Preparation method of high-purity pravastatin sodium D-type crystal

Abstract

The invention relates to the technical field of pharmaceutical crystal structures, in particular to a preparation method of a high-purity pravastatin sodium D-type crystal, the preparation method comprises the steps of crystallization liquid pretreatment, first nitrogen drying, washing, second nitrogen drying and vacuum drying, the vacuum drying is a programmed drying process, the pravastatin sodium crystallization material is pumped or pressed to dry by utilizing different nitrogen pressures, so that accelerated separation and programmed vacuum drying of mother liquor in crystallization liquid can be promoted, generation of amorphous pravastatin sodium or pravastatin sodium of other crystal forms is reduced, and the technical problems that pravastatin sodium is easy to cake in the drying process, the drying time is long, mixed crystal forms are generated and the like are solved; the bulk density of the finally obtained high-purity pravastatin sodium D-type crystal is 0.3-0.5 g / mL, the hardness is proper, the subsequent crushing operation is convenient, and the pravastatin sodium D-type crystal is very suitable for being applied to medicines and preparations.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical manufacturing, and particularly relates to a method for preparing high-purity pravastatin sodium D-type crystal. Background Art

[0002] Solid substances can be divided into crystals and non-crystals according to whether the arrangement of their particles in the structure is periodic. When a substance crystallizes, it is affected by various factors, which changes the bonding mode within or between molecules, resulting in different arrangements of the molecules or atoms in the lattice space of the crystal, forming different crystal structures, that is, crystals of different crystal forms. This phenomenon is called polymorphism. Due to the different crystal structures, the interaction forces and binding energies between particles of crystals of different crystal forms are also different, and their physical, chemical and optical properties are also different, resulting in different stability of different crystal forms. Most drugs have polymorphism. The stability of polymorphism is an important indicator of its quality and efficacy, and changes in crystal form may affect the properties and efficacy of the drug. The study of drug polymorphism has become a necessary research content for controlling drug production and designing new drugs. Understanding the polymorphic forms of drugs and their properties will help solve the following problems: 1) ensuring the stability of the effective crystal form of the drug during preparation and storage; 2) improving the dissolution rate and bioavailability, reducing toxicity, and enhancing the therapeutic effect of the drug; 3) determining the formulation process to ensure the equivalence between each batch of produced drugs; 4) improving the tableting performance of drug powders, etc.

[0003] Pravastatin sodium (CAS No. 81131-70-6) is a 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-COA reductase) inhibitor and is the only statin drug that can be used for primary and secondary defense of heart disease and stroke in patients with high cholesterol levels or coronary heart disease. Pravastatin sodium is a polymorphic drug, including A-type, B-type, C-type, D-type, E-type, F-type, G-type, H-type, H1-type, I-type, J-type, K-type, L-type and other crystal forms, wherein the D-type crystal of pravastatin sodium is characterized in that its powder X-ray diffraction spectrum has characteristic peaks at diffraction angles 2θ°=3.6±0.2, 6.3±0.2, 9.8±0.2 and 17.1±0.2°. Compared with other crystal forms of pravastatin sodium, D-type pravastatin sodium crystals are stable in nature, not easy to transform into other crystal forms, not easy to be oxidized, and not easy to produce oxidized impurities. Therefore, they are more conducive to the preparation and preservation of pharmaceutical preparations and extend the shelf life of pharmaceutical preparations. However, the current production process of D-type pravastatin sodium generally has the following shortcomings: (1) the crystal form is unstable, and it is easy to have non-D crystal forms or mixed crystal forms; (2) the crystal color is yellow or gray, and the product appearance is not good; (3) the drying process takes a long time and is not suitable for industrial-scale production; (4) the D-type pravastatin sodium obtained by drying is severely agglomerated, has high hardness and is difficult to be broken into a particle size suitable for preparation use; (5) the obtained D-type pravastatin sodium has a high bulk density and is not suitable for preparation process use. For example, U.S. Pat. No. 7,262,218 and its family patents (WO01 / 43723, CN1434702A, etc.) disclose a method for preparing D-type pravastatin sodium crystals, wherein the D-type pravastatin sodium crystals are prepared by solvent-mediated transformation. The preparation process requires a large amount of organic solvents, and the solvent recovery is difficult. In the process of industrial scale-up, there are economic and environmental obstacles. The patent controls the crystal form by the type and proportion of the crystallization solvent, the crystallization temperature, the cooling rate, etc., rather than by a drying method, and does not disclose whether pravastatin sodium with a bulk density suitable for pharmaceutical use is obtained; U.S. Pat. No. 20060194984 and its family patents (CN101115706 (A), WO2006086680 (A1), etc.) disclose a method for first obtaining L-type pravastatin sodium and then preparing D-type pravastatin sodium from L-type pravastatin sodium, and Martin-Islan AP et al. (Martin-Islan AP, Cruzado MC, Asensio R.Crystalline Polymorphism and Molecular Structure of Sodium Pravastatin[J].The journal of physical chemistry,B.Condensed matter,materials,surfaces,interfaces&biophysical,2006,110(51)) studied the conversion of E-type pravastatin sodium into D-type pravastatin sodium at 120°C or even 165°C. The process for preparing D-type pravastatin sodium by crystal transformation is relatively complicated. Chinese patent CN201610488796.9 discloses a process for large-scale preparation of D-type pravastatin sodium crystals, which uses a vacuum drying oven. The method and equipment are inconvenient to operate and have low efficiency.

[0004] In summary, developing a scaled-up production process suitable for D-type pravastatin sodium crystals, and a process for preparing D-type pravastatin sodium crystals with high purity and high yield is very critical for preparing related pravastatin sodium drugs. Summary of the invention

[0005] The purpose of the present invention is to overcome the deficiencies in the above-mentioned prior art. The purpose of the present invention is to provide a method for preparing high-purity D-type pravastatin sodium crystals. The pressure, temperature and drying time of the filtration, washing and drying processes are controlled by a three-in-one filter program to obtain a high-purity D-type pravastatin sodium product, thereby solving the problem of easy agglomeration or long drying time during the drying process. The obtained D-type pravastatin sodium has a suitable hardness, is convenient for subsequent crushing operations, and has a bulk density of 0.3 to 0.5 g / mL, which is suitable for preparation use.

[0006] In a first aspect, the present invention provides a method for preparing high-purity pravastatin sodium D-type crystals, characterized in that the preparation method comprises the following steps:

[0007] S1. Crystallization liquid pretreatment

[0008] The pravastatin sodium crystal solution is placed in a filter for vacuum filtration;

[0009] S2, first nitrogen drying

[0010] Under reduced pressure filtration without stirring, nitrogen is introduced into the filter to press dry to obtain a filter cake;

[0011] S3, washing, second nitrogen drying

[0012] Add detergent to the filter cake for stirring, dispersing and washing, stop stirring and filter under reduced pressure, and then introduce nitrogen into the filter under reduced pressure and filter to dry;

[0013] S4. Vacuum drying

[0014] The filter cake squeezed out in step S3 is subjected to the following operations:

[0015] The temperature is controlled at 10°C to 30°C and the vacuum condition is 0MPa to -0.05MPa for 2 to 4 hours;

[0016] Control the temperature at 30℃~40℃ and dry for 4~8 hours under vacuum condition of -0.05MPa~-0.07MPa;

[0017] Control the temperature at 40°C to 60°C and dry for 4 to 8 hours under vacuum conditions of -0.07MPa to -0.085MPa;

[0018] The temperature is controlled at 60°C to 80°C, and the mixture is dried for 4 to 8 hours under a vacuum condition of -0.085 MPa to -0.095 MPa with stirring.

[0019] Optionally, the “controlling the temperature at 10°C to 30°C” includes but is not limited to 10°C, 13°C, 15°C, 18°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C and the like.

[0020] Optionally, the "control temperature at 30℃ ~ 40℃" includes but is not limited to 30℃, 30.5℃, 31℃, 31.5℃, 32℃, 32.5℃, 33℃, 33.5℃, 34℃, 34.5℃, 35℃, 35.5℃, 36℃, 36.5℃, 37℃, 37.5℃, 38℃, 38.5℃, 39℃, 39.5℃, 40℃ and the like.

[0021] Optionally, the "control temperature 40℃~60℃" includes but is not limited to 40℃, 40.5℃, 41℃, 41.5℃, 42℃, 42.5℃, 43℃, 43.5℃, 44℃, 44.5℃, 45℃, 45.5℃, 46℃, 46.5℃, 47℃, 47.5℃, 48℃, 48.5℃, 49℃, 49.5℃, 50℃, 50.5℃, 51℃, 51.5℃, 52℃, 52.5℃, 53℃, 53.5℃, 54℃, 54.5℃, 55℃, 55.5℃, 56℃, 56.5℃, 57℃, 57.5℃, 58℃, 58.5℃, 59℃, 59.5℃, 60℃ and the like.

[0022] Optionally, the "control temperature at 60℃~80℃" includes but is not limited to 60℃, 60.5℃, 61℃, 61.5℃, 62℃, 62.5℃, 63℃, 63.5℃, 64℃, 64.5℃, 65℃, 65.5℃, 66℃, 66.5℃, 67℃, 67.5℃, 68℃, 68.5℃, 69℃, 69.5℃, 70℃, 70.5℃, 71℃, 71.5℃, 72℃, 72.5℃, 73℃, 73.5℃, 75℃, 75.5℃, 75℃, 75.5℃, 76℃, 76.5℃, 77℃, 77.5℃, 78℃, 78.5℃, 79℃, 79.5℃, 80℃ and the like.

[0023] The pravastatin sodium solution used in the present invention comprises a mixed solution of any crystalline or amorphous pravastatin sodium, an organic solvent, and water in a mass volume ratio of 5-10 (m): 90-80 (v): 5-10 (v). The pravastatin sodium solution can be prepared by any of the following preparation methods (1) or (2):

[0024] (1) any crystalline or amorphous pravastatin sodium, an organic solvent, and water are mixed in proportion and dissolved by heating or without heating. If necessary, the order of adding materials can be adjusted or the solution of the proportion can be obtained by concentration;

[0025] Further, the organic solvent is selected from acetonitrile and / or acetone, or a mixed organic solvent formed by one or more of ethyl acetate, toluene, n-butyl acetate, isobutyl acetate and methanol and / or ethanol;

[0026] Optionally, the volume ratio of one or more of ethyl acetate, toluene, n-butyl acetate, isobutyl acetate to methanol and / or ethanol in the mixed organic solvent is 5-9:1-5, further including but not limited to 5:5, 6:4, 7:3, 8:2, 9:1 and the like.

[0027] (2) The pravastatin sodium solution is formed after extraction and purification of the pravastatin fermentation broth.

[0028] Furthermore, any crystal form includes but is not limited to one or more of the crystal forms such as type A, type B, type C, type D, type E, type F, type G, type H, type H1, type I, type J, type K, type L, etc.

[0029] The step S1 in the method for preparing high-purity pravastatin sodium D-type crystals adopted in the present invention satisfies at least one of the following conditions (1) to (5):

[0030] (1) The pravastatin sodium crystal solution in step S1 is obtained by cooling the pravastatin sodium solution to no higher than 20° C. and then heat-preserving and crystallizing;

[0031] (2) the filter in step S1 includes selecting a three-in-one filter;

[0032] (3) The filtration temperature in step S1 is controlled at 10°C to 20°C;

[0033] (4) The decompression and filtration pressure in step S1 is -0.05MPa to 0MPa;

[0034] (5) The vacuum filtration time in step S1 is 2 to 4 hours;

[0035] In some embodiments of the present invention, the reduced pressure filtration process in step S1 is: first filtration at -0.03 to 0 MPa for 1 to 2 hours, and then filtration at -0.05 MPa to -0.03 MPa for 1 to 2 hours.

[0036] In the method for preparing high-purity pravastatin sodium D-type crystals adopted by the present invention, the nitrogen is introduced into the drying process in step S2 to maintain a pressure of -0.03 to -0.01 MPa, and the nitrogen drying time is 1 to 2 hours.

[0037] In some embodiments of the present invention, in step S2, nitrogen is introduced into the pressure drying process and maintained at -0.03 to -0.01 MPa for 1 to 2 hours to obtain a filter cake.

[0038] In the method for preparing high-purity pravastatin sodium D-type crystals adopted by the present invention, the vacuum filtration in step S3 is at -0.05 to 0 MPa, the vacuum drying time is 1 to 4 hours, and the nitrogen is introduced into the drying process to maintain -0.03 to -0.01 MPa, and the nitrogen drying time is 1 to 2 hours.

[0039] In some embodiments of the present invention, the vacuum filtration in step S3 is performed under -0.05 to 0 MPa conditions for 1 to 4 hours;

[0040] The washing process of step S3 in the preparation method of high-purity pravastatin sodium D-type crystals adopted by the present invention is as follows: the volume of the detergent is 1 to 2 times the mass of the filter cake, the detergent temperature is 5 to 10° C., the washing time is 0.5 to 1 hour, and the detergent is selected from a solvent or a mixed solvent with a boiling point below 100° C. and / or water;

[0041] Optionally, the solvent with a boiling point lower than 100° C. includes, but is not limited to, one or more of acetonitrile, acetone, and ethyl acetate.

[0042] In some embodiments of the present invention, the detergent in step S3 is a solvent with a boiling point lower than 100° C.: water = 7 to 10:1, v / v.

[0043] In some embodiments of the present invention, the detergent in step S3 is selected from an acetone aqueous solution, and the ratio of acetone to water in the acetone aqueous solution is 9:1 (v / v).

[0044] In some embodiments of the present invention, nitrogen is introduced into the drying process in step S3 and maintained at -0.03 to -0.01 MPa for 1 to 2 hours.

[0045] In a second aspect, the present invention also provides use of the high-purity D-type pravastatin sodium crystals obtained according to the preparation method in the preparation of a preparation for treating hypercholesterolemia or hyperlipidemia.

[0046] Furthermore, the bulk density of the high-purity pravastatin sodium D-type crystal is 0.3-0.5 g / mL.

[0047] The main purpose of the present invention using programmed nitrogen drying is:

[0048] 1) In steps S2 and S3, nitrogen is introduced and a suitable vacuum value is maintained, which can accelerate the separation of the mother liquor in the crystallization liquid and avoid the formation of solid agglomerates;

[0049] 2) Not starting stirring in steps S2 and S3 can prevent the material from agglomerating. If agglomerates are formed, it will be difficult to dry and the bulk density of the dried product will be too high, making it unsuitable for medicinal use;

[0050] 3) Step S4 uses programmed temperature control and vacuum value to ensure that high-purity D-crystalline pravastatin sodium is obtained, otherwise amorphous or other crystalline pravastatin sodium is easily produced.

[0051] 4) In step S4, stirring is started at the final stage of drying to accelerate the drying of the product.

[0052] Compared with the prior art, the present invention has the following beneficial effects:

[0053] The present invention adopts a three-in-one filter program to control the pressure, temperature and drying time of the filtering, washing and drying processes to obtain a high-purity D-crystalline pravastatin sodium product, thereby solving the technical problems of easy agglomeration and long drying time of pravastatin sodium in the drying process. The obtained D-crystalline pravastatin sodium has suitable hardness, is convenient for subsequent crushing operations, has a bulk density of 0.3-0.5 g / mL, and is suitable for use in preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 This is the X-ray diffraction pattern PXRD of the high-purity pravastatin sodium D-type crystals prepared in Example 1 of the present invention.

[0055] Figure 2 This is the X-ray diffraction pattern PXRD of the low-purity pravastatin sodium D-type crystals prepared in Comparative Example 6 of the present invention.

[0056] Figure 3 This is the X-ray diffraction pattern PXRD of the pravastatin sodium F-type crystal prepared in Comparative Example 4 of the present invention. DETAILED DESCRIPTION

[0057] The experimental methods in the following examples of the present invention, where no specific conditions are specified, are usually carried out under conventional conditions or under conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0058] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0059] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that these descriptions are exemplary only and are not intended to limit the scope of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concept of the present invention.

[0060] The present invention is further described in the following examples, but the examples are not intended to limit the scope of protection of the present invention.

[0061] The preparation process of the pravastatin sodium solution used in the present invention can be obtained by using any one of the following preparation methods 1) or 2):

[0062] 1) using any crystalline or amorphous pravastatin sodium to dissolve it at a mass volume ratio of pravastatin sodium, organic solvent and water of 5-10 (m): 90-80 (v): 5-10 (v) by heating or not heating, wherein the mass volume ratio within the range includes but is not limited to 5m:90v:5v, 6m:86v:8v, 7m:87v:6v, 8m:85v:7v, 9m:82v:9v, 10m:80v:10v, 5m:85v:10v, 5m:88v:7v, etc., all of which can realize the technical scheme of the present invention. If necessary, the order of feeding can be adjusted or the solution of the ratio can be obtained by concentration;

[0063] 2) After the pravastatin fermentation broth is extracted and purified, a pravastatin sodium solution containing any crystalline or amorphous pravastatin sodium, an organic solvent, and water in a mass volume ratio of 5-10 (m): 90-80 (v): 5-10 (v) is formed. The mass volume ratio within this range includes but is not limited to 5m:90v:5v, 6m:86v:8v, 7m:87v:6v, 8m:85v:7v, 9m:82v:9v, 10m:80v:10v, 5m:85v:10v, 5m:88v:7v, etc., all of which can realize the technical scheme of the present invention.

[0064] The three-in-one filter used in the embodiments of the present invention is of model UNFCD1600 and was purchased from Jiangsu Saideli Pharmaceutical Machinery Manufacturing Co., Ltd.

[0065] Example 1 Preparation of high-purity pravastatin sodium D-type crystals

[0066] The preparation method of high-purity pravastatin sodium D-type crystal of the present invention is specifically as follows:

[0067] S1. Crystallization liquid pretreatment

[0068] A pravastatin sodium solution containing 60 kg, acetone and water, 860 L and 80 L respectively, was cooled to 10°C for heat preservation and crystallization to obtain a pravastatin sodium crystal liquid. The pravastatin sodium crystal liquid was placed in a three-in-one filter, the temperature was controlled at 10°C, and it was first filtered at -0.01 MPa for 1.5 hours, and then filtered at -0.04 MPa for 1.5 hours.

[0069] S2, first nitrogen drying

[0070] Under reduced pressure filtration without stirring, nitrogen was introduced into the filter and the pressure was maintained at -0.02 MPa for 1.5 hours to obtain a filter cake.

[0071] S3, washing, second nitrogen drying

[0072] Add 10°C detergent (acetone: water = 9:1 (v / v) solution) to the filter cake for stirring, dispersion and washing, wherein the filter cake: detergent = 1:2 (m / v), and dry it at -0.03 MPa for 2 hours, then introduce nitrogen into the filter under the suction filtration state, maintain -0.02 MPa vacuum and dry it for 1.5 hours;

[0073] S4. Vacuum drying

[0074] The filter cake squeezed dry in step S3 is subjected to the following operations:

[0075] The temperature was controlled at 28°C and the vacuum was -0.03 MPa for 3 hours;

[0076] The temperature was controlled at 35°C and the vacuum was -0.06MPa for 6 hours;

[0077] The temperature was controlled at 50°C and the vacuum was -0.075MPa for 6 hours;

[0078] The temperature was controlled at 70°C and the vacuum was dried for 6 hours at -0.090 MPa.

[0079] Example 2 Preparation of high-purity pravastatin sodium D-type crystals

[0080] The preparation method of high-purity pravastatin sodium D-type crystal of the present invention is specifically as follows:

[0081] S1. Crystallization liquid pretreatment

[0082] A pravastatin sodium solution containing 100 kg of pravastatin sodium, 1800 L of acetonitrile and 100 L of water, respectively, was cooled to 20°C for heat preservation and crystallization to obtain a pravastatin sodium crystal liquid. The pravastatin sodium crystal liquid was placed in a three-in-one filter, the temperature was controlled at 20°C, and it was first filtered at -0.03 MPa for 1 hour, and then filtered at -0.05 MPa for 1 hour.

[0083] S2, first nitrogen drying

[0084] Under reduced pressure filtration without stirring, nitrogen was introduced into the filter and the pressure was maintained at -0.03 MPa for 1 hour to obtain a filter cake.

[0085] S3, washing, second nitrogen drying

[0086] Add 10°C detergent (acetonitrile: water = 9:1 (v / v) solution) to the filter cake for stirring, dispersion and washing, wherein the filter cake: detergent = 1:2 (m / v), and dry it for 1 hour under a vacuum value of -0.05 MPa, and then, under the suction and filtration state, pass clean nitrogen into the filter, maintain a vacuum of -0.03 MPa and dry it for 1 hour;

[0087] S4. Vacuum drying

[0088] The filter cake squeezed dry in step S3 is subjected to the following operations:

[0089] The temperature was controlled at 25°C and the vacuum was -0.05 MPa for 4 hours;

[0090] The temperature was controlled at 30°C and the vacuum was -0.07MPa for 8 hours;

[0091] The temperature was controlled at 40°C and the vacuum was -0.085MPa for 8 hours;

[0092] The temperature was controlled at 60°C and the vacuum was dried for 8 hours at -0.095 MPa.

[0093] Example 3 Preparation of high-purity pravastatin sodium D-type crystals

[0094] The preparation method of high-purity pravastatin sodium D-type crystal of the present invention is specifically as follows:

[0095] S1. Crystallization liquid pretreatment

[0096] A pravastatin sodium solution containing 100 kg, 800 L and 100 L of water, respectively, was cooled to 15°C for heat preservation and crystallization to obtain a pravastatin sodium crystal liquid. The pravastatin sodium crystal liquid was placed in a three-in-one filter, the temperature was controlled at 15°C, and it was first filtered at -0.01 MPa for 2 hours, and then filtered at -0.03 MPa for 2 hours.

[0097] S2, first nitrogen drying

[0098] Under reduced pressure filtration without stirring, nitrogen was introduced into the filter and the pressure was maintained at -0.01 MPa for 2 hours to obtain a filter cake.

[0099] S3, washing, second nitrogen drying

[0100] Add 10°C detergent (acetone: water = 9:1 (v / v) solution) to the filter cake for stirring, dispersion and washing, wherein the filter cake: detergent = 1:2 (m / v), and dry it for 4 hours under a vacuum value of -0.01 MPa, and then, under the suction and filtration state, pass clean nitrogen into the filter, maintain a vacuum of -0.01 MPa and dry it for 2 hours;

[0101] S4. Vacuum drying

[0102] The filter cake squeezed out in step S3 is subjected to the following operations:

[0103] The temperature was controlled at 30°C and the vacuum was -0.01 MPa for 2 hours;

[0104] The temperature was controlled at 40°C and the vacuum was -0.05MPa for 4 hours.

[0105] The temperature was controlled at 60°C and the vacuum was -0.07MPa for 4 hours.

[0106] The temperature was controlled at 80°C and the vacuum was dried for 6 hours at -0.085 MPa.

[0107] Example 4 Preparation of high-purity pravastatin sodium D-type crystals

[0108] The preparation method of high-purity pravastatin sodium D-type crystal of the present invention is specifically as follows:

[0109] S1. Crystallization liquid pretreatment

[0110] The pravastatin sodium solution containing 70 kg, 870 L and 60 L of water, respectively, was cooled to 10°C for heat preservation and crystallization to obtain pravastatin sodium crystal liquid. The pravastatin sodium crystal liquid was placed in a three-in-one filter, the temperature was controlled at 10°C, and it was first filtered at -0.01 MPa for 1.5 hours, and then filtered at -0.04 MPa for 1.5 hours.

[0111] S2, first nitrogen drying

[0112] Under reduced pressure filtration without stirring, nitrogen was introduced into the filter and the pressure was maintained at -0.02 MPa for 1.5 hours to obtain a filter cake.

[0113] S3, washing, second nitrogen drying

[0114] Add 10°C detergent (ethyl acetate: water = 9:1 (v / v) solution) to the filter cake for stirring, dispersion and washing, wherein: detergent = 1:2 (m / v), and dry it at -0.03 MPa for 2 hours, then introduce nitrogen into the filter under suction and filtration, maintain -0.02 MPa vacuum and dry it for 1.5 hours;

[0115] S4. Vacuum drying

[0116] The filter cake squeezed dry in step S3 is subjected to the following operations:

[0117] The temperature was controlled at 30°C and the vacuum was -0.05 MPa for 4 hours;

[0118] The temperature was controlled at 40°C and the vacuum was -0.07 MPa for 12 hours.

[0119] The temperature was controlled at 80°C and the vacuum was dried for 8 hours at -0.095 MPa.

[0120] Example 5 Preparation of high-purity pravastatin sodium D-type crystals

[0121] The preparation method of high-purity pravastatin sodium D-type crystal of the present invention is specifically as follows:

[0122] S1. Crystallization liquid pretreatment

[0123] The pravastatin sodium solution containing 80 kg, 850 L and 70 L of water, respectively, was cooled to 10°C for heat preservation and crystallization to obtain pravastatin sodium crystal liquid. The pravastatin sodium crystal liquid was placed in a three-in-one filter, the temperature was controlled at 10°C, and it was first filtered at -0.01 MPa for 1.5 hours, and then filtered at -0.04 MPa for 1.5 hours.

[0124] S2, first nitrogen drying

[0125] Under reduced pressure filtration without stirring, nitrogen was introduced into the filter and the pressure was maintained at -0.02 MPa for 1.5 hours to obtain a filter cake.

[0126] S3, washing, second nitrogen drying

[0127] Add 10°C detergent (acetone: water = 9:1 (v / v) solution) to the filter cake for stirring, dispersion and washing, wherein the filter cake: detergent = 1:2 (m / v), and dry it at -0.03 MPa for 2 hours, then introduce nitrogen into the filter under the suction filtration state, maintain -0.02 MPa vacuum and dry it for 1.5 hours;

[0128] S4. Vacuum drying

[0129] The filter cake squeezed out in step S3 is subjected to the following operations:

[0130] The temperature was controlled at 30°C and the vacuum was maintained at -0.05 MPa for 8 hours;

[0131] The temperature was controlled at 40°C and the vacuum was -0.085 MPa for 6 hours;

[0132] The temperature was controlled at 60°C and the vacuum was dried for 6 hours at -0.095 MPa.

[0133] Experimental Example 1: Characterization of High-Purity Pravastatin Sodium D-Type Crystals

[0134] The high-purity pravastatin sodium crystals prepared in Examples 1 to 5 were subjected to an X-ray diffraction spectrum test according to the Chinese Pharmacopoeia powder X-ray diffraction method (PXRD). The X-ray diffraction spectrum test results showed that the pravastatin sodium prepared in Examples 1 to 5 were all D-type crystals, and the X-ray diffraction spectrum (PXRD) of the pravastatin sodium sample prepared in Example 1 was as follows: Figure 1 As shown in the figure, it can be seen that the spectrum has high peaks, which is a manifestation of high crystal purity.

[0135] Test Example 2: Bulk Density Test of High-Purity Pravastatin Sodium D-Type Crystals

[0136] The high-purity pravastatin sodium D-type crystals prepared in Examples 1 to 5 were tested for bulk density, and the test method was as follows:

[0137] Weigh about 50 g of the pravastatin sodium sample prepared in any one of Examples 1 to 5 in a beaker, let it all pass through an 18-mesh sieve, pass through a funnel, let the sample all fall freely and vertically into a 250 mL measuring cylinder, gently smooth the surface of the sample in the measuring cylinder with a glass rod, read the volume of the sample, and calculate the bulk density of the sample according to the formula of bulk density P (g / mL) = W / V;

[0138] Where: W-weight of sample, g; V-volume of sample, mL;

[0139] The results obtained by the above determination method are shown in Table 1:

[0140] Table 1:

[0141] sample Bulk density (g / mL) Example 1 0.39 Example 2 0.35 Example 3 0.46 Example 4 0.32 Example 5 0.33

[0142] From the results in Table 1, it can be seen that the bulk density of the high-purity pravastatin sodium D-type crystals prepared by the method of the present invention is in the range of 0.3-0.5 g / mL, the hardness is appropriate, and the subsequent crushing operation is convenient, which is very suitable for use in drugs and preparations, wherein the bulk density is more preferably in the range of 0.35-0.45 g / mL.

[0143] Comparative Example 1

[0144] The difference between this comparative example and the best embodiment 1 is that the drying process of step S2 is different. In this comparative example, nitrogen is not charged into the drying process of step S2. Specifically, the vacuum filtration is carried out at -0.02 MPa for 1.5 hours without starting stirring.

[0145] Comparative Example 2

[0146] The difference between this comparative example and the best embodiment 1 is that step S2 is different. In this comparative example, stirring is performed during the drying process in step S2, specifically:

[0147] S2, first nitrogen drying

[0148] Under reduced pressure suction filtration and stirring, nitrogen was introduced into the filter and suction was performed for 2 hours while maintaining -0.01 MPa to obtain a filter cake.

[0149] Comparative Example 3

[0150] The difference between this comparative example and the best embodiment 1 is that the drying process of step S3 is different. Nitrogen is not filled in the drying process of step S3 of this comparative example. Specifically, a 10°C detergent (acetone: water = 9:1 (v / v) solution) is added to the filter cake for stirring, dispersion and washing, wherein the filter cake: detergent = 1:2 (m / v), and the filter cake is dried for 2 hours at -0.03 MPa, and then, under the suction state, the vacuum of -0.02 MPa is maintained for drying for 1.5 hours.

[0151] Comparative Example 4

[0152] The difference between this comparative example and the best embodiment 1 is that the vacuum drying process of step S4 is different. The vacuum drying process of step S4 of this comparative example is:

[0153] The filter cake squeezed dry in step S3 is subjected to the following operations:

[0154] The temperature was controlled at 60°C to 80°C, and the mixture was dried for 18 hours under a vacuum condition of -0.085 MPa to -0.095 MPa with stirring.

[0155] Comparative Example 5

[0156] The difference between this comparative example and the best embodiment 1 is that the vacuum drying process of step S4 is different. The vacuum drying process of step S4 of this comparative example is:

[0157] The filter cake squeezed dry in step S3 is subjected to the following operations:

[0158] The temperature was controlled at 40°C to 60°C and the vacuum was dried for 18 hours at -0.07MPa to -0.085MPa.

[0159] Comparative Example 6

[0160] The difference between this comparative example and the best embodiment 1 is that the vacuum drying process of step S4 is different. The vacuum drying process of step S4 of this comparative example is:

[0161] The filter cake squeezed dry in step S3 is subjected to the following operations:

[0162] The temperature was controlled at 50°C and the vacuum was -0.03 MPa for 6 hours;

[0163] The temperature was controlled at 70°C and the vacuum was dried for 4 hours at -0.07 MPa.

[0164] Comparative Example 7

[0165] The difference between this comparative example and the best embodiment 1 is that the vacuum drying process of step S4 is different. The vacuum drying process of step S4 of this comparative example is:

[0166] The filter cake squeezed dry in step S3 is subjected to the following operations:

[0167] The temperature was controlled at 35°C and the vacuum was -0.06MPa for 9 hours;

[0168] The temperature was controlled at 70°C and the vacuum was dried for 6 hours at -0.090 MPa.

[0169] Test Example 3: Crystal form test of pravastatin sodium crystals

[0170] The test method of this test example is consistent with that of test example 1 and test example 2. The specific test results of the crystal form test and bulk density test of comparative examples 1 to 7 are shown in Table 2;

[0171] Table 2: Crystal form test of pravastatin sodium crystals

[0172] sample Crystal form test results Bulk density (g / mL) Comparative Example 1 D crystal form 0.67 Comparative Example 2 D crystal form 0.72 Comparative Example 3 D crystal form 0.58 Comparative Example 4 F crystal form ( Figure 3 ) 0.36 Comparative Example 5 F crystal form 0.48 Comparative Example 6 Crystalline D with low crystal purity ( Figure 2 ) 0.34 Comparative Example 7 Crystal form D with low crystal purity 0.32

[0173] contrast Figure 1 and Figure 2 , Figure 3 visible, Figure 2 The X-ray diffraction spectrum (PXRD) is not a high peak, compared to Figure 1 Obviously the crystal purity is low. Figure 3 It is the spectrum of crystal form F. It can be seen that although comparative examples 1-3 can obtain crystal form D products, the bulk density exceeds the range of 0.3-0.5 g / mL, and the hardness and other properties are not convenient for crushing operations, and it is difficult to use in drugs and preparations. The bulk density of comparative examples 4-7 meets the requirements, but either the crystal form D products with low crystal purity or the obtained products are not crystal form D products, that is, the different vacuum drying procedures used cannot obtain higher purity pravastatin sodium D crystals.

[0174] It should be noted that the specific features, structures, materials or characteristics described in this specification can be combined arbitrarily. In order to make the description concise, not all possible combinations of the various technical features in the above embodiments are described. If there is no contradiction, technicians in this field can combine and combine the different embodiments and features of different embodiments described in this specification.

[0175] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing high-purity pravastatin sodium D-type crystals, characterized in that: The preparation method comprises the following steps: S1. Crystallization liquid pretreatment The pravastatin sodium crystal solution is placed in a filter and filtered under reduced pressure; S2, first nitrogen drying Under reduced pressure filtration without stirring, nitrogen is introduced into the filter to press dry to obtain a filter cake; S3, washing, second nitrogen drying Add detergent to the filter cake for stirring, dispersing and washing, stop stirring and filter under reduced pressure, and then introduce nitrogen into the filter under reduced pressure and filter to dry; S4. Vacuum drying The filter cake squeezed out in step S3 is subjected to the following operations: The temperature is controlled at 10-30°C and the vacuum condition is 0MPa to -0.05MPa for 2-4 hours; Control the temperature at 30℃~40℃ and dry it at -0.05MPa~-0.07MPa vacuum condition for 4~8 hours; Control the temperature at 40°C to 60°C and dry for 4 to 8 hours under vacuum conditions of -0.07MPa to -0.085MPa; The temperature is controlled at 60°C to 80°C, and the mixture is dried for 4 to 8 hours under a vacuum condition of -0.085 MPa to -0.095 MPa with stirring.

2. The method for preparing high-purity pravastatin sodium D-type crystal according to claim 1, characterized in that: The step S1 satisfies at least one of the following conditions (1) to (4): (1) The pravastatin sodium crystal solution in step S1 is obtained by cooling the pravastatin sodium solution to no higher than 20° C. and then heat-preserving and crystallizing; Optionally, the pravastatin sodium solution consists of any crystalline or amorphous pravastatin sodium, an organic solvent and water; (2) The filtration temperature in step S1 is controlled below 20° C. (3) The decompression and filtration pressure in step S1 is -0.05MPa to 0MPa; (4) The vacuum filtration time in step S1 is 2 to 4 hours.

3. The method for preparing high-purity pravastatin sodium D-type crystal according to claim 1, characterized in that: The pravastatin sodium solution comprises a mixed solution of any crystalline or amorphous pravastatin sodium, an organic solvent, and water in a mass volume ratio of 5-10 (m): 90-80 (v): 5-10 (v). The pravastatin sodium solution can be prepared by any of the following preparation methods (1) or (2): (1) any crystalline or amorphous pravastatin sodium, an organic solvent, and water are mixed in proportion and dissolved by heating or without heating. If necessary, the order of adding materials can be adjusted or the solution of the proportion can be obtained by concentration; Optionally, the organic solvent includes one or more of acetonitrile, acetone, ethyl acetate, toluene, n-butyl acetate, and isobutyl acetate; (2) The pravastatin sodium solution is formed after extraction and purification of the pravastatin fermentation broth.

4. The method for preparing high-purity pravastatin sodium D-type crystal according to claim 3, characterized in that: The reduced pressure filtration process in step S1 is: firstly filtration under the condition of -0.03 to 0 MPa for 1 to 2 hours, and then filtration under the condition of -0.05 MPa to -0.03 MPa for 1 to 2 hours.

5. The method for preparing high-purity pravastatin sodium D-type crystal according to claim 1, characterized in that: In step S2, the nitrogen is introduced into the drying process to maintain a pressure of -0.03 to -0.01 MPa, and the nitrogen drying time is 1 to 2 hours.

6. The method for preparing high-purity pravastatin sodium D-type crystal according to claim 1, characterized in that: In step S3, the pressure reduction filtration is carried out at -0.05 to 0 MPa, and the pressure reduction drying time is 1 to 4 hours. The nitrogen is introduced into the drying process to maintain -0.03 to -0.01 MPa, and the nitrogen drying time is 1 to 2 hours.

7. The method for preparing high-purity pravastatin sodium D-type crystal according to claim 1, characterized in that: In step S3, the volume of the detergent added is 1 to 2 times the mass of the filter cake, the detergent temperature is 5 to 10° C., the washing time is 0.5 to 1 hour, and the detergent is selected from a solvent or a mixed solvent with a boiling point below 100° C. and / or water, and the solvent with a boiling point below 100° C. is selected from one or more of acetonitrile, acetone, and ethyl acetate.

8. The method for preparing high-purity pravastatin sodium D-type crystal according to claim 7, characterized in that: In the step S3, the detergent is a solvent with a boiling point lower than 100° C.: water=7-10:1, v / v.

9. Use of the high-purity D-type pravastatin sodium crystal obtained by the preparation method according to any one of claims 1 to 8 in the preparation of a preparation for treating hypercholesterolemia or hyperlipidemia.

10. The use according to claim 9, characterized in that The bulk density of the high-purity pravastatin sodium D-type crystal is 0.3-0.5 g / mL.

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