Novel crystal form and preparation method of treprostyl sodium salt

Abstract

This invention discloses a new crystal form of treprostene sodium salt (structural formula shown in Formula 1) and its preparation method. Specifically, this invention discloses the 5.5 hydrate of treprostene sodium salt and its partially dehydrated crystal form. The new crystal form has good stability and hygroscopicity, and as a raw material for treprostene, it can meet the requirements for storage and transportation and has stable quality, so as to ensure the quality control of subsequent formulation products.

Description

Technical Field

[0001] This invention relates to the field of drug preparation, and specifically, it discloses a new crystal form of treprostinil sodium salt and its preparation method. Background Technology

[0002] Treprostrin is a drug for treating pulmonary arterial hypertension. It is a prostacyclin derivative with platelet aggregation inhibition and vasodilatory activity. Approved marketing formulations include injections, inhalers, and oral tablets. The active pharmaceutical ingredient (API) for the injection and inhalation formulations is treprostrin sodium salt.

[0003] Existing technologies have limited reports on the crystal form and preparation of treprostene sodium salt. US Patent No. 9550716 and WO2016 / 055819 describe the preparation of treprostene sodium salt in organic solvents and water-mixed solvent systems, respectively. The inventors prepared treprostene sodium salt according to the methods reported in these two documents and found problems such as poor crystallization, significant moisture absorption and formation of a viscous substance during filtration, and insufficient solid-state stability, which could not meet the quality stability requirements for commercial production of active pharmaceutical ingredients and formulations (Examples 3 and 4).

[0004] Active pharmaceutical ingredients (APIs) typically need to possess good stability, hygroscopicity, and crystallinity to ensure that they meet storage and transportation requirements and maintain stable quality, thereby ensuring the quality control of subsequent formulation products.

[0005] Therefore, as an important drug for treating pulmonary hypertension, there is an urgent need for a crystalline form of treprostene sodium salt with controllable quality and stability that meets the requirements of the active pharmaceutical ingredient, as well as a stable method for preparing the corresponding crystalline form. This will provide high-quality treprostene drug products to better meet therapeutic needs. Summary of the Invention

[0006] This invention discloses a novel crystalline form of treprostene sodium salt (structural formula shown in Formula 1) and its preparation method. Specifically, this invention discloses the 5.5-hydrate of treprostene sodium salt and its partially dehydrated crystalline form, as well as their preparation methods. The novel crystalline form possesses good stability and hygroscopicity, and as a treprostene raw material, it can meet the requirements for storage and transportation and maintain stable quality, thus ensuring the quality control of subsequent formulation products.

[0007]

[0008] The first aspect of this invention provides treprostyl sodium salt 5.5 hydrate, whose powder X-ray diffraction (Cu-Ka, The spectrum has characteristic peaks at the following 2Theta angle positions:

[0009] 4.3°±0.2°, 8.7°±0.2° and 17.6°±0.2°.

[0010] In one embodiment of the first aspect of the invention, powder X-ray diffraction (Cu-Ka) of the sodium treprostinil 5.5 hydrate was performed. The spectrum also shows characteristic peaks at the following 2Theta angle positions:

[0011] 13.1°±0.2°, 19.7°±0.2° and 24.3°±0.2°.

[0012] In another embodiment of the first aspect of the invention, powder X-ray diffraction (Cu-Ka) of the sodium treprostinil 5.5 hydrate was performed. The spectrum shows characteristic peaks at the 2Theta angle positions listed in Table 1.

[0013] In another embodiment of the first aspect of the invention, powder X-ray diffraction (Cu-Ka) of the sodium treprostinil 5.5 hydrate was performed. The spectrum is shown in Figure 1.

[0014] A second aspect of the present invention provides treprostene sodium salt 5.5 hydrate having the unit cell parameters listed in Table 2.

[0015] A third aspect of this invention provides a method for preparing the above-mentioned treprostine sodium salt 5.5 hydrate, characterized in that the method comprises the following steps:

[0016] (1) Dissolve treprostinil in an aqueous sodium hydroxide solution;

[0017] (2) Add acetonitrile to a sodium hydroxide solution of treprostinil to crystallize.

[0018] There are no special restrictions on temperature, time, stirring, etc. in the above steps (1) and (2). Those skilled in the art can choose appropriate conditions according to actual needs.

[0019] In one embodiment of the third aspect of the invention, the weight (g) to volume (ml) ratio of treprostinil to the aqueous sodium hydroxide solution is 1:1 to 1:5, for example 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5.

[0020] In one embodiment of the third aspect of the invention, the concentration of the sodium hydroxide aqueous solution is from 5 wt% to 15 wt%, for example, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, or 15 wt%.

[0021] In one embodiment of the third aspect of the invention, the volume (ml) : volume (ml) ratio of the sodium hydroxide aqueous solution to acetonitrile is 1:15 to 1:55.

[0022] In one embodiment of the third aspect of the invention, the crystallization temperature is from 0°C to 30°C, for example, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C or 30°C.

[0023] The fourth aspect of this invention provides a partially dehydrated crystal form I of treprostyl sodium salt 5.5 hydrate, the powder X-ray diffraction (Cu-Ka, The spectrum has characteristic peaks at the following 2Theta angle positions:

[0024] 4.8°±0.2°, 9.6°±0.2° and 19.3°±0.2°.

[0025] In one embodiment of the fourth aspect of the invention, the powder X-ray diffraction (Cu-Ka) of the partially dehydrated treprostyl sodium salt 5.5 hydrate is shown to be of type I. The spectrum also shows characteristic peaks at the following 2Theta angle positions:

[0026] 20.9°±0.2°, 22.1°±0.2° and 23.5°±0.2°.

[0027] In another embodiment of the fourth aspect of the invention, the powder X-ray diffraction (Cu-Ka) of the partially dehydrated treprostyl sodium salt 5.5 hydrate is shown to be of type I. The spectrum shows characteristic peaks at the 2Theta angle positions listed in Table 7.

[0028] In another embodiment of the fourth aspect of the invention, the powder X-ray diffraction (Cu-Ka) of the partially dehydrated treprostyl sodium salt 5.5 hydrate is shown to be of type I. The spectrum is shown in Figure 5.

[0029] The fifth aspect of this invention provides a partially dehydrated crystal type II of treprostyl sodium salt 5.5 hydrate, the powder X-ray diffraction (Cu-Ka, The spectrum has characteristic peaks at the following 2Theta angle positions:

[0030] 5.3°±0.2°, 10.6°±0.2° and 16.0°±0.2°.

[0031] In one embodiment of the fifth aspect of the invention, the powder X-ray diffraction (Cu-Ka) of the partially dehydrated treprostyl sodium salt 5.5 hydrate is shown to be of crystal type II. The spectrum also shows characteristic peaks at the following 2Theta angle positions:

[0032] 20.1°±0.2°, 21.4°±0.2° and 26.8°±0.2°.

[0033] In another embodiment of the fifth aspect of the invention, the powder X-ray diffraction (Cu-Ka) of the partially dehydrated treprostyl sodium salt 5.5 hydrate is shown to be of crystal type II. The spectrum shows characteristic peaks at the 2Theta angle positions listed in Table 8.

[0034] In another embodiment of the fifth aspect of the invention, the powder X-ray diffraction (Cu-Ka) of the partially dehydrated treprostyl sodium salt 5.5 hydrate is shown to be of crystal type II. The spectrum is shown in Figure 6.

[0035] The sixth aspect of the present invention provides a method for preparing a pharmaceutical composition, characterized by comprising the steps of:

[0036] (1) The above-mentioned treprostene sodium salt pentoxide hydrate, treprostene sodium salt pentoxide hydrate partially dehydrated crystal form I and / or treprostene sodium salt pentoxide hydrate partially dehydrated crystal form II are used as the raw material solid form of the active ingredient treprostene;

[0037] (2) The treprostane sodium salt 5.5 hydrate, treprostane sodium salt 5.5 hydrate partially dehydrated crystal form I and / or treprostane sodium salt 5.5 hydrate partially dehydrated crystal form II are mixed with a pharmaceutically acceptable carrier to obtain a pharmaceutical composition.

[0038] A seventh aspect of the present invention provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises the above-mentioned treprostine sodium salt 5.5 hydrate, treprostine sodium salt 5.5 hydrate partially dehydrated crystal form I and / or treprostine sodium salt 5.5 hydrate partially dehydrated crystal form II and a pharmaceutically acceptable carrier.

[0039] The eighth aspect of the present invention provides the use of the above-mentioned treprostine sodium salt 5.5 hydrate, treprostine sodium salt 5.5 hydrate partially dehydrated crystal form I, treprostine sodium salt 5.5 hydrate partially dehydrated crystal form II and / or pharmaceutical compositions, characterized in that they are used alone or in combination with other drugs to prepare drugs for treating pulmonary hypertension, pulmonary fibrosis, interstitial lung disease, chronic obstructive pulmonary disease, asthma, ischemic diseases, heart failure, arteriosclerosis, postoperative anticoagulation, central retinal vein occlusion, thrombotic microangiopathy, peripheral vascular disease, heart and lung transplantation, etc.

[0040] Compared with the prior art, the main advantages of the present invention include:

[0041] (1) The 5.5 hydrate of treprostone sodium salt disclosed in this invention has good stability and hygroscopicity, ensuring that the active pharmaceutical ingredient can meet the requirements for storage and transportation and maintain stable quality.

[0042] (2) The 5.5 hydrate of treprostone sodium salt disclosed in this invention has a good impurity removal effect, which is beneficial to the preparation of high-quality treprostone sodium salt raw material.

[0043] (3) The preparation process of treprostol sodium salt 5.5 hydrate disclosed in this invention is stable and conducive to the preparation of high-quality treprostol sodium salt raw materials and preparations.

[0044] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0045] Figure 1: XRPD of treprostine sodium salt 5.5 hydrate Atlas.

[0046] Figure 2: Single crystal analysis of quintillary sodium hydrate. result.

[0047] Figure 3: Comparison of XRPD spectra of monohydrate (Form A) and polyhydrate (Form C) provided by WO2016055819.

[0048] Figure 4: Comparison of XRPD spectra of three consecutive batches of treprostone sodium salt 5.5 hydrate.

[0049] Figure 5: Partial dehydrated crystallization type I XRPD spectrum of treprostyl sodium salt 5.5 hydrate.

[0050] Figure 6: XRPD spectrum of partial dehydrated form II of treprostyl sodium salt 5.5 hydrate. Detailed Implementation

[0051] Through long-term and in-depth research, the inventors have surprisingly discovered that treprostyl sodium salt can form a 5.5-valent hydrate. This 5.5-valent hydrate exhibits good crystallinity, excellent stability and hygroscopicity, and also demonstrates good purification effects. Furthermore, its partially dehydrated crystal forms I and II also possess good crystallinity. Based on these findings, the inventors have completed this invention.

[0052] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer.

[0053] the term

[0054] XRPD X-ray powder diffraction

[0055] DVS Dynamic Moisture Adsorption

[0056] Rel.Int. Relative intensity

[0057] wt% (weight percentage)

[0058] Example 1

[0059] Preparation of treprostine free acid

[0060] The preparation method of treprostene free acid reported in J.Org.Chem.2004,69,1890-1902, uses (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-1-[(3S)-3-hydroxyoctyl]-1H-phenyl[f]indene-2,5-diol as the starting material to obtain 34.5 g of treprostene free acid with an HPLC purity of 98.9%.

[0061] Example 2

[0062] Preparation of treprostine sodium salt 5.5 hydrate

[0063] Weigh 1 gram of crude treprostinil into a 50 ml pear-shaped flask, add 1.5 ml of 7 wt% sodium hydroxide aqueous solution, and stir until clear.

[0064] Under stirring, 28.5 mL of acetonitrile was slowly added dropwise to form a suspension. This suspension was then stirred overnight at 25°C.

[0065] The solid was filtered out and dried for 1 day at 25±2℃ and 60±5% relative humidity to obtain 1.2 g of white solid, with a yield of ~90%. The purity of the solid was determined by high performance liquid chromatography, the solid speciation was characterized by XRPD, and the water content was determined by Karl Fischer method. The specific test methods are as follows.

[0066] High performance liquid chromatography: Column: Agilent Proshell C18, column temperature: 30℃, flow rate: 0.5mL / min, detection wavelength: 210nm.

[0067] XRPD: Cu target, Ka wavelength, tube voltage 40KV, tube current 40mA. Scan range: 3-40°2-Theta; step: 0.02°; scan speed: 1 step / second.

[0068] Karl Fischer method: Volumetric water titrator.

[0069] Liquid chromatography analysis showed that after treprostone crude product was crystallized into treprostone sodium salt 5.5 hydrate, its purity increased from 98.9% to 99.9%, indicating a significant impurity removal effect.

[0070] Karl Fischer titration results showed that the moisture content after drying was 20.9 wt%.

[0071] The XRPD pattern of treprostene sodium salt 5.5 hydrate is shown in Figure 1. The main diffraction peaks and their relative intensities are shown in Table 1.

[0072] Table 1. XRPD data of treprostinil sodium salt 5.5 hydrate

[0073] Pos. [°2Th.] Rel.Int.[%] 4.3 79.4 8.7 100.0 11.9 1.0 13.1 1.0 16.5 1.2 17.6 14.6 18.0 1.0 19.2 1.1 19.7 4.6 21.5 1.2 21.7 2.2 23.0 1.6 24.3 2.9 30.9 1.0 31.0 1.1 35.6 1.6

[0074] The single-crystal diffraction pattern of treprogenyl sodium salt 5.5 hydrate is shown in Figure 2. The single-crystal diffraction results indicate that there are 5.5 water molecules of crystallization. The unit cell parameters are shown in Table 2.

[0075] Table 2. Cell parameters of treprostene sodium salt 5.5 hydrate

[0076]

[0077] Different crystallization process parameters, including sodium hydroxide concentration, acetonitrile volume and temperature, were screened. The operation steps are as described above, as shown in Table 3. The results show that the same crystal form of treprostinil sodium salt 5.5 hydrate was obtained under different crystallization process parameters.

[0078] Table 3. Summary of products obtained with different crystallization process parameters

[0079]

[0080] Example 3

[0081] Treprostine sodium salt as described in US9550716

[0082] The sodium treprostinil salt was prepared according to the method described in US9550716, as follows:

[0083] 1.5 g of crude treprostinil was dissolved in 37 ml of acetone, heated to 30 °C, and 0.9 ml of 5 M NaOH was slowly added dropwise while maintaining the temperature at 30 °C and stirring for 15 minutes. After stirring the reaction system at room temperature for 1 hour, white crystals precipitated. The reaction system was then placed in an ice-water bath and stirred for another hour. The solid was filtered and washed with acetone. During the washing and filtration process, the solid rapidly became sticky. After drying the obtained solid at room temperature, 0.8 g of solid was obtained, with a yield of ~52%.

[0084] When this solid was placed at 25 degrees Celsius and 80% relative humidity for 24 hours, it was found that the solid deliquesced into a viscous solution, proving that it has extremely strong hygroscopic properties and cannot meet the requirements of drug product quality stability.

[0085] Example 4

[0086] Treprostine sodium salt as described in WO2016055819

[0087] The sodium treprostinil salt was prepared according to the method described in WO2016055819, but the crystal form described in that patent could not be obtained. The specific process is as follows:

[0088] Form A

[0089] 0.25 g of crude treprostinil was dissolved in 3.3 ml of ethanol, and 87 mg of sodium carbonate monohydrate was added. The solution was stirred at room temperature for 16 hours under N2 protection. The pH of the solution was tested and found to be 6, which failed to meet the pH requirement of 7-9 described in WO2016055819. This is because sodium carbonate has low solubility in ethanol. After filtering off the insoluble sodium carbonate, the ethanol solution was evaporated to dryness using a rotary evaporator to obtain an oily substance. Then, 2 ml of water-saturated methyl tert-butyl ether was added, and the mixture was stirred overnight to obtain a white, viscous semi-solid, which was confirmed to be amorphous by polarized light microscopy.

[0090] Form B

[0091] 0.25 g of crude treprostinil was dissolved in 3.3 ml of ethanol, and 87 mg of sodium carbonate monohydrate was added. The mixture was stirred at room temperature for 16 hours under N2 protection. The pH of the solution was tested and found to be 6, which failed to meet the pH requirement of 7-9 described in WO2016055819. This is because sodium carbonate has low solubility in ethanol. After filtering off the insoluble sodium carbonate, the ethanol solution was evaporated to dryness using a rotary evaporator to obtain an oily substance. Then, 2 ml of methyl tert-butyl ether was added, and the mixture was stirred overnight to obtain a white, viscous semi-solid, which was confirmed to be amorphous by polarized light microscopy.

[0092] According to WO2016055819, both Form A and Form B will transform into Form C at 60% relative humidity, indicating that the solid-state stability of these two crystal forms cannot meet the requirements for the commercial production of treprostone sodium salt API / formulation.

[0093] Form C (polyhydrate)

[0094] According to the description in WO2016055819, Form C can only be obtained through the transformation of Form A and / or Form B, and it is not disclosed that it can be obtained directly through crystallization. Furthermore, comparing the XRPD spectra of the monohydrate (Form A) and polyhydrate (Form C) provided in WO2016055819 (Figure 4), it can be found that Form C is not a single crystal form, but rather a combination of Form A (diffraction peaks marked with *) and other crystal forms (marked with *). The mixture consists of diffraction peaks. As a mixed crystal form, it is difficult to ensure that the mixing ratio remains constant between different batches. Therefore, the polyhydrate Form C cannot meet the crystal form stability requirements for the commercial production of treprostyl sodium active pharmaceutical ingredient / formulation.

[0095] Example 5

[0096] Hygroscopicity of treprostone sodium salt 5.5 hydrate

[0097] Hygroscopicity is one of the key physicochemical properties of pharmaceuticals, significantly affecting drug stability, powder properties, and subsequent processing techniques. The hygroscopicity of treprostine sodium salt 5.5 hydrate was evaluated using dynamic moisture adsorption (DVS), and the results are shown in Table 4.

[0098] Table 4. Moisture content of treprostine sodium 5.5 hydrate at the following humidity (RH%) / temperature (°C)

[0099] Humidity / Temperature Moisture content (wt%) 40.0 / 25℃ 18.6 45.0 / 25℃ 18.7 50.0 / 25℃ 18.7 55.0 / 25℃ 18.8 60.0 / 25℃ 18.8 65.0 / 25℃ 18.9 70.0 / 25℃ 18.9 75.0 / 25℃ 19.0 80.0 / 25℃ 19.7 85.0 / 25℃ 19.9 90.0 / 25℃ 20.5 95.0 / 25℃ 22.6

[0100] When the relative humidity increases from 40% to 80%, the increase in water content (i.e., the hygroscopicity) of treprostyl sodium 5.5 hydrate is 1.1 wt%. According to the European Pharmacopoeia's definition of hygroscopicity, it is slightly hygroscopic. This proves that after forming 5.5 hydrate, treprostyl sodium can maintain a low degree of hygroscopicity within the normal humidity range, thereby ensuring the quality stability of treprostyl sodium raw material.

[0101] Example 6

[0102] The sodium treprostinil hydrate was placed in a petri dish and spread into a thin layer with a thickness of no more than 1 mm. It was then placed in a stability test chamber with a temperature of 40±2℃ and a relative humidity of 75±5% for 6 months.

[0103] The purity of the samples after the stability test was checked by HPLC, the moisture content was checked by Karl Fischer titration, and the crystal form was checked by XRPD. The results are shown in Table 5. Treprostene sodium salt 5.5-hydrate exhibited excellent chemical and solid-state stability, fully meeting the stability requirements of the active pharmaceutical ingredient.

[0104] Table 5. Accelerated stability of treprostone sodium salt 5.5 hydrate

[0105] time Appearance purity% Moisture% Crystal form 0 days off-white powder 99.97 20.1 Treprostine sodium salt 5.5 hydrate 1 month off-white powder 99.97 20.4 Treprostine sodium salt 5.5 hydrate 3 months off-white powder 99.96 20.0 Treprostine sodium salt 5.5 hydrate 6 months off-white powder 99.98 20.2 Treprostine sodium salt 5.5 hydrate

[0106] Example 7

[0107] Stability of treprostone sodium salt 5.5 hydrate crystallization process

[0108] Three consecutive batches of treprostone sodium salt pentoxide hydrate were prepared using the crystallization process of treprostone sodium salt pentoxide hydrate in Example 2 of this invention. The results are shown in Table 6 and Figure 4. The results of the three batches show that the crystallization process has good repeatability and stable product quality, which fully meets the requirements of commercial production.

[0109] Table 6: Data on three consecutive batches of treprostone sodium salt 5.5 hydrate

[0110] batch number Moisture,% purity,% 1# 20.4 99.9 2# 20.3 99.9 3# 20.4 99.9

[0111] Example 8

[0112] Treprostone sodium salt 5.5 hydrate partially dehydrated crystal type I

[0113] The sodium treprostinil hydrate was placed in a sealed container and the relative humidity was controlled at 30%. After it reached a constant weight, the solid form was characterized by XRPD.

[0114] The XRPD pattern of the partially dehydrated crystal type I of treprostyl sodium salt 5.5 hydrate is shown in Figure 5. The main diffraction peaks and their relative intensities are shown in Table 7.

[0115] Table 7. XRPD data of dehydrated crystal form I of treprostone sodium 5.5 hydrate

[0116]

[0117]

[0118] Example 9

[0119] Treprostone sodium salt 5.5% hydrate partially dehydrated crystal type II

[0120] The sodium treprostinil hydrate was placed in a sealed container, and the relative humidity of the environment was controlled at 10%. After constant weight, the solid form was characterized by XRPD.

[0121] The XRPD pattern of treprostyl sodium pentoxide hydrate partially dehydrated crystal form II is shown in Figure 6. The main diffraction peaks and their relative intensities are shown in Table 8. The XRPD pattern indicates that treprostyl sodium pentoxide hydrate partially dehydrated crystal form II is mixed with a small amount of treprostyl sodium pentoxide hydrate partially dehydrated crystal form I.

[0122] Table 8. XRPD data of treprostinil sodium 5.5 hydrate decrystallization type II

[0123] Pos. [°2Th.] Rel.Int.[%] 5.3 100.0 10.6 53.6 16.0 2.9 20.1 0.7 21.4 4.6 26.8 2.3

[0124] Example 10

[0125] Comparison of water solubility of treprostone sodium salt 5.5 hydrate, treprostone sodium salt 5.5 hydrate partially dehydrated crystal form I, treprostone sodium salt 5.5 hydrate partially dehydrated crystal form II, and treprostone free acid

[0126] Weigh 20 mg of treprostone free acid into a volumetric flask, add 200 mL of water, and place in a water bath (temperature controlled at 25 ± 2 °C). Shake vigorously for 30 seconds every 5 minutes and observe the dissolution over 30 minutes. The results show that treprostone free acid is insoluble, and its water solubility is less than 0.1 mg / mL.

[0127] Approximately 100 mg of treprostyl 5.5 hydrate, treprostyl sodium 5.5 hydrate (partially dehydrated crystal form I), and treprostyl sodium 5.5 hydrate (partially dehydrated crystal form II) were weighed into separate volumetric flasks. 1 mL of water was added, and the flasks were placed in a water bath (temperature controlled at 25±2℃). The mixture was vigorously shaken for 30 seconds every 5 minutes, and the dissolution was observed over 30 minutes. The results showed that treprostyl 5.5 hydrate, treprostyl sodium 5.5 hydrate (partially dehydrated crystal form I), and treprostyl sodium 5.5 hydrate (partially dehydrated crystal form II) were all completely soluble, with solubility greater than 100 mg / mL.

[0128] Treprostrenil sodium 5.5 hydrate and its partially dehydrated forms I and II have significantly better water solubility than treprostrenil free acid. Solubility is a key factor limiting drug release in vivo; insufficient solubility leads to incomplete drug release and thus affects bioavailability. Therefore, treprostrenil sodium 5.5 hydrate and its partially dehydrated forms I and II have better practical application effects.

[0129] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. The powder X-ray diffraction (Cu-Ka, 1.54178 Å) pattern of treprostene sodium salt 5.5 hydrate shows characteristic peaks at the following 2 Theta angle positions: 4.3º±0.2º, 8.7º±0.2º and 17.6º±0.2º.

2. The treprostinil sodium salt 5.5 hydrate as described in claim 1, its powder X-ray diffraction (Cu-Ka, 1.54178 Å) pattern also shows characteristic peaks at the following 2Theta angle positions: 13.1º±0.2º, 19.7º±0.2º and 24.3º±0.2º.

3. The powder X-ray diffraction (Cu-Ka, 1.54178 Å) pattern of the sodium treprostinil hydrate as described in claim 1 is shown in Figure 1.

4. A method for preparing treprostene sodium salt 5.5 hydrate according to claim 1, characterized in that, The method includes the following steps: (1) Dissolve treprostinil in a 7wt% sodium hydroxide aqueous solution; (2) Add acetonitrile to the sodium hydroxide solution of treprostinil to form a suspension, and then 25 μL of this suspension... Stir overnight to allow crystallization; and (3) Filter out the solids and at 25°C 2 and relative humidity 60 The treprostinil sodium salt 5.5 hydrate was obtained by drying under 5% conditions for 1 day.

5. A method for preparing a pharmaceutical composition, characterized in that, Including the following steps: 1) The sodium treprostinil hydrate of claim 1 is used as the raw material solid form of the active ingredient treprostinil; 2) The pharmaceutical composition is prepared by mixing the treprostinil sodium salt 5.5 hydrate according to claim 1 with a pharmaceutically acceptable carrier.

6. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises treprostinil sodium salt 5.5 hydrate as described in claim 1 and a pharmaceutically acceptable carrier.

7. The use of the treprostine sodium salt 5.5 hydrate according to claim 1 or the pharmaceutical composition according to claim 6, characterized in that, It is used alone or in combination with other drugs to prepare drugs for the treatment of pulmonary hypertension, pulmonary fibrosis, interstitial lung disease, chronic obstructive pulmonary disease, asthma, ischemic disease, heart failure, arteriosclerosis, postoperative anticoagulation, central retinal vein occlusion, thrombotic microangiopathy, peripheral vascular disease or heart and lung transplantation.

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