form has a DSC spectrum as shown in FIG2 .

3. The amorphous allisartan medoxomil according to claim 1, characterized in that The amorphous form has a DSC spectrum as shown in FIG3 .

4. The amorphous allisartan medoxomil according to claim 1, characterized in that The amorphous form has a DSC spectrum as shown in FIG4 .

5. The method for preparing amorphous allisartan medoxomil according to any one of claims 1 to 4, characterized in that: The method comprises the following steps: 1) dissolving allisartan medoxomil in an organic solvent at room temperature or by heating; 2) concentrating the obtained solution to dryness under reduced pressure, vacuum drying to constant weight and then cooling to room temperature to obtain amorphous allisartan medoxomil; wherein, the organic solvent in step 1) is solvent A and / or solvent B, when the organic solvent is solvent A and solvent B, V solvent A:V solvent B = 100:1-5, the solvent A is one of dichloromethane and acetone, the solvent B is one of ethanol, ethyl acetate, n-heptane, n-hexane, methyl tert-butyl ether, and the volume-mass ratio of the organic solvent to allisartan medoxomil is controlled at 1.5-5 mL / g; The relative pressure of the reduced pressure concentration in step 2) is ≤-0.08MPa, and the temperature is 30-40°C; the relative pressure of the vacuum drying is ≤-0.1MPa, and the temperature is 40-50°C.

6. The preparation method according to claim 5, characterized in that: The relative pressure of the reduced pressure concentration is -0.09 MPa or -0.1 MPa.

7. The preparation method according to claim 5, characterized in that: The temperature of the reduced pressure concentration is 40°C.

8. The preparation method according to claim 5, characterized in that: The relative pressure of the vacuum drying is -0.1 MPa.

9. The preparation method according to claim 5, characterized in that: The vacuum drying temperature is 50°C.

10. An allisartan medoxomil pharmaceutical composition, characterized in that: The allisartan medoxomil pharmaceutical composition contains the amorphous allisartan medoxomil as described in any one of claims 1 to 4 and a pharmaceutically acceptable carrier or excipient.

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