A method for preparing a plurality of crystalline solid forms of sodium phosphatidylglycerol

Abstract

The application discloses a preparation method of various crystal solid forms of phosphatidyl glycerol sodium, which comprises the following steps: A, completely dissolving crude phosphatidyl glycerol sodium in an organic mixed solvent to obtain phosphatidyl glycerol sodium intermediate I; B, cooling and crystallizing the phosphatidyl glycerol sodium intermediate I to obtain phosphatidyl glycerol sodium intermediate II; C, performing solid-liquid separation on the phosphatidyl glycerol sodium intermediate II to obtain filter residue, and vacuum drying the filter residue to obtain phosphatidyl glycerol sodium finished product; the crystal shape of the phosphatidyl glycerol sodium finished product comprises one of flocculent shape, granular shape and needle shape. The advantage crystal form is granular or needle-shaped. The advantage crystal form of the method is easy to be separated by solid-liquid separation, is not easy to adsorb solvent, has less residual solvent, and has high product purity and good yield, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of phospholipid technology, and more specifically to a method for preparing sodium phosphatidylglycerol in multiple crystalline forms. Background Technology

[0002] Different crystal forms of compounds may result in differences in physicochemical properties such as filterability, flowability, solubility, and stability, which may in turn affect the efficacy, safety, and stability of the final solid dosage form of the drug. Sodium phosphatidylglycerol (PG-Na), such as distearatel phosphatidylglycerol sodium (DSPG-Na), often caking occurs during purification processes such as crystallization, leading to residual solvent exceeding relevant requirements. This is because sodium phosphatidylglycerol has long fatty acid chains at the tail end, which easily form cotton-like flocculent solids during conventional crystallization. However, these flocculent solids easily adsorb solvent during filtration, resulting in long filtration times and a tendency to caking, affecting subsequent drying effects.

[0003]

[0004] On the other hand, for sodium phosphatidylglycerol, different crystal shapes exhibit varying degrees of stability during subsequent storage and transportation. Therefore, in this technical field, obtaining various specific crystal shapes from crude sodium phosphatidylglycerol, rather than just flocculent solids, is of great significance for improving production efficiency and reducing costs. Summary of the Invention

[0005] To address the aforementioned problems, the present invention aims to provide a method for preparing various specific crystal forms of sodium phosphatidylglycerol from crude sodium phosphatidylglycerol, particularly methods for crystallizing granular and needle-like solids, so that the product can be easily separated into solid and liquid phases during filtration or centrifugation after crystallization, and facilitates subsequent product drying.

[0006] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0007] A method for preparing sodium phosphatidylglycerol in multiple crystalline forms includes the following steps:

[0008] A. Dissolve the crude sodium phosphatidylglycerol completely in an organic mixed solvent to obtain sodium phosphatidylglycerol intermediate I;

[0009] B. The sodium phosphatidylglycerol intermediate I is cooled and crystallized to obtain sodium phosphatidylglycerol intermediate II;

[0010] C. The sodium phosphatidylglycerol intermediate II is subjected to solid-liquid separation to obtain filter residue, and the filter residue is vacuum dried to obtain the sodium phosphatidylglycerol finished product; the crystal shape of the sodium phosphatidylglycerol finished product includes one of flocculent, granular and needle-like.

[0011] Preferably, in step A, the organic mixed solvent comprises a mixture of alkane or halogenated hydrocarbon and lower alcohol, and water, wherein the alkane or halogenated hydrocarbon includes dichloromethane, chloroform, and C5-C64 hydrocarbons. 10 Alkanes or C5-C 10 One or more of the cycloalkanes, wherein the lower alcohols include one or more of the C1 to C4 alcohols.

[0012] As a preferred embodiment of the preparation method of the present invention, in step A, the volume ratio of the organic mixed solvent to the mass of the crude sodium phosphatidylglycerol includes 1-5 ml:1 g, and the volume ratio of the alkane or haloalkane to the lower alcohol and water includes 4:4:1; in step B, the cooling and crystallization operation includes: the sodium phosphatidylglycerol intermediate I is directly cooled and allowed to stand to crystallize; in step C, the crystalline shape of the obtained sodium phosphatidylglycerol product is needle-shaped.

[0013] Preferably, in the preparation method of the aforementioned sodium phosphatidylglycerol product with needle-shaped crystals, the cooling and crystallization time in step B includes 8 to 10 hours.

[0014] In a preferred embodiment of the preparation method of the present invention, in step A, the volume ratio of the alkane or haloalkane to the lower alcohol and water is 12-14:4-8:1. ； In step B, the cooling and crystallization operation includes: adding the sodium phosphatidylglycerol intermediate I to the antisolvent, cooling and stirring to crystallize, with a stirring speed of 20-80 rpm, and the ratio of the volume of the antisolvent added to the mass of the crude sodium phosphatidylglycerol being 4-10 ml: 1 g; in step C, the crystalline shape of the obtained sodium phosphatidylglycerol product is granular.

[0015] As a preferred embodiment of the preparation method of the present invention, in step B, the cooling and crystallization operation includes: adding the sodium phosphatidylglycerol intermediate I to the antisolvent, cooling and allowing it to stand to crystallize; in step C, the vacuum drying time includes 12 to 24 hours, and the crystalline shape of the sodium phosphatidylglycerol product is flocculent.

[0016] Preferably, in the preparation method of the aforementioned sodium phosphatidylglycerol product having a flocculent or granular crystal shape, in step B, the antisolvent includes one or more of C1-C4 alcohols, acetone, and acetonitrile.

[0017] As a preferred embodiment of the preparation method of the present invention, in step A, the volume ratio of the alkane or haloalkanes to the lower alcohol and water is 4-16:4-16:1, and the volume ratio of the organic mixed solvent to the mass of the crude sodium phosphatidylglycerol is 1-10 ml:1 g; in step B, the cooling and crystallization time is 4-10 h.

[0018] Preferably, in step A, the dissolution operation includes: taking the crude sodium phosphatidylglycerol, adding the organic mixed solvent, stirring and dissolving completely to obtain the sodium phosphatidylglycerol intermediate I, and the dissolution temperature includes 20-80℃; in step B, the cooling and crystallization temperature includes room temperature; in step C, the solid-liquid separation operation includes: filtering the sodium phosphatidylglycerol intermediate II to obtain the filter residue; the vacuum drying operation includes: placing the filter residue into a vacuum drying oven to obtain the finished sodium phosphatidylglycerol, the vacuum drying time includes 2-24 hours, and the vacuum drying temperature includes 40-80℃.

[0019] The crude sodium phosphatidylglycerol in step A above is prepared by an enzymatic method, which includes: phosphatidylcholine is catalyzed by immobilized phospholipase D (PLD) in a two-phase solvent to undergo a transphosphatidyl reaction with glycerol to obtain a crude phosphatidylglycerol reaction solution; PLD in the reaction solution is recovered, and the aqueous layer and organic layer are separated; the organic layer is reacted with an inorganic base to form a salt, and the solution is concentrated to obtain crude sodium phosphatidylglycerol.

[0020] The present invention also provides a sodium phosphatidylglycerol product obtained by any of the aforementioned methods for preparing sodium phosphatidylglycerol in various crystalline solid forms.

[0021] Preferably, the crystalline shape of the sodium phosphatidylglycerol product includes either granular or needle-like shapes.

[0022] Preferably, the sodium phosphatidylglycerol product is of high purity.

[0023] To prepare a non-flocculated sodium phosphatidylglycerol sample, the inventors systematically investigated the solvent system, temperature, and crystallization method, and unexpectedly prepared granular and needle-shaped solids. They also determined the specific range requirements for the good solvent combination, antisolvent and its amount, and crystallization method for preparing granular solids, while the preparation of needle-shaped solids could only be achieved by meeting specific good solvent combinations and amounts.

[0024] Compared with the prior art, implementing the present invention has the following beneficial effects:

[0025] 1. The preparation method of the present invention can selectively crystallize sodium phosphatidylglycerol into its preferred crystal forms, such as granular or needle-like solids, filling this technical gap in the field.

[0026] 2. The preparation method of the present invention can produce sodium phosphatidylglycerol with high purity and good yield, and the solvent residue of the finished product meets the requirements, with a significant reduction in solvent residue in the dominant crystal form.

[0027] 3. The preferred preparation method of the present invention is beneficial to the solid-liquid separation after product crystallization and the subsequent drying of solid products, and also facilitates the long-term storage and transportation of products. Therefore, the present invention significantly improves production efficiency while extending product life.

[0028] 4. In addition to improving production efficiency and optimizing products, reducing costs and increasing efficiency, this invention also has the characteristic of good method repeatability, thus having a significant advantage in large-scale industrial production. Attached Figure Description

[0029] Figure 1 Microscopic images of the sodium phosphatidylglycerol products prepared in Examples 2-4, where a is the granular solid of Example 2, b is the needle-like solid of Example 3, and c is the flocculent solid of Example 4;

[0030] Figure 2 The HPLC-ELSD chromatogram of the sodium phosphatidylglycerol granular solid product prepared in Example 2 is shown below.

[0031] Figure 3 The image shows the HPLC-ELSD chromatogram of the sodium phosphatidylglycerol needle-like solid product prepared in Example 3.

[0032] Figure 4 The image shows the HPLC-ELSD chromatogram of the sodium phosphatidylglycerol flocculent solid product prepared in Example 4. Detailed Implementation

[0033] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments and comparative examples. Unless otherwise specified, the reagents and materials used in the following embodiments and comparative examples are commercially available products.

[0034] Example 1

[0035] Weigh 100g dipalmitoylphosphatidylcholine into a 2L round-bottom flask, add 500ml dichloromethane, and stir until completely dissolved in a 30℃ water bath. Then add 500ml purified water, 600g glycerol, 3.77g anhydrous calcium chloride, 525ul acetic acid, 5.08g sodium acetate, and 90U immobilized phospholipase D (PLD) in sequence. Continue stirring in a 30℃ water bath for 8 hours, then stop the reaction. The reaction system becomes porridge-like.

[0036] Add 1000 ml of methanol to the reaction system, stir well, and place in a separatory funnel. After the immobilized PLD settles to the bottom, release the immobilized PLD from the bottom of the funnel. After washing with methanol, n-hexane, and purified water, it can be reused. Add 1000 ml of chloroform to the remaining mixed suspension in the funnel, mix well, let stand, and then separate the contents.

[0037] The lower layer of mixed organic suspension was released and placed in a beaker. 100 ml of water and 14.43 g of sodium carbonate were added, and the mixture was stirred at room temperature for 1 hour to neutralize. During the stirring process, the lower organic layer gradually became clear. After the reaction was completed, the neutralized solution was poured into a separatory funnel, allowed to stand, and then separated.

[0038] The lower organic layer was released and concentrated to obtain crude dipalmitoylphosphatidylglycerol sodium (DPPG-Na).

[0039] Example 2

[0040] In this embodiment, crude dipalmitoylphosphatidylglycerol sodium was prepared according to the method of Example 1. 10g of crude dipalmitoylphosphatidylglycerol sodium was weighed into a round-bottom flask, and 100ml of an organic mixed solvent (volume ratio of hexane:methanol:water = 60:30:5) was added. The flask was then placed in a 40°C water bath and stirred until completely dissolved. Next, 100ml of methanol was added, and the mixture was cooled to room temperature while stirring at 50rpm to allow crystallization. After 4 hours of crystallization, a sample was taken and observed under a microscope. The crystal shape was as follows... Figure 1 As shown in figure a, the sample was a granular solid. The remaining sample was filtered, and solid-liquid separation was good. The filter residue was vacuum dried at 50℃ for 4 hours, and 9.1 g of the finished product was obtained as powder. The HPLC results of the finished product are shown below. Figure 2 As shown, the purity is 100.0%, and the solvent residue test results are: hexane: 93 ppm, methanol: 6 ppm, water: 0.02%, which meets the relevant solvent residue requirements in ICH Q3C (Guideline for Solvent Residue).

[0041] Example 3

[0042] In this embodiment, crude dipalmitoylphosphatidylglycerol sodium was prepared according to the method of Example 1. 10g of crude dipalmitoylphosphatidylglycerol sodium was weighed into a round-bottom flask, and 50ml of an organic mixed solvent (volume ratio of hexane:methanol:water = 10:10:2.5) was added. The mixture was then stirred and dissolved completely in a 40°C water bath. After cooling and crystallization at room temperature for 8 hours, a sample was taken and observed under a microscope. The crystal shape was as follows... Figure 1 As shown in b, the sample was a needle-like solid. The remaining sample was filtered, and solid-liquid separation was good. The filter residue was vacuum dried at 50℃ for 4 hours, and 9.0 g of the finished product was collected as powder. The HPLC results of the finished product are shown below. Figure 3 As shown, the purity is 99.75%, and the solvent residue test results are: n-hexane: 121 ppm, methanol: 11 ppm, water: 0.03%, which meets the relevant solvent residue requirements in ICH Q3C.

[0043] Example 4

[0044] In this embodiment, crude dipalmitoylphosphatidylglycerol sodium was prepared according to the method of Example 1. 10g of crude dipalmitoylphosphatidylglycerol sodium was weighed into a round-bottom flask, and 100ml of an organic mixed solvent (volume ratio of hexane:methanol:water = 60:30:5) was added. The flask was then placed in a 40°C water bath and stirred until completely dissolved. Next, 100ml of methanol was added, and the mixture was allowed to cool and settle at room temperature to crystallize. After 4 hours of crystallization, a sample was taken and observed under a microscope. The crystal shape was as follows... Figure 1 As shown in Figure c, the solid is flocculent. The remaining sample was filtered, but solid-liquid separation was slow, requiring a long filtration time. After filtration, the filter residue was vacuum-dried at 50℃ for 4 hours and 12 hours, and samples were taken afterward. During drying, the solid clumped together and needed to be crushed. 9.1 g of powder was obtained, with a purity of 100.0%. Solvent residue detection after 4 hours of drying showed hexane: 501 ppm, methanol: 112 ppm, and water: 0.21%. The hexane content did not meet the relevant solvent residue requirements in ICH Q3C. The HPLC results of the finished product after 12 hours of drying are as follows... Figure 4 As shown, the purity is 99.74%, and the solvent residue test results are: n-hexane: 150 ppm, methanol: 84 ppm, water: 0.1%, which meets the relevant solvent residue requirements in ICH Q3C.

[0045] Example 5

[0046] In this embodiment, crude dioleoylphosphatidylglycerol sodium was prepared according to the method of Example 1, except that dipalmitoylphosphatidylcholine was replaced with dioleoylphosphatidylcholine. 20g of crude dioleoylphosphatidylglycerol sodium was weighed into a round-bottom flask, and 200ml of a mixed organic solvent (chloroform:isopropanol:water = 40:20:3 by volume) was added. The mixture was then stirred and dissolved completely in a 40°C water bath. 170ml of ethanol was then added, and the mixture was cooled to room temperature and stirred at 55rpm to induce crystallization. After 4 hours of crystallization, a sample was taken and observed under a microscope; the solid was granular. The remaining sample was filtered, and solid-liquid separation was good. After filtration, the filter residue was vacuum dried at 40°C for 2 hours to obtain 18.9g of the finished product, with a yield of 94.5%. The purity of the finished product was 100.0%, and the solvent residue was chloroform: 17ppm, isopropanol: 71ppm, ethanol: 83ppm, and water: 0.09%, meeting the relevant solvent residue requirements in ICH Q3C.

[0047] Example 6

[0048] In this embodiment, crude distearylphosphatidylglycerol sodium was prepared according to the method of Example 1, except that dipalmitoylphosphatidylcholine was replaced with distearylphosphatidylcholine. 50g of crude distearylphosphatidylglycerol sodium was weighed into a round-bottom flask, and 500ml of a mixed organic solvent (volume ratio of cyclohexane:ethanol:water = 60:20:5) was added. The mixture was then stirred and dissolved completely in a 50°C water bath. 200ml of ethanol was then added, and the mixture was cooled to room temperature and stirred at 65rpm to induce crystallization. After 4 hours of crystallization, a sample was taken and observed under a microscope; the crystals were granular solids. The remaining sample was filtered, and solid-liquid separation was good. After filtration, the filter residue was vacuum dried at 60°C for 2 hours to obtain 46.6g of the final product, with a yield of 93.2%. The purity of the final product was 100.0%, and the solvent residue was 23ppm for cyclohexane, 77ppm for ethanol, and 0.09% for water, meeting the relevant solvent residue requirements in ICH Q3C.

[0049] Example 7

[0050] In this embodiment, crude dimyristoylphosphatidylglycerol sodium was prepared according to the method of Example 1, except that dipalmitoylphosphatidylcholine was replaced with dimyristoylphosphatidylcholine. 30g of crude dimyristoylphosphatidylglycerol sodium was weighed into a round-bottom flask, and 150ml of an organic mixed solvent (volume ratio of n-heptane:methanol:water = 10:10:2.5) was added. The mixture was then stirred and dissolved completely in a 30°C water bath. After cooling to room temperature, crystals were precipitated. After 10 hours of crystallization, a sample was taken and observed under a microscope; the crystals were needle-shaped solids. The remaining sample was filtered, and solid-liquid separation was good. After filtration, the filter residue was vacuum dried at 60°C for 2 hours to obtain 28.4g of the finished product, with a yield of 94.7%. The purity of the finished product was 100.0%, and the solvent residue was n-heptane: 109ppm, methanol: 93ppm, and water: 0.08%, meeting the relevant solvent residue requirements in ICH Q3C.

[0051] Comparative Example 1

[0052] In this comparative example, crude dipalmitoylphosphatidylglycerol sodium was prepared according to the method in Example 1. 10g of crude dipalmitoylphosphatidylglycerol sodium was weighed into a round-bottom flask and dissolved using conventional methods. 40ml of tetrahydrofuran, 40ml of dichloromethane, and 8ml of water were added, followed by the addition of 100ml of ethanol, which precipitated the crystals. Microscopic observation of the sample revealed it to be a flocculent solid. After 4 hours of crystallization, the sample was filtered. Solid-liquid separation was slow, requiring a long filtration time. After filtration, the filter residue was vacuum-dried at 50°C for 4 hours and 12 hours, and samples were taken after each drying. During the drying process, the solid clumped together and needed to be crushed. 4.1g of powder was obtained. After drying for 4 hours, the solvent residue was detected as follows: tetrahydrofuran: 927 ppm, dichloromethane: 718 ppm, and water: 0.33%. The tetrahydrofuran and dichloromethane residues did not meet the relevant solvent residue requirements in ICH Q3C. After drying for 12 hours, the solvent residue was detected as follows: tetrahydrofuran: 483 ppm, dichloromethane: 326 ppm, and water: 0.13%, which met the relevant solvent residue requirements in ICH Q3C.

[0053] It is evident that the traditional reagent combination and crystallization method, in addition to producing flocculent solid crystals that are prone to solvent residue and are not conducive to drying and preservation during production, also have a yield (41%) that is far lower than that of the embodiments of the present invention (over 90%).

[0054] In the following examples, the crude dipalmitoylphosphatidylglycerol sodium was prepared according to the method in Example 1.

[0055] Example 1: Solvent Evaluation

[0056] The main solvents for the dissolution and crystallization of crude sodium dipalmitoylphosphatidylglycerol were investigated. Twenty portions (1 g each) of crude sodium dipalmitoylphosphatidylglycerol were weighed into round-bottom flasks, dissolved in different solvents, and crystals were observed. The phenomena were recorded, and samples of the crystals were observed under a microscope. The solvents investigated, related procedures, experimental phenomena, and results are shown in Table 1.

[0057] Table 1. Analysis of Major Solvents

[0058]

[0059]

[0060] As shown in Table 1, the preparation of particulate solids has specific requirements for solvents, antisolvents and their amounts, and crystallization methods. However, the preparation of needle-shaped solids can only be achieved when specific solvent combinations and amounts are met.

[0061] Example 2: Effects of stirring speed and solvent on particulate solids

[0062] To further investigate the specific effects of stirring, solvent, and other factors on the preparation of granular solids, eight portions of crude dipalmitoylphosphatidylglycerol sodium were weighed into round-bottom flasks, each weighing 1 g. After dissolving in a mixed organic solvent, the product was crystallized at room temperature with different stirring speeds. Crystal samples were taken and observed under a microscope. The results are shown in Table 2.

[0063] Table 2. Effects of stirring speed and solvent on particulate solids.

[0064]

[0065]

[0066] As can be seen from Table 2, both excessively low and excessively high stirring speeds are not conducive to the formation of particulate solids. In addition, when dissolving samples, the amount of highly polar solvent in the mixed solvent should not be excessive; otherwise, excessively rapid crystallization is also not conducive to the formation of particulate solids.

[0067] Example 3: Investigation of Factors Affecting Needle-like Solids

[0068] To further investigate the specific effect of the solvent on the preparation of needle-like solids, 5 portions of crude dipalmitoylphosphatidylglycerol sodium were weighed into round-bottom flasks, each weighing 1 g. After dissolving in a mixed organic solvent, the samples were allowed to stand at room temperature to crystallize. The crystals were then observed under a microscope, and the results are shown in Table 3.

[0069] Table 3. Investigation of Needle-shaped Solid Solvents

[0070]

[0071] As can be seen from Table 3, when preparing needle-like solids, the ratio of low-polarity solvent to high-polarity solvent in the mixed solvent is close; in addition, the mixed solvent should not be too much during dissolution, otherwise it will not be conducive to the formation of needle-like solids.

[0072] Example 4: Accelerated Stability Test

[0073] Based on the stability characteristics of phospholipid compounds and the relevant guidelines of the 2020 edition of the Chinese Pharmacopoeia, accelerated stability tests were designed for dipalmitoylphosphatidylglycerol sodium granular, needle-like, and flocculent solid samples (finished products) in Examples 2, 3, and 4 at 5±3℃. The results are shown in Table 4.

[0074] Table 4. Accelerated stability test results of samples with different crystal forms

[0075]

[0076] The accelerated test results in Table 4 show that sodium dipalmitoylphosphatidylglycerol with different crystal morphologies has different solid stability. The granular solid has the best stability, followed by the needle-like solid. The flocculent solid is presumably less stable because it has a larger specific surface area and is easily oxidized in the air.

[0077] The experimental results above show that granular and needle-shaped solids are beneficial for product filtration and drying during solid-liquid separation after crystallization. Furthermore, the accelerated stability test results of granular and needle-shaped solids are better than those of flocculent solids. Therefore, granular and needle-shaped solids are more conducive to the long-term preservation and transportation of products compared to flocculent solids.

[0078] The above-disclosed embodiments are merely preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention. Therefore, any equivalent variations made in accordance with the claims of the present invention are still within the scope of the present invention.

Claims

1. A method for preparing sodium phosphatidylglycerol in multiple crystalline forms, characterized in that, Includes the following steps: A. Dissolve the crude sodium phosphatidylglycerol in an organic mixed solvent to obtain sodium phosphatidylglycerol intermediate I; B. The sodium phosphatidylglycerol intermediate I is cooled and crystallized to obtain sodium phosphatidylglycerol intermediate II; C. The sodium phosphatidylglycerol intermediate II is subjected to solid-liquid separation to obtain filter residue, and the filter residue is vacuum dried to obtain the sodium phosphatidylglycerol finished product; the crystal shape of the sodium phosphatidylglycerol finished product includes one of flocculent, granular and needle-like.

2. The method for preparing sodium phosphatidylglycerol in multiple crystalline forms according to claim 1, characterized in that, In step A, the organic mixed solvent comprises a mixture of alkanes or halogenated hydrocarbons and lower alcohols and water, wherein the alkanes or halogenated hydrocarbons include dichloromethane, chloroform, and C5-C64 hydrocarbons. 10 Alkanes or C5-C 10 One or more of the cycloalkanes, wherein the lower alcohols include one or more of the C1 to C4 alcohols.

3. The method for preparing sodium phosphatidylglycerol in multiple crystalline forms according to claim 2, characterized in that, In step A, the volume ratio of the organic mixed solvent to the mass of the crude sodium phosphatidylglycerol is 1-5 ml:1 g, and the volume ratio of the alkane or haloalkane to the lower alcohol and water is 4:4:1; in step B, the cooling and crystallization operation includes: the sodium phosphatidylglycerol intermediate I is directly cooled and allowed to stand to crystallize; in step C, the crystalline shape of the obtained sodium phosphatidylglycerol product is needle-shaped.

4. The method for preparing sodium phosphatidylglycerol in multiple crystalline forms according to claim 3, characterized in that, In step B, the cooling and crystallization time includes 8 to 10 hours.

5. The method for preparing sodium phosphatidylglycerol in multiple crystalline forms according to claim 2, characterized in that, In step A, the volume ratio of the alkane or haloalkane to the lower alcohol and water is 12-14:4-8:1; in step B, the cooling and crystallization operation includes: adding the sodium phosphatidylglycerol intermediate I to the antisolvent, cooling and stirring to crystallize, the stirring speed is 20-80 rpm, and the ratio of the volume of the antisolvent added to the mass of the crude sodium phosphatidylglycerol is 4-10 ml:1 g; in step C, the crystalline shape of the obtained sodium phosphatidylglycerol product is granular.

6. The method for preparing sodium phosphatidylglycerol in multiple crystalline forms according to claim 2, characterized in that, In step B, the cooling and crystallization process includes: adding an antisolvent to the sodium phosphatidylglycerol intermediate I, cooling and allowing it to stand to crystallize; in step C, the vacuum drying time includes 12 to 24 hours, and the resulting sodium phosphatidylglycerol product has a flocculent crystal shape.

7. The method for preparing sodium phosphatidylglycerol in multiple crystalline solid forms according to any one of claims 5 to 6, characterized in that, In step B, the antisolvent includes one or more of C1-C4 alcohols, acetone, and acetonitrile.

8. The method for preparing sodium phosphatidylglycerol in multiple crystalline solid forms according to claim 2, characterized in that, In step A, the volume ratio of the alkane or haloalkane to the lower alcohol and water is 4-16:4-16:1, and the volume ratio of the organic mixed solvent to the mass of the crude sodium phosphatidylglycerol is 1-10 ml:1 g; in step B, the cooling and crystallization time is 4-10 h.

9. The method for preparing sodium phosphatidylglycerol in multiple crystalline solid forms according to claim 1, characterized in that, In step A, the dissolution operation includes: taking the crude sodium phosphatidylglycerol, adding the organic mixed solvent, stirring and dissolving completely to obtain the sodium phosphatidylglycerol intermediate I, the dissolution temperature including 20-80℃; in step B, the cooling crystallization temperature including room temperature; in step C, the solid-liquid separation operation includes: filtering the sodium phosphatidylglycerol intermediate II to obtain the filter residue; the vacuum drying operation includes: placing the filter residue into a vacuum drying oven to obtain the finished sodium phosphatidylglycerol, the vacuum drying time including 2-24 hours, the vacuum drying temperature including 40-80℃.

10. A sodium phosphatidylglycerol product obtained by a method for preparing sodium phosphatidylglycerol in multiple crystalline forms according to any one of claims 1 to 9.

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