阅读说明：本技术 用于制备曲前列环素二乙醇胺盐的多晶型b的方法 (Process for preparing polymorph B of treprostinil diethanolamine salt ) 是由 I·霍托巴吉 I·拉斯洛 Z·瓦尔加 I·尤哈斯 I·里茨 Z·卡多斯 于 2019-03-07 设计创作，主要内容包括：本发明涉及用于制备曲前列环素二乙醇胺盐的多晶型B的稳健且可重现的方法,其包括以下步骤：a.将曲前列环素溶于甲醇中,b.向步骤a)的溶液中添加二乙醇胺或其甲醇溶液,c.将步骤b)的反应混合物搅拌直至溶解,d.当在步骤c)中完成了盐的形成时,将第一部分的非质子溶剂添加至所述溶液中,e.过滤步骤d)的溶液以除去不溶性杂质,f.将步骤e)的滤液用曲前列环素二乙醇胺盐的多晶型B进行种晶,g.向步骤f)中所获得的晶体悬浮液中添加第二部分的所述非质子溶剂,h.搅拌步骤g)的悬浮液直到结晶完成,i.将所述晶体分离、洗涤并干燥。(The present invention relates to a robust and reproducible process for the preparation of polymorph B of treprostinil diethanolamine salt, comprising the steps of: a. dissolving treprostinil in methanol, B. adding diethanolamine or its methanol solution to the solution of step a), c. stirring the reaction mixture of step B) until dissolution, d. when the salt formation is completed in step c), adding a first portion of aprotic solvent to the solution, e. filtering the solution of step d) to remove insoluble impurities, f. seeding the filtrate of step e) with polymorph B of treprostinil diethanolamine salt, g. adding a second portion of the aprotic solvent to the crystal suspension obtained in step f), h. stirring the suspension of step g) until crystallization is completed, i. isolating, washing and drying the crystals.)

1. A robust, reproducible, one-step process for preparing polymorph B of treprostinil diethanolamine salt, comprising the steps of:

a. the treprostinil is dissolved in methanol,

b. adding diethanolamine or a methanol solution thereof into the solution of the step a),

c. the reaction mixture of step b) is stirred until dissolved,

d. after completion of the salt formation in step c), adding a first portion of the aprotic solvent to the solution,

e. filtering the solution of step d) and,

f. seeding the filtrate of step e) with polymorph B of treprostinil diethanolamine salt,

g. adding a second portion of said aprotic solvent to the crystal suspension obtained in step f),

h. stirring the suspension of step g) until crystallization is complete,

i. the crystals are isolated, washed and dried.

2. The method of claim 1, wherein the dissolution of treprostinil and diethanolamine is performed at 25-50 ℃.

3. The method of claim 2, wherein the dissolution of treprostinil and diethanolamine is performed at 30-40 ℃.

4. A process according to any one of claims 1 to 3, characterized in that ethers, such as methyl tert-butyl ether, diisopropyl ether, ketone solvents, such as acetone, ester solvents, such as ethyl acetate, or acetonitrile are used as aprotic solvents.

5. The process according to claim 4, characterized in that methyl tert-butyl ether is used as aprotic solvent.

6. A process for uniformly converting polymorph a or a mixture of polymorphs a and B of treprostinil diethanolamine salt to polymorph B, comprising the steps of:

a. dissolving treprostinil diethanolamide salt in methanol,

b. adding a first portion of an aprotic solvent to the solution of step a),

c. filtering the solution of step b) and,

d. seeding the filtrate of step c) with polymorph B of treprostinil diethanolamine salt,

e. adding a second portion of said aprotic solvent to the crystal suspension obtained in step d),

f. stirring said suspension of step e) until crystallization is complete,

g. the crystals are isolated, washed and dried.

7. A process according to claim 6, characterized in that ethers, such as methyl tert-butyl ether, diisopropyl ether, polar ketone solvents, such as acetone, ester solvents, such as ethyl acetate, or acetonitrile are used as aprotic solvents.

8. The process according to claim 7, characterized in that methyl tert-butyl ether is used as aprotic solvent.

9. The method of any one of claims 6 to 8, wherein the dissolution of treprostinil and diethanolamine is performed at 25-50 ℃.

10. The method of claim 9, wherein the dissolution of treprostinil and diethanolamine is performed at 30-40 ℃.

Technical Field

Treprostinil of formula (II)

Is a synthetic prostacyclin derivative with the functions of inhibiting platelet aggregation and vasodilation. It is the only prostacyclin derivative that can be used in subcutaneous, intravenous or inhaled and oral forms.

Its therapeutic field relates to Pulmonary Arterial Hypertension (PAH), Drugs, 2012, 72(18) 2351-.

http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_ designation/2009/10/WC500005505.pdf, download: 2017Year 2, month 15).

Treprostinil sodium salt of formula (III)

In the market place so as to

For injection purposes, toFor inhalation purposes.

Treprostinil diethanolamine salt of formula (I) is tableted

The active ingredient of (1).

Two polymorphic forms (form A and form B) of crystalline treprostinil diethanolamine salt are first described in patent specification WO 2005/007081. These polymorphs are characterized by their melting point, X-ray powder diffraction pattern, DSC (differential scanning calorimetry) and TGA (thermogravimetric analysis) profiles, and by their hygroscopicity.

They point out

Metastable form A is hygroscopic, melts at 103 deg.C, has an endothermic peak at 103 deg.C in the DSC curve, and as shown by TGA, the crystals do not contain any solvated solvent

The more stable form B is much less hygroscopic, melts at 107 ℃, exhibits an endothermic peak at 107 ℃ in the DSC curve, and exhibits minimal weight loss at 100 ℃ in the TGA curve.

Forms A and B exhibit different powder diffraction patterns: the more stable form B has a characteristic peak at 17.2 ° θ.

Form a in suspensions made from various organic solvents (1, 4-dioxane, isopropanol, tetrahydrofuran, toluene) is converted to form B with stirring at different temperatures.

The publications Organic Process & Development, 2009, 13, 242-249(crystallization Process Development for Stable polymorphism of Treprostinil; Batra, H.; Penmasa, R.; Phares, K.; Staszewski, J.; Tuladhadhar, S.M; D.A. Walsh, United Therapeutics) describe in detail the physical properties of these two polymorphs and carry out experiments on their preparation. The metastable form A which is first separated is converted into the thermodynamically more stable form B after standing.

Several different ratios of solvent-anti-solvent mixtures were investigated. Form A is predominantly obtained from a mixture of isopropanol, methyl tert-butyl ether (TBME), but conversion of form A to form B does not occur on scale-up, when the crystal suspension is stirred for several hours.

If the solution is seeded with form B and cooling is very slow, controlled with several temperature steps, crystallization from a mixture of ethanol to acetone to 7:1 (yield 85-90%) and ethanol to ethyl acetate to 7:1 (yield 90%) gives form B homogeneously.

Patent specification WO 2009/078965 discloses the preparation of highly pure treprostinil sodium salt by crystallization of treprostinil diethanolamine salt.

To a solution of treprostinil in ethyl acetate was added anhydrous ethanol and diethanolamine. The clear solution was stirred at 60-75 ℃ for 30-60 minutes, cooled to 55 ± 5 ℃ and seeded with 1% amount of polymorph B of treprostinil diethanolamine salt. The precipitated crystals were stirred for 1 hour while maintaining the temperature, and then the crystal suspension was cooled to 20-22 ℃. After stirring for 16-24 hours, the crystals were collected by filtration, washed with ethyl acetate and dried, yield 88%.

Form B is obtained if the melting point of the treprostinil diethanolamine crystals is >104 ℃.

If the melting point of the resulting treprostinil diethanolamine crystals is <104 ℃, a mixture of form a and form B is present. In that case, the crystal mixture was repeatedly crystallized from a solvent mixture of ethanol and ethyl acetate.

Thus, the above-described method is neither robust nor reproducible, usually resulting in a mixture of forms a + B.

Patent specification WO 2014/089385 describes the preparation of treprostinil, treprostinil sodium and treprostinil diethanolamine salt.

For the preparation of treprostinil diethanolamine salt, a solution of treprostinil in ethyl acetate was treated with a solution of diethanolamine in anhydrous ethanol, the resulting suspension was heated, and the resulting suspension was maintained at reflux temperature for 15 minutes while all components were dissolved. The solution was then slowly cooled to room temperature over 18 hours. The precipitated white crystalline material was filtered off, washed with ethyl acetate and dried under vacuum at 50 ℃ for 24 hours. The yield was 76%. The physical properties of the salt are not given.

Patent specification IN 2014CH02963-a discloses the preparation of treprostinil, treprostinil sodium and treprostinil diethanolamine salt.

To an aqueous solution of diethanolamine is added a solution of treprostinil in acetone at 25-30 ℃. Optionally, the solution is seeded and then stirred for 15 minutes while maintaining the temperature. The crystal suspension is cooled to 0-5 ℃, after stirring for 90 minutes, the crystals are filtered off, washed and dried. Yield: 79% of polymorph A.

Polymorphic form a crystals of treprostinil diethanolamine salt were suspended in acetone and then ethanol was added to the suspension at reflux temperature in an amount of about 0.2%. After stirring at reflux temperature for 6 hours and subsequent cooling to 25-30 ℃, the crystals are filtered off, washed and dried. Yield 100%, polymorph B.

In the above process, polymorph B of treprostinil diethanolamine salt can only be prepared in two steps.

In the process described in patent specification US 2016/0152548, for salt formation treprostinil and diethanolamine are dissolved in ethanol and ethyl acetate at 70 ℃, after stirring for 30 minutes the solution is cooled to 55 ℃, seeded with 1 wt% treprostinil diethanolamine salt polymorph B seeds, the suspension is stirred at 55 ℃ for 1 hour and cooled to room temperature. After stirring for 16 hours, the crystals are filtered off, washed and dried. Yield: 93 percent. The physical properties of the crystals (melting point, X-ray powder diagram, DSC, TGA) are not given.

Again in the above process, similar to the process of patent specification WO 2014/089385, the crystallisation is carried out using an ethanol-ethyl acetate mixture, which is known to be not robust and reproducible and in many cases results in a mixture of form a + B.

Our aim was to develop a robust and reproducible process for the preparation of crystalline treprostinil diethanolamine salt and which provides a more stable polymorph B of the salt in one step (i.e. one crystallization step of treprostinil diethanolamine salt, which comprises the sequence of seeding, addition of anti-solvent, cooling and filtration).

It is known from the literature that treprostinil diethanolamine salt can crystallize in two polymorphic forms. The lower melting point (melting point 103 ℃) polymorph is metastable form a, while the higher melting point (melting point 107 ℃) polymorph is thermodynamically more stable form B, and thus polymorph B is the desired crystalline form for the preparation of a pharmaceutical active ingredient.

However, it is not an easy task to prepare the thermodynamically more stable form B: even if we find a suitable solvent/anti-solvent ratio, dissolution at reflux temperature, seeding with form B, cooling very slowly in a controlled manner with several temperature steps, it is not guaranteed that this process will provide a more stable form B in every case. As shown in the literature, it often happens that forms a and B crystallize together even if the predetermined parameters are strictly followed, and the desired polymorph is finally obtained from the mixture of forms a and B after additional operating steps (repeated crystallization, long stirring of the crystal suspension).

We collated the literature data and investigated what crystalline forms were obtained by using various solvents or solvent mixtures. (watch I)

Methods of preparing crystalline treprostinil DEA in the literature

Crystallization from solution stirring of a suspension of crystals containing form A or form A + B

Scaling up crystallization and repeating crystallization if A + B precipitates

From table I, which is simplified and does not contain a crystallization temperature profile, the following conclusions can be drawn:

the crystallization process of patent specification WO2005/007081 (1) gives a mixture of form A or form A + B. The desired form B can be obtained by subsequent stirring of the crystal suspension for several days.

According to publication (2) org.proc.res. & dev.:

form a and form a + B mixtures initially obtained were completely converted to form B under the effect of stirring with isopropanol or a mixture of isopropanol-methyl tert-butyl ether for a long time during laboratory experiments, however, form B was not successfully obtained during scale-up.

Form A is obtained by crystallizing from a mixture of isopropanol and methyl tert-butyl ether.

By crystallization from an EtOH acetone mixture, a mixture of 1:7 ratio generally yields form B, but sometimes a mixture of form a + B is obtained. In this case, the crystallization must be repeated until form B crystals are uniformly obtained. In this process, the solution had to be seeded with form B, a complex temperature profile had to be followed, and the entire crystallization process took 3 days. However, this method is not robust, since only small changes in the solvent ratio may lead to crystallization of the mixture of form a + B. Surprisingly, a 1:10 mixture of EtOH to acetone was selected to replace the 1:7 solvent mixture of EtOH to acetone as determined in laboratory experiments during scale-up.

By crystallization from an EtOH ethyl acetate mixture, a mixture of 1:7 ratio generally yields form B, but in some cases a mixture of form a + B is obtained. In that case, the crystallization must be repeated until form B crystals are uniformly obtained. In this process, the solution must be seeded with form B and a complex temperature profile must be followed, the entire crystallization process requiring a short time of about 1.5 days. However, this method is also not robust with this solvent mixture, since small changes in the solvent ratio may lead to crystallization of the mixture of form a + B. Surprisingly, in this process, also in scale-up, another solvent ratio (EtOH: ethyl acetate ═ 1:8) was chosen instead of the solvent ratio found to be the most suitable in laboratory experiments (EtOH: ethyl acetate ═ 1: 7).

In patent specification WO 2009/078965 a1(3), the crystallization of treprostinil diethanolamine salt was carried out with a mixture of EtOH: ethyl acetate ═ 1: 7. If form B is not crystallized, repeated crystallization is required and the process is therefore not robust.

In patent specification WO 2014/089385 a2(4), the crystallization of treprostinil diethanolamine salt was carried out with a mixture of EtOH: ethyl acetate ═ 1: 8. The crystals were not characterized, but it can be learned from literature data that this method is not robust to preparation B.

Treprostinil diethanolamine salt crystallized from an acetone: water mixture according to patent specification IN 2014CH02963(5) to give form a. Crystalline form A converts to form B after stirring in an acetone/EtOH mixture.

In the process of patent specification US 2016/0152548 a1(6), treprostinil diethanolamine salt is crystallized from a solvent mixture EtOH: ethyl acetate ═ 1: 7. From the specification, form B was obtained, but it was known from literature data that this method was not robust.

However, for industrial implementation, the technology must be robust, simple, scalable, reproducible, and easy to implement.

In view of the above, we aimed to develop a process that can provide treprostinil diethanolamine salt of formula I in a thermodynamically more stable crystalline polymorph form B reproducibly in one step in each case.

We performed a number of experiments to develop a process for preparing polymorph B of treprostinil diethanolamine salt. Our aim was to carry out salt formation using solvents in which only polymorph B crystallizes.

In the experiment, 1.0g of treprostinil (II) was dissolved in the selected solvent. To this solution was added 0.3g of diethanolamine (IV), and the reaction mixture was stirred at 35 ℃ for 30 minutes. The first portion of the anti-solvent was added to the homogeneous solution, then the mixture was cooled to room temperature and seeded with polymorph B of treprostinil diethanolamine salt (I). After stirring for 1-2 hours, a second portion of the anti-solvent is added to the crystal suspension and stirring is continued for a further 16-24 hours at room temperature.

The treprostinil diethanolamine (I) crystals were filtered off, washed and dried in vacuo at 45 ℃. The crystalline form was determined by DSC and X-ray powder diffraction (XRPD) studies.

To our surprise, we found that only form B crystallized from methanol with any of the anti-solvents (methyl tert-butyl ether, acetone, ethyl acetate, diisopropyl ether, acetonitrile) (see figure 1 for X-ray powder diffractogram), while both forms a and B formed using the solvents described in the literature.

Table II: preparation of crystalline treprostinil diethanolamine salt from methanol

It is noted that toluene is not a suitable anti-solvent for crystallizing treprostinil diethanolamine salt and toluene cannot be successfully used to obtain the salt in crystalline form.

The solvent found to be most suitable for the preparation of crystalline polymorph B of treprostinil diethanolamine salt is methanol, since crystallization from this solvent always results in uniform crystallization of form B.

Methyl tert-butyl ether was chosen as anti-solvent, which proved to be the most suitable for technical reasons.

The formation of treprostinil diethanolamine salt was repeated four times on a 1g scale using methanol-methyl tert-butyl ether as solvent-anti-solvent mixture, and the process was then scaled up starting with 70g treprostinil (II) (example 7). In each case, polymorph B of the salt was obtained homogeneously.

Thus, our method is robust, reproducible and yields the desired form B in one step.

In addition, our process is technically more convenient because programmed cooling, as used in prior art processes, is not required.

To further demonstrate the robustness of our process, the preparation of treprostinil diethanolamine salt at the 1g scale was repeated 5 times. The amount of anti-solvent methyl tert-butyl ether used for crystallization varies within wide limits.

Treprostinil (II) was dissolved in methanol (4ml) and diethanolamine (0.3g) was added to the solution. After the salt formation was complete, a first portion of methyl tert-butyl ether (15ml) was added. The solution was filtered and a second portion of methyl tert-butyl ether was added dropwise to complete the crystallization.

In all cases, form B of treprostinil diethanolamine crystallized as confirmed by XRPD and DSC. The characteristic peak of form B, i.e. 17.2 ° 2 θ, is present in the XRPD pattern, while the characteristic peak of form a disappears completely. In addition, in all cases, the DSC showed endothermic peaks at temperatures around 105 ℃ or higher.

Drawings

FIG. 1: x-ray powder diffraction patterns of different polymorphic forms of treprostinil diethanolamine salt crystallized from methanol as solvent and different anti-solvents (examples 1 to 6):

1.1: MeOH/methyl tert-butyl ether

1.2: MeOH/acetone

1.3: MeOH/ethyl acetate

1.4: MeOH/diisopropyl ether

1.6: MeOH/acetonitrile

"A": treprostinil diethanolamine polymorph form a

"B": treprostinil diethanolamine polymorph B

FIG. 2: XRPD pattern of treprostinil diethanolamine salt polymorph B crystallized from MeOH/methyl tert-butyl ether mixture (example 7)

FIG. 3: DSC profile of treprostinil diethanolamine salt polymorph B crystallized from MeOH/methyl tert-butyl ether mixture (Peak: 106.56 ℃, example 7)

FIG. 4: XRPD pattern of treprostinil diethanolamine salt polymorph B crystallized from MeOH/methyl tert-butyl ether mixture (example 8)

FIG. 5: DSC profile of treprostinil diethanolamine salt polymorph B crystallized from MeOH/methyl tert-butyl ether mixture (Peak: 106.23 ℃, example 8)

FIG. 6: XRPD pattern of treprostinil diethanolamine salt polymorph B crystallized from MeOH/methyl tert-butyl ether mixture (example 9)

FIG. 7: DSC profile of treprostinil diethanolamine salt polymorph B crystallized from MeOH/methyl tert-butyl ether mixture (Peak: 105.37 ℃, example 9)

FIG. 8: XRPD pattern of treprostinil diethanolamine salt polymorph B crystallized from MeOH/methyl tert-butyl ether mixture (example 10)

FIG. 9: DSC profile of treprostinil diethanolamine salt polymorph B crystallized from MeOH/methyl tert-butyl ether mixture (Peak: 104.91 ℃, example 10)

FIG. 10: XRPD pattern of treprostinil diethanolamine salt polymorph B crystallized from MeOH/methyl tert-butyl ether mixture (example 11)

FIG. 11: DSC profile of treprostinil diethanolamine salt polymorph B crystallized from MeOH/methyl tert-butyl ether mixture (Peak: 106.10 ℃, example 11)

FIG. 12: XRPD pattern of treprostinil diethanolamine salt polymorph B crystallized from MeOH/methyl tert-butyl ether mixture (example 12)

FIG. 13: DSC profile of treprostinil diethanolamine salt polymorph B crystallized from MeOH/methyl tert-butyl ether mixture (Peak: 107.42 ℃, example 12)

FIG. 14: XRPD pattern of treprostinil diethanolamine salt polymorph A + B crystallized from EtOH/ethyl acetate mixture (example 13)

FIG. 15: DSC curves of treprostinil diethanolamine salt polymorph A + B crystallized from EtOH/Ethyl acetate mixture (peaks: 103.84 ℃ and 105.94 ℃, example 13)

FIG. 16: DSC profile of treprostinil diethanolamine salt polymorph B crystallized from MeOH/methyl tert-butyl ether mixture (Peak: 107.34 ℃, example 14)

FIG. 17: DSC profile of treprostinil diethanolamine salt polymorph B crystallized from MeOH/water/acetone mixture (Peak: 106.56 ℃, example 15)

FIG. 18: DSC profile of treprostinil diethanolamine salt polymorph B crystallized from MeOH/methyl tert-butyl ether mixture at 40 deg.C to 50 deg.C (peak: 106.23 deg.C, example 16)

FIG. 19: XRPD pattern of treprostinil diethanolamine salt polymorph C crystallized from MeOH/methyl tert-butyl ether mixture at-70 deg.C (example 17)

FIG. 20: DSC profile of treprostinil diethanolamine salt polymorph C crystallized from MeOH/methyl tert-butyl ether mixture at-70 deg.C (peaks: 87.66 deg.C and 102.58 deg.C, example 17)

FIG. 21: method for preparing treprostinil diethanolamine salt obtained in DMSO at 500MHz¹³C and¹HNMR data

Examples	Amount of TBME	Ratio of Me: OH: TBME	Yield of
				8	15ml+20ml	1:8.75*	91％
9	15ml+25ml	1:10	91％
				10	15ml+29ml	1:11	92％
11	15ml+9ml	1:6	81％
				12	15ml+5ml	1:5	75％

Ratio used for scaling up

Crystallization was also performed using an ethanol-ethyl acetate solvent/anti-solvent mixture. In this case, in agreement with the literature data, a mixture of forms A + B is obtained (example 13). If this mixture of treprostinil diethanolamine salt forms a and B is crystallized from a methanol-methyl tert-butyl ether solvent mixture, polymorph B of the salt is uniformly obtained (example 14).

Dissolving treprostinil diethanolamine salt in aqueous methanol (about 30% water) and precipitating with acetone we again uniformly obtained polymorph B, but with a yield of only 61% (example 15).

Polymorphic form B of treprostinil diethanolamine salt is also obtained if the salt is dissolved in methanol, the solution is made milky white with methyl tert-butyl ether at 45 ℃ and then the crystallization is completed at room temperature (yield 87%) (example 16).

However, crystallization from a methanol-methyl t-butyl ether solvent solution at-70 ℃ gave crystals with a low melting point and high hygroscopicity. This form is referred to as polymorph C (example 17). Based on the DSC profile, polymorph C is a less stable form with a melting point of 86-88 deg.C, and it transforms into a more stable, higher melting form (101-.

Based on the above, the subject of the present invention is a process for the preparation of polymorph B of treprostinil diethanolamine salt, comprising the following steps:

a. the treprostinil is dissolved in methanol,

b. adding diethanolamine or a methanol solution thereof into the solution of the step a),

c. the reaction mixture of step b) is stirred until dissolved,

d. when the salt formation is completed in step c), a first portion of the aprotic solvent is added to the solution,

e. filtering the solution of step d) to remove insoluble impurities,

f. seeding the filtrate of step e) with polymorph B of treprostinil diethanolamine salt,

g. adding a second portion of aprotic solvent to the crystal suspension obtained in step f),

h. stirring the suspension of step g) until crystallization is complete,

i. the crystals are isolated, washed and dried.

Another subject of the present invention is a process for the homogeneous conversion of polymorph a or a mixture of polymorphs a and B of treprostinil diethanolamine salt to polymorph B, comprising the steps of:

a. dissolving treprostinil diethanolamide salt in methanol,

b. adding a first portion of an aprotic solvent to the solution of step a),

c. filtering the solution of step b) to remove insoluble impurities,

d. seeding the filtrate of step c) with polymorph B of treprostinil diethanolamine salt,

e. adding a second portion of aprotic solvent to the crystallization suspension of step d),

f. stirring said suspension of step e) until crystallization is complete,

g. the crystals are isolated, washed and dried.

In a preferred embodiment of the invention, the dissolution of treprostinil and diethanolamine or the dissolution of treprostinil diethanolamine salt is carried out at 25-50 ℃, preferably at 30-40 ℃.

For the aprotic solvent ether, for example, methyl t-butyl ether, diisopropyl ether, ketone solvents such as acetone, ester solvents such as ethyl acetate or acetonitrile, preferably methyl t-butyl ether, are used.

The ratio of solvent (methanol) to anti-solvent is preferably 1:4 to 20, more preferably 1:5 to 15, even more preferably 1:7 to 11.

In one embodiment of the method according to the present invention, crystalline form B of treprostinil diethanolamine salt is prepared in the following manner: treprostinil was dissolved in methanol at 35 ℃, solid diethanolamine base was added thereto, and the mixture was stirred at 35 ℃ until dissolved. To this was then added a first portion of the anti-solvent methyl tert-butyl ether, the solution was filtered, the filtrate solution was seeded with polymorph B of treprostinil diethanolamine salt and the mixture was stirred at room temperature. A second portion of the anti-solvent is added to the crystallization suspension and the mixture is stirred at room temperature until crystallization is complete. Polymorph a or a mixture of polymorph a and B of treprostinil diethanolamine salt was recrystallized from methanol-methyl tert-butyl ether to give form B of treprostinil diethanolamine salt.

The advantages of our method over previous methods are:

the method is simple, robust, scalable and reproducible,

the desired form B is provided in one step,

easy application scale-up since no complex heating-cooling curve is required

The following is not required: the subsequent transformation of the crystal form is carried out,

omicron repeated crystallization and/or

Stirring the crystal suspension for a long time, and/or

Complex heating-cooling curve

Reproducibly providing the desired, more stable polymorph B,

the method is equally applicable to form B for obtaining treprostinil diethanolamine salt

Omicron by forming a salt starting from treprostinil and diethanolamine (IV), and then crystallizing the resulting salt

Form a or the mixture of form a + B is uniformly converted to form B by crystallization.

The details of the present invention are illustrated by the following examples, but the present invention is not limited thereto.

The measurement conditions applied in the method according to the invention are:

x-ray diffraction pattern:

starting position [ ° 2 θ ]: 2.0084

End position [ ° 2 θ ]: 39.9864

Measurement temperature [ ° c ]: 25.00

Anode material: cu

K-α11.54060

K-α21.54443

DSC：

The instrument comprises the following steps: METTLER TOLEDO DSC1 STARe System, Star Basic V9.30

The method comprises the following steps: initial temperature: 30 deg.C

Final temperature: 150 ℃ C

Heating rate: 5 ℃/min

Quantity: 2-6mg, porous aluminum crucible (40. mu.l)

NMR：

The instrument comprises the following steps: bruker Avance III 500MHz

Solvent: DMSO (dimethylsulfoxide)