阅读说明：本技术 鲁比前列酮(lubiprostone)晶体以及其制备方法 (Lubiprostone (lubiprosone) crystal and preparation method thereof ) 是由 魏士益 郑建邦 于 2019-07-10 设计创作，主要内容包括：本发明揭示一种新颖的鲁比前列酮(Lubiprostone)晶体以及其制备方法。本发明提供的制备方法可有效地减少或除去所获得的鲁比前列酮晶体中的杂质。(The invention discloses a novel Lubiprostone (Lubiprostone) crystal and a preparation method thereof. The preparation method provided by the invention can effectively reduce or remove impurities in the obtained lubiprostone crystal.)

1. A Lubiprostone (Lubiprostone) crystal VI having an X-ray powder diffraction (XRPD) pattern exhibiting its five most intense characteristic peaks at the following 2 Θ reflection angles: 7.5 +/-0.2 degrees, 10.3 +/-0.2 degrees, 13.9 +/-0.2 degrees, 18.7 +/-0.2 degrees and 21.1 +/-0.2 degrees.

2. The lubiprostone crystal VI of claim 1, wherein the XRPD pattern further comprises characteristic peaks at the following 2 Θ reflection angles: 6.2 +/-0.2 degrees, 12.5 +/-0.2 degrees, 14.8 +/-0.2 degrees, 15.3 +/-0.2 degrees, 17.0 +/-0.2 degrees, 19.3 +/-0.2 degrees, 22.3 +/-0.2 degrees, 23.8 +/-0.2 degrees and 26.2 +/-0.2 degrees.

3. The lubiprostone crystal VI of claim 2, wherein the XRPD pattern is substantially as shown in figure 9.

4. The lubiprostone crystal VI of claim 1, having a Differential Scanning Calorimetry (DSC) thermogram comprising an endothermic peak with a peak onset temperature of 47.4 ± 1 ℃ and a peak maximum of 50.7 ± 1 ℃.

5. The lubiprostone crystal VI of claim 4, wherein the DSC thermogram is substantially as shown in figure 10.

6. A process for preparing lubiprostone crystal VI of any one of claims 1 to 5, comprising the steps of:

dissolving lubiprostone in paraxylene to form a homogeneous solution;

reducing the temperature and/or adding a solvent selected from the group consisting of: pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof; and

stirring until a precipitate forms.

7. The method of claim 6, further comprising the step of seeding with lubiprostone crystal VI prior to the stirring step.

8. The method of claim 6, further comprising the steps of:

filtering the precipitate, thereby isolating the lubiprostone crystals VI; and

optionally drying the lubiprostone crystals VI.

9. A lubiprostone crystal V having an X-ray powder diffraction (XRPD) pattern exhibiting its five most intense characteristic peaks at the following 2 Θ reflection angles: 6.5 + -0.2 deg., 13.2 + -0.2 deg., 15.6 + -0.2 deg., 18.9 + -0.2 deg., and 20.2 + -0.2 deg., wherein a half-peak width of the characteristic peak at the 2 theta reflection angle is between 0.3 deg. and 2 deg..

10. The lubiprostone crystal V of claim 9, wherein the XRPD pattern is substantially free of characteristic peaks at 2 Θ reflection angles of 7.6 ± 0.2 °.

11. The lubiprostone crystal V of claim 10, wherein the XRPD pattern is substantially as shown in figure 6.

12. The lubiprostone crystal V of claim 9, having a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm with a peak onset temperature of 60.6 ± 1 ℃ and a peak maximum of 64.7 ± 1 ℃.

13. The lubiprostone crystal V of claim 12, wherein the DSC thermogram is substantially as shown in figure 7.

14. The lubiprostone crystal V of claim 9, having a size in cm^-11% KBr Fourier Transform Infrared (FTIR) spectra showing peaks at 3388 + -4, 2938 + -4, 2872 + -4, 1729 + -4, 1713 + -4, 1415 + -4, 1247 + -4, 1222 + -4, 1207 + -4, 1180 + -4, 1105 + -4, 1091 + -4, 1060 + -4, 1006 + -4, 987 + -4, 918 + -4, 761 + -4 and 723 + -4.

15. The lubiprostone crystal V of claim 14, wherein the FTIR spectrum is substantially as shown in figure 8.

16. A process for preparing lubiprostone crystal V of any one of claims 9 to 15 comprising the steps of:

dissolving lubiprostone in a first solvent to form a homogeneous solution, the first solvent selected from the group consisting of: ortho-xylene, meta-xylene, and mixtures thereof;

reducing the temperature and/or adding a second solvent to the homogeneous solution until a phase separated fluid is formed at the bottom, the second solvent selected from the group consisting of: pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof;

removing the upper clear solution by suction and collecting the remaining phase separated fluid; and

the phase separation fluid was evaporated under high vacuum until a precipitate formed.

17. The method of claim 16, further comprising the steps of: optionally seeding the pipetting step with lubiprostone crystals V.

18. The method of claim 16, further comprising the steps of:

adding the second solvent to rinse the precipitate;

filtering the precipitate, thereby isolating said lubiprostone crystals V; and

optionally drying the lubiprostone crystals V.

19. A process for preparing lubiprostone crystal V of any one of claims 9 to 15 comprising the steps of:

dissolving lubiprostone in a third solvent to form a homogeneous solution, the third solvent selected from the group consisting of: o-xylene, m-xylene, ethyl ether, isopropyl ether, methyl tert-butyl ether, and mixtures thereof;

reducing the temperature and/or adding a fourth solvent selected from the group consisting of: pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof;

seeding with lubiprostone crystals V; and

stirring until a precipitate forms.

20. The method of claim 19, further comprising the steps of:

filtering the precipitate, thereby isolating said lubiprostone crystals V; and

optionally drying the lubiprostone crystals V.

Technical Field

The present invention relates to a novel lubiprostone crystal and a method for preparing the same, and more particularly, to a high purity lubiprostone crystal and a method for preparing the same.

Background

Lubiprostone is a medicine for treating diseases such as chronic idiopathic constipation, constipation related to acute irritable bowel syndrome and opioid-induced constipation

The active pharmaceutical ingredient of (1). Lubiprostone is classified as the less stable prostaglandin E1, which degrades easily and quickly to prostaglandin a1 (hereinafter referred to as impurity a) under acidic or basic conditions, or even at room temperature, as shown in scheme a below:

procedure A

Thus, a certain amount of impurity a is generated during the preparation and purification process of lubiprostone, as shown in scheme a. Impurity a is considered to be the major degradation product or major impurity of lubiprostone. Although impurity a can be removed by silica gel chromatography, additional impurity a is again produced in the purified lubiprostone solution during the subsequent high temperature, long time concentration process. In view of this, it can be seen that the best and final purification step for the commercial production of lubiprostone is a crystallization process that does not require high temperature or long time concentration processes.

Many prior art methods have disclosed the crystallization of lubiprostone, but none of them disclose the impurity a content before or after crystallization. The prior art has focused on the type of crystalline form of lubiprostone. Therefore, the advantages for purifying lubiprostone by conventional crystallization methods cannot be evaluated based on prior art.

For example, WO 2009/121228 discloses a crystalline form of lubiprostone (hereinafter lubiprostone crystals I) that can be made using various low boiling point solvent systems, such as ethyl acetate/n-hexane, acetone/n-hexane, dichloromethane/n-hexane, isopropanol/n-hexane, acetone/water, and methanol/water. Since the low-boiling solvent can be easily removed from the resulting crystal by evaporation alone, it is commonly used in the crystallization method. Lubiprostone crystal I has an X-ray powder diffraction pattern and a differential scanning calorimetry pattern substantially as shown in figure 1, the differential scanning calorimetry pattern comprising an endothermic peak having a peak onset temperature of 59.34 ℃ and a peak maximum of 60.97 ℃.

US 2010/056808 discloses a crystalline lubiprostone (hereinafter lubiprostone crystalline II) prepared by the solvent system isopropyl acetate/heptane. US 2010/056808 teaches that two crystallographically independent molecules, chiral isomers, are found by light microscopy in the unit cell of lubiprostone crystal II. US 2010/056808 further discloses calculation of an ideal powder map from the single crystal data; this figure is shown in fig. 2 and 3. By comparison, the graph shown in fig. 3 was found to be substantially identical to fig. 1, and it can be seen that polymorph B of lubiprostone shown in fig. 3 (i.e., fig. 3 of US 2010/056808) may be identical to lubiprostone crystal I. However, US 2010/056808 does not directly illustrate the X-ray powder diffraction spectrum of lubiprostone crystal II. Furthermore, US 2010/056808 does not teach the ratio of the contents of the two enantiomers nor which crystal form of lubiprostone the enantiomer is in.

WO 2011/091513 discloses another crystalline form of lubiprostone, APO-II (hereinafter lubiprostone crystal III), having an X-ray powder diffraction pattern and a differential scanning calorimetry thermogram comprising an endothermic peak having a peak onset temperature of about 76 ℃ and a peak maximum of about 77 ℃, substantially as shown in figure 4.

CN 104710398 discloses another crystalline form of lubiprostone (hereinafter lubiprostone crystal IV) having an X-ray powder diffraction pattern substantially as shown in figure 5 and a differential scanning calorimetry pattern comprising a peak maximum at 58 ± 2 ℃.

Therefore, there is a need to develop a crystallization process that can efficiently and economically produce high purity lubiprostone crystals that can effectively reduce or avoid unwanted impurities, especially impurity a, or can easily remove impurities during the crystallization purification process.

Disclosure of Invention

The present inventors have conducted a series of studies in view of the above problems, and have unexpectedly found that a novel crystalline form of lubiprostone having high purity can be obtained using a high boiling point solvent. The present invention relates at least in part to two crystalline forms of lubiprostone, one form obtained by precipitation using ortho-xylene or meta-xylene, hereinafter referred to as lubiprostone crystals V, and the other form obtained by precipitation using para-xylene, hereinafter referred to as lubiprostone crystals VI; the invention also relates to a process for preparing lubiprostone crystal V and lubiprostone crystal VI.

In one aspect, the present invention provides a process for preparing lubiprostone crystals V comprising: dissolving lubiprostone in a first solvent to form a homogeneous solution, the first solvent selected from the group consisting of: ortho-xylene, meta-xylene, and mixtures thereof; reducing the temperature and/or adding a second solvent to the homogeneous solution until a phase separated fluid is formed at the bottom, the second solvent selected from the group consisting of: pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof; pipetting out the supernatant solution and collecting the remaining phase separated fluid; and evaporating the phase separated fluid under high vacuum until a precipitate is formed.

The present invention further provides a process for preparing lubiprostone crystal V, comprising: dissolving lubiprostone in a third solvent to form a homogeneous solution, the third solvent selected from the group consisting of: o-xylene, m-xylene, ethyl ether, isopropyl ether, methyl tert-butyl ether, and mixtures thereof; reducing the temperature and/or adding a fourth solvent to the homogenous solution, the fourth solvent selected from the group consisting of: pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof; seeding with lubiprostone crystals V; and stirring until a precipitate is formed.

In one aspect, the invention provides lubiprostone crystal V having an X-ray powder diffraction (XRPD) pattern exhibiting its five most intense characteristic peaks at the following 2 Θ reflection angles: 6.5 + -0.2 deg., 13.2 + -0.2 deg., 15.6 + -0.2 deg., 18.9 + -0.2 deg., and 20.2 + -0.2 deg., wherein a half-peak width of a characteristic peak at a 2 theta reflection angle is between about 0.3 deg. and about 2 deg..

In another aspect, the present invention provides a process for preparing lubiprostone crystals VI comprising dissolving lubiprostone in paraxylene to form a homogeneous solution; reducing the temperature and/or adding a solvent selected from the group consisting of: pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof; and stirring until a precipitate is formed.

The invention also provides lubiprostone crystal VI having an X-ray powder diffraction pattern showing its five most intense peaks at the following 2-theta reflection angles: 7.5 +/-0.2 degrees, 10.3 +/-0.2 degrees, 13.9 +/-0.2 degrees, 18.7 +/-0.2 degrees and 21.1 +/-0.2 degrees.

In another aspect, the present invention provides novel lubiprostone crystals suitable for use in the manufacture of high purity lubiprostone by crystallization.

Brief description of the drawings

FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of lubiprostone crystal I.

FIG. 2 is an ideal X-ray powder diffraction (XRPD) pattern calculated from single crystal data of lubiprostone crystal II.

FIG. 3 is another idealized X-ray powder diffraction (XRPD) pattern calculated from single crystal data for lubiprostone crystal II.

Figure 4 shows an X-ray powder diffraction (XRPD) pattern of lubiprostone crystal III.

Figure 5 shows an X-ray powder diffraction (XRPD) pattern of lubiprostone crystal IV.

FIG. 6 shows an X-ray powder diffraction (XRPD) pattern of lubiprostone crystal V.

FIG. 7 shows a Differential Scanning Calorimetry (DSC) thermogram of lubiprostone crystal V.

FIG. 8 shows a Fourier Transform Infrared (FTIR) spectrum of lubiprostone crystal V.

FIG. 9 shows an X-ray powder diffraction (XRPD) pattern for lubiprostone crystal VI.

FIG. 10 shows a Differential Scanning Calorimetry (DSC) thermogram of lubiprostone crystal VI.

11(a) to 11(h) show XRPD patterns of lubiprostone crystals from an isopropyl acetate/heptane system at (a)30 ℃, 18h, 100 rpm; (b)25 ℃, 18h, 100 rpm; (c)20 ℃, 18h and 100 rpm; (d)10 ℃, 18h and 100 rpm; (e)0 ℃, 18h and 100 rpm; (f)20 ℃, 18h and 50 rpm; (g)20 ℃, 18h and 200 rpm; and (h)20 ℃, 18h, 250 rpm.

Fig. 12(a) and 12(b) show the crystalline form conversion of lubiprostone crystal V stirred in isopropyl acetate/heptane for (a)20 ℃, 0h and (b)20 ℃, 2 h.

Detailed Description

As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. The use of any and all examples, or exemplary language (such as) and (e) herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention, nor is the language in the specification necessarily to be construed as indicating any non-claimed method or condition as essential to the practice of the invention.

Lubiprostone crystal V and preparation thereof

In the present invention, a method for producing lubiprostone crystal V comprises the steps of:

(a) dissolving crude lupbiprostone in a first solvent to form a homogeneous solution, the first solvent selected from the group consisting of: ortho-xylene, meta-xylene, and mixtures thereof.

(b) Reducing the temperature and/or adding a second solvent to the homogeneous solution until a phase separated fluid is formed at the bottom, the second solvent selected from the group consisting of: pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof;

(c) removing the upper clear solution by suction and collecting the remaining phase separated fluid;

(d) optionally seeding with lubiprostone crystals V;

(e) evaporating the phase separated fluid under high vacuum until a precipitate is formed;

(f) adding a second solvent to rinse the precipitate;

(g) filtering the precipitate, thereby isolating the lubiprostone crystals V; and

(h) optionally drying the lubiprostone crystals V.

The choice of the first solvent is critical to whether and/or the kind of crystalline form of lubiprostone obtained is available. In the present invention, the first solvent for dissolving crude lupbiprostone is selected from the group consisting of: ortho-xylene, meta-xylene and mixtures thereof, preferably ortho-xylene. The volume of the first solvent is in the range of about 0.5ml to about 10ml, preferably about 1ml to about 5ml, and more preferably about 1.5ml to about 4ml per 1g of crude lupeol prostate ketone. The crude lupbiprostone may be dissolved in the first solvent at a temperature in the range of from about 0 ℃ to about 80 ℃, preferably from about 20 ℃ to about 70 ℃, and more preferably from room temperature to about 60 ℃.

In a preferred embodiment, the second solvent is selected from the group consisting of: pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane and mixtures thereof, and preferably n-pentane, n-hexane, cycloheptane, n-heptane and mixtures thereof. The volume of the second solvent is in the range of about 0.5ml to about 30ml, preferably about 1ml to about 15ml, and more preferably about 2ml to about 10ml per 1ml of the first solvent. The second solvent may be added at a temperature in the range of about-10 ℃ to about 80 ℃, preferably about-5 ℃ to about 60 ℃, and more preferably about 0 ℃ to about 30 ℃.

In one embodiment of the invention, the temperature of the homogeneous solution is reduced to a temperature in the range of about-10 ℃ to about 40 ℃, preferably about 0 ℃ to about 30 ℃, and more preferably about 10 ℃ to about 25 ℃.

In one embodiment of the invention, the precipitation of crystals may be carried out at a temperature in the range of about-10 ℃ to about 40 ℃, preferably about 0 ℃ to about 30 ℃, and more preferably about 10 ℃ to about 25 ℃.

In one embodiment of the invention, the step of evaporating the phase separated fluid may be at about 10 deg.f^-4About 25 torr, preferably about 10 torr^-2About 10 torr, and preferably about 10 torr^-1Under reduced pressure of about 1 torr.

The foregoing process can directly produce novel lubiprostone crystals V in substantially single crystal form without the addition of any seed crystals and free of any other crystalline form of lubiprostone. The lubiprostone crystal V thus produced can be used as a seed for replicating the lubiprostone crystal V.

The present invention further provides a method for replicating lubiprostone crystal V, comprising the steps of:

(a) dissolving lubiprostone in a third solvent to form a homogeneous solution, the third solvent selected from the group consisting of: o-xylene, m-xylene, ethyl ether, isopropyl ether, methyl tert-butyl ether, and mixtures thereof;

(b) reducing the temperature and/or adding a fourth solvent to the homogenous solution, the fourth solvent selected from the group consisting of: pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof;

(c) seeding with lubiprostone crystals V;

(d) stirring until a precipitate is formed;

(e) filtering the precipitate, thereby isolating the lubiprostone crystals V; and

(f) optionally drying the lubiprostone crystals V.

In one embodiment of the invention, the third solvent is selected from the group consisting of: o-xylene, m-xylene, ethyl ether, isopropyl ether, methyl tert-butyl ether and mixtures thereof, preferably isopropyl ether. The volume of the third solvent is in the range of about 0.5ml to about 10ml, preferably about 1ml to about 5ml, and more preferably about 1.5ml to about 4ml per 1g of crude lupeol prostate ketone. The crude lupbiprostone may be dissolved in the third solvent at a temperature in the range of from about 0 ℃ to about 80 ℃, preferably from about 20 ℃ to about 70 ℃, and more preferably from room temperature to about 60 ℃.

In one embodiment of the present invention, the fourth solvent is selected from the group consisting of: pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane and mixtures thereof, and preferably n-pentane, n-hexane, cycloheptane, n-heptane and mixtures thereof. The volume of the fourth solvent is in the range of about 0.5ml to about 30ml, preferably about 1ml to about 15ml, and more preferably about 2ml to about 10ml per 1ml of the third solvent. The fourth solvent may be added at a temperature in the range of about-50 ℃ to about 80 ℃, preferably about-10 ℃ to about 60 ℃, and more preferably about 0 to about 30 ℃.

In one embodiment of the invention, the temperature of the homogeneous solution may be reduced to a temperature in the range of about-30 ℃ to about 40 ℃, preferably about-10 ℃ to about 30 ℃, and more preferably about 10 ℃ to about 25 ℃.

The precipitation of crystals may be carried out at a temperature in the range of about-10 ℃ to about 40 ℃, preferably about 0 ℃ to about 30 ℃, and more preferably about 10 ℃ to about 25 ℃.

The step of filtering the precipitate includes washing the precipitate with a fourth solvent or a mixture of the third solvent and the fourth solvent. The mixed solvent may contain the third solvent and the fourth solvent in a ratio of about 1:1 to about 1:100, preferably about 1:1 to about 1: 10.

In this method, the third solvent is critical in determining whether lubiprostone crystals V can be directly replicated using seed crystals of lubiprostone crystals V. For example, the inventors have found that when an ester such as isopropyl acetate is used as the third solvent, lubiprostone crystals V rapidly convert to lubiprostone crystals I; therefore, the solvent cannot be used to replicate lubiprostone crystals V. Even if a large amount of lubiprostone crystals V is used as a seed crystal, lubiprostone crystals V cannot be obtained. However, the present inventors have surprisingly found that using o-xylene, m-xylene, ethyl ether, isopropyl ether or methyl tert-butyl ether as the third solvent, lubiprostone crystals V are very stable and very unlikely to be converted into lubiprostone crystals I. Based on this method, lubiprostone crystal V of high purity can be obtained in the presence of seed crystals of lubiprostone crystal V. If seed crystals of lubiprostone crystal V are not added, the process produces only lubiprostone crystal I or a mixture of lubiprostone crystal I and lubiprostone crystal V. In addition, the crystal V of lubiprostone is substantially free of the impurity A regardless of the content of the impurity A contained in the seed crystal of lubiprostone crystal V or crude lubiprostone. In other words, the crystallization process is effective in removing impurity A from seed crystals of crude lubiprostone and lubiprostone.

In one embodiment of the invention, lubiprostone crystal V has an XRPD pattern exhibiting its five most intense characteristic peaks at the following 2 θ reflection angles: 6.5 +/-0.2 degrees, 13.2 +/-0.2 degrees, 15.6 +/-0.2 degrees, 18.9 +/-0.2 degrees and 20.2 +/-0.2 degrees. In a preferred embodiment, the XRPD pattern further comprises characteristic peaks at the following 2 θ reflection angles: 10.8 +/-0.2 degrees, 14.0 +/-0.2 degrees, 14.8 +/-0.2 degrees, 16.0 +/-0.2 degrees, 17.8 +/-0.2 degrees, 21.0 +/-0.2 degrees and 21.4 +/-0.2 degrees. More preferably, the XRPD pattern of lubiprostone crystal V is in accordance with fig. 6. Specific data for lubiprostone crystal V are shown in table 1 below.

TABLE 1

In one embodiment, the invention provides lubiprostone crystal V having an XRPD pattern exhibiting its five most intense characteristic peaks at the following 2 Θ reflection angles: 6.5 + -0.2 deg., 13.2 + -0.2 deg., 15.6 + -0.2 deg., 18.9 + -0.2 deg., and 20.2 + -0.2 deg., wherein the half-peak width of the characteristic peak at 2 theta reflection angle is between about 0.3 and about 2 deg..

In one embodiment, the invention provides lubiprostone crystal V having an XRPD pattern substantially as shown in figure 6.

The lubiprostone crystals V produced by the process of the invention are substantially in single crystal form and do not contain any other crystalline forms, such as lubiprostone crystals I. As shown in fig. 6, there is only one characteristic peak at 2 θ reflection angle between 2 ° and 10 ° (i.e., at 6.5 ± 0.2 °), but there is no characteristic peak at 7.6 ± 0.2 ° (one characteristic peak of lubiprostone crystal I). In a preferred embodiment, the invention provides lubiprostone crystal V having an XRPD pattern exhibiting its five most intense characteristic peaks at the following 2 Θ reflection angles: 6.5 + -0.2 DEG, 13.2 + -0.2 DEG, 15.6 + -0.2 DEG, 18.9 + -0.2 DEG and 20.2 + -0.2 DEG, and substantially does not contain a characteristic peak at a 2 theta reflection angle of 7.6 + -0.2 deg. In the present invention, the term "substantially free" or "substantially free" means that the peak intensity at 7.6 ± 0.2 ° is less than 5%, preferably less than 1%, of the peak intensity at 6.5 ± 0.2 ° in the XRPD pattern.

In one embodiment, the present invention provides lubiprostone crystal V having a Differential Scanning Calorimetry (DSC) thermogram comprising an endothermic peak with a peak onset temperature of 60.6 + -1 ℃ and a peak maximum of 64.7 + -1 ℃.

In one embodiment, the present invention provides lubiprostone crystal V having a DSC thermogram substantially as shown in figure 7.

In one embodiment, the invention provides lubiprostone crystals V having a size in cm^-1Representing a 1% KBr Fourier Transform Infrared (FTIR) spectrum comprising peaks at 3388 + -4, 2938 + -4, 2872 + -4, 1729 + -4, 1713 + -4, 1415 + -4, 1247 + -4, 1222 + -4, 1207 + -4, 1180 + -4, 1105 + -4, 1091 + -4, 1060 + -4, 1006 + -4, 987 + -4, 918 + -4, 761 + -4 and 723 + -4.

In one embodiment, the invention provides lubiprostone crystals V having a 1% KBr FTIR spectrum substantially as shown in figure 8.

The lubiprostone crystals V of the invention contain no more than about 0.3%, preferably no more than about 0.2% or about 0.1% of impurity a, and more preferably contain undetectable levels of impurity a, as determined by the HPLC method, which has a detection limit of more than 0.02%.

Furthermore, the lubiprostone crystals V of the invention show good stability and are free of degradation products of other crystalline forms or of impurity a, even after six months of storage at the typical storage temperature of lubiprostone (about-20 ℃).

Lubiprostone crystal VI and preparation thereof

In one embodiment, the process of the present invention for preparing lubiprostone crystal VI comprises the steps of:

(a) dissolving crude lupbiprostone in paraxylene to form a homogeneous solution;

(b) reducing the temperature and/or adding a fifth solvent to the homogenous solution, the fifth solvent selected from the group consisting of: pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof;

(c) optionally seeding with lubiprostone crystals VI;

(d) stirring the mixture until precipitation occurs, whereby a precipitate is formed;

(e) filtering the precipitate, thereby isolating the lubiprostone crystals VI; and

(f) optionally drying the lubiprostone crystals VI.

In one embodiment, the volume of paraxylene ranges from about 0.5ml to about 10ml, preferably from about 1ml to about 5ml, and more preferably from about 1.5ml to about 4ml, per 1g of crude lupetaprost. Crude lupbiprostone may be dissolved in paraxylene at a temperature in the range of about 10 ℃ to about 80 ℃, preferably about 20 ℃ to about 70 ℃, and more preferably about room temperature to about 60 ℃.

In one embodiment, the fifth solvent is selected from the group consisting of: pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane and mixtures thereof, and preferably n-pentane, n-hexane, cycloheptane, n-heptane and mixtures thereof. The volume of the fifth solvent is in the range of about 0.5ml to about 30ml, preferably about 1ml to about 15ml, and preferably about 2ml to about 10ml per 1ml of p-xylene. The solvent may be added at a temperature in the range of about 10 ℃ to about 80 ℃, preferably about 15 ℃ to about 60 ℃, and more preferably about 20 ℃ to about 50 ℃.

In one embodiment of the invention, the temperature of the homogeneous solution may be reduced to a temperature in the range of about 0 ℃ to about 40 ℃, preferably about 15 ℃ to about 30 ℃, and more preferably about 15 ℃ to about 25 ℃.

The crystal precipitation may be conducted at a temperature in the range of about 10 ℃ to about 40 ℃, preferably about 12 ℃ to about 30 ℃, and more preferably about 15 ℃ to about 25 ℃.

The step of filtering the precipitate also includes washing the precipitate with a fifth solvent or a mixture of p-xylene and a fifth solvent. The content ratio of p-xylene to the fifth solvent in the mixed solvent is about 1:1 to about 1:100, preferably about 1:1 to about 1: 10.

The lubiprostone crystals VI produced by the aforementioned process of the invention are substantially in single crystal form and contain low amounts or even are substantially free of impurity a.

In the present invention, lubiprostone crystal VI has an XRPD pattern exhibiting its five most intense characteristic peaks at the following 2 θ reflection angles: 7.5 +/-0.2 degrees, 10.3 +/-0.2 degrees, 13.9 +/-0.2 degrees, 18.7 +/-0.2 degrees and 21.1 +/-0.2 degrees. More preferably, the XRPD pattern of lubiprostone crystal VI is in accordance with fig. 9. Specific data for lubiprostone crystal VI are shown in table 2 below.

TABLE 2

In one embodiment, the present invention provides lubiprostone crystal VI having a DSC thermogram comprising an endothermic peak with a peak onset temperature of about 47.4 ± 1 ℃ and a peak maximum of about 50.7 ± 1 ℃. In a preferred embodiment, the present invention provides lubiprostone crystal VI having a DSC thermogram substantially as shown in figure 10.

The lubiprostone crystals VI of the present invention contain no more than about 0.3%, preferably no more than about 0.2%, preferably no more than about 0.1% of impurity a, and more preferably contain undetectable levels of impurity a, as determined by the HPLC method, which has a detection limit of more than 0.02%.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

Examples of the invention

X-ray powder diffraction (XRPD) analysis: XRPD patterns were collected on a Bruker D2 PHASER diffractometer with a fixed divergence slit and a 1D LYNXEYE detector. The sample (approximately 100mg) was placed flat on the specimen holder. Using CuK_αThe prepared samples were analyzed by irradiation at an energy of 10mA and 30kV in the 2 theta range of 5 DEG to 50 DEG step size of 0.02 DEG and step time of 1 second. CuK removal by diverging beam nickel filter_βAnd (4) irradiating.

Differential Scanning Calorimetry (DSC) analysis: DSC images were collected on a TA discover DSC25 instrument. The sample (approximately 5mg) was weighed into an aluminum pan with a crimped-on aluminum lid. The prepared samples were analyzed from 10 ℃ to 100 ℃ under a nitrogen flow (approximately 50ml/min) at a scan rate of 10 ℃/min. The melting point temperature and the heat of fusion were calibrated by indium (In) before measurement.

Fourier Transform Infrared (FTIR) analysis: FTIR spectra were collected on a Perkin Elmer SPECTRUM 100 instrument. The sample was mixed with potassium bromide (KBr) using an agate mortar and pestle at a ratio (w/w) of about 1: 100. At about 1The mixture is pressed into the granulation die under a pressure of 0 to 13 tons for 2 minutes. At 4cm^-1From 4000cm at resolution^-1To 650cm^-1The resulting disc was scanned 4 times against the collected background. Data were baseline corrected and normalized.

Example 1

Preparation of crude lubiprostone

4-methoxybenzyl 7- [ (2R,4aR,5R,7aR) -2- (1, 1-difluoro-pentyl) -octahydro-2-hydroxy-6-ketocyclopenta [ b ] pyran-5-yl) heptanoate (60g, 117.5mmol, enantiomeric purity ≥ 99%) is dissolved in 600ml ethyl acetate and then 5% palladium on activated carbon is added under hydrogen for 3 hours. Subsequently, the reaction mixture was filtered through a pad of celite. The solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exsolution to obtain 40g lubiprostone as an oil. HPLC analysis of the product showed 1.1% impurity a.

Example 2

Preparation of lubiprostone crystals VI

Oily robepristone (0.51g from example 1) and p-xylene (1.0ml) were heated at 40 ℃ to dissolve and then cooled to room temperature. N-pentane solvent (1.0ml) was slowly added dropwise and the mixture was stirred in an ice-water bath for 1 hour until solid precipitation occurred. The resulting suspension was filtered and washed, and then dried at room temperature under high vacuum for 4 hours to give 0.38g lubiprostone crystal VI. HPLC analysis of the product showed no impurity a. XRPD and DSC results are shown in fig. 9 and 10.

Example 3

Preparation of lubiprostone crystals VI

Oily robepristone (0.52g from example 1) and p-xylene (1.3ml) were heated at 40 ℃ to dissolve and then cooled to room temperature. The mixture was stirred in an ice-water bath for 1 hour until solid precipitation occurred. The resulting suspension was filtered and washed, and then dried under high vacuum at room temperature for 4 hours to give 0.41g lubiprostone crystal VI. HPLC analysis of the product showed no impurity a. The XRPD and DSC results are the same as shown in fig. 9 and 10.

Example 4

Preparation of lubiprostone crystals VI

Oily robepristone (0.50g from example 1) and p-xylene (1.0ml) were heated at 40 ℃ to dissolve and then cooled to room temperature. N-pentane solvent (1.0ml) was slowly added dropwise and the mixture was stirred for 1 hour until solid precipitation occurred. Subsequently, the resulting suspension was filtered and washed, and then dried under high vacuum at room temperature for 4 hours to give 0.41g lubiprostone crystal VI. HPLC analysis of the product showed no impurity a. The XRPD and DSC results are the same as shown in fig. 9 and 10.

Example 5

Preparation of lubiprostone crystals VI

Oily robepristone (0.20g from example 1) and p-xylene (1.0ml) were heated at 40 ℃ to dissolve and then cooled to room temperature. N-hexane solvent (1.0ml) was slowly added dropwise and the mixture was stirred for 1 hour until solid precipitation occurred. The resulting suspension was filtered and washed, and then dried under high vacuum at room temperature for 4 hours to give 0.14g lubiprostone crystal VI. HPLC analysis of the product showed no impurity a. The XRPD and DSC results are the same as shown in fig. 9 and 10.

Example 6

Preparation of lubiprostone crystals V

Oily robepristone (0.20g from example 1) and o-xylene (0.5ml) were heated at 40 ℃ to dissolve and then cooled to room temperature. N-pentane solvent (1.0ml) was slowly added dropwise and the mixture was stirred in an ice-water bath for 2 hours until a phase separated fluid was formed. The phase separated fluid was then separated and evaporated at ambient temperature under vacuum until solid precipitation occurred. The resulting precipitate was washed with 1.0ml of n-pentane and isolated by filtration and dried under vacuum at ambient temperature to give 0.10g lubiprostone crystals V. HPLC analysis of the product showed 0.21% impurity a. XRPD, DSC, and FTIR results are shown in fig. 6, 7, and 8.

Example 7

Preparation of lubiprostone crystals V

Oily robepristone (0.20g from example 1) and o-xylene (0.5ml) were heated at 40 ℃ to dissolve and then cooled to room temperature. N-pentane solvent (1.0ml) was slowly added dropwise and the mixture was stirred for 2 hours until a phase separated fluid was formed. The phase separated fluid was then separated and evaporated at ambient temperature under vacuum until solid precipitation occurred. The resulting precipitate was washed with 1.0ml of n-pentane and isolated by filtration and dried under vacuum at ambient temperature to give 0.12g lubiprostone. XRPD, DSC, and FTIR results were the same as shown in fig. 6, 7, and 8. HPLC analysis of the product showed 0.18% impurity a.

Example 8

Preparation of lubiprostone crystals V

Oily robepristone (0.20g from example 1) and m-xylene (0.5ml) were heated at 40 ℃ to dissolve and then cooled to room temperature. N-heptane solvent (1.0ml) was slowly added dropwise and stirred for half an hour until a phase separated fluid was formed. The phase separated fluid was then separated and evaporated under vacuum at ambient temperature until solid precipitation occurred. The resulting precipitate was washed with 1.0ml of n-heptane and isolated by filtration and dried under vacuum at ambient temperature to give 0.11g lubiprostone crystals. XRPD, DSC, and FTIR results were the same as shown in fig. 6, 7, and 8. HPLC analysis of the product showed 0.1% impurity a.

Example 9

Replicating lubiprostone crystals V

Oily robepristone (0.50g from example 1) and o-xylene (2.0ml) were heated at 40 ℃ to dissolve and then cooled to room temperature. N-pentane solvent (4.0ml) was slowly added dropwise and then seed crystals (10mg, crystal V prepared as in example 6) were added and the mixture was stirred for 1 hour until solid precipitation occurred. The resulting suspension was filtered and washed, and then dried under high vacuum at room temperature for 4 hours to give lubiprostone crystal V (0.32 g). XRPD, DSC, and FTIR results were the same as shown in fig. 6, 7, and 8. HPLC analysis of the product showed no impurity a.

Example 10

Replicating lubiprostone crystals V

Oily robepristone (0.20g from example 1) and isopropyl ether (0.6ml) were heated at 40 ℃ to dissolve and then cooled to room temperature. N-heptane solvent (0.6ml) was slowly added dropwise, and then seed crystals (10mg, crystal V prepared as in example 6) were added and the mixture was stirred for 1 hour until solid precipitation occurred. The resulting suspension was filtered and washed and then dried under high vacuum for half an hour at room temperature to give lubiprostone crystals V (0.11 g). XRPD, DSC, and FTIR results were the same as shown in fig. 6, 7, and 8. HPLC analysis of the product showed no impurity a.

Example 11

Replicating lubiprostone crystals V

Oily robepristone (0.20g from example 1) and methyl tert-butyl ether (0.6ml) were heated at 40 ℃ to dissolve and then cooled to room temperature. N-pentane solvent (0.6ml) was slowly added dropwise and then seed crystals (10mg, crystal V prepared as in example 6) were added and the mixture was stirred for 1 hour until solid precipitation occurred. The resulting suspension was filtered and washed, and then dried under high vacuum at room temperature for half an hour to give lubiprostone crystals V (0.10 g). XRPD, DSC, and FTIR results were the same as shown in fig. 6, 7, and 8. HPLC analysis of the product showed no impurity a.

Example 12

Replicating lubiprostone crystals V

Oily robepristone (0.20g from example 1) and ethyl ether (0.6ml) were heated at 40 ℃ to dissolve and then cooled to room temperature. N-hexane solvent (0.8ml) was slowly added dropwise, and then seed crystals (10mg, crystal V prepared as in example 6) were added and the mixture was stirred for 1 hour until solid precipitation occurred. The resulting suspension was filtered and washed and then dried under high vacuum for half an hour at room temperature to give lubiprostone crystals V (0.14 g). XRPD, DSC, and FTIR results were the same as shown in fig. 6, 7, and 8. HPLC analysis of the product showed no impurity a.

Example 13

Reconstitution of lubiprostone crystals II according to paragraph [0038] of the specification of US 2010/056808

Oily lubiprostone (0.20g from example 1, > 99% enantiomeric purity) and isopropyl acetate (0.16ml, 0.8 parts) were heated at 40 ℃ to dissolve and then cooled to 30 ℃, 25 ℃, 20 ℃, 10 ℃ and 0 ℃ respectively. Heptane (0.84ml, 4.2 parts) was slowly added dropwise and the mixture was stirred (at 50, 100, 200 or 250 rpm) for 18 hours until solid precipitation occurred at 30 ℃, 25 ℃, 20 ℃, 10 ℃ and 0 ℃ respectively. The resulting suspension was filtered and washed, and then dried under high vacuum at room temperature to give lubiprostone crystals II. XRPD results are shown in fig. 11(a) to 11 (h).

As shown in fig. 11(a) to 11(h), only the graphs shown in fig. 1 and 3 (lubiprostone crystal I) can be seen in the XRPD graphs of fig. 11(a) to 11(h), but not the graph shown in fig. 2. It can be seen that figures 1 and 3 (figure 3 of US 2010/056808) relate to the XRPD pattern of the crystalline form of lubiprostone, whereas figure 2 (figure 2 of US 2010/056808) relates to the XRPD pattern of the enantiomer of lubiprostone. This is because the oily robustone used in this example contains only less than 1% of the enantiomer, which is below the detection limit of XRPD analysis, so the antipodal isomer of robustone cannot be seen in all XRPD patterns. It is thus demonstrated that figure 2 of US 2010/0056808 shows an XRPD pattern of the chiral isomer of lubiprostone, rather than the crystalline form of lubiprostone.

Thus, although the XRPD pattern of lubiprostone crystal V shown in figure 6 is similar to figure 2, the polymorph a shown in figure 2 of US 2010/056808 is the chiral isomer of lubiprostone, rather than the single crystal form of lubiprostone crystal V. In addition, it can be found that the main difference between fig. 2 and fig. 6 is the half-peak width of the characteristic peak at 2 θ reflection angle. The half-peak width at 2 theta reflection of lubiprostone crystal V is between about 0.3 ° and about 2 °, but the half-peak width at 2 theta reflection is less than 0.3 ° as shown in fig. 2, meaning that the average crystal sizes of lubiprostone crystal V and the chiral isomer of lubiprostone are not the same.

Example 14

Conversion of crystalline forms of lubiprostone

Lubiprostone crystal V (0.20g from example 9) was added to a mixture of isopropyl acetate (0.16ml) and heptane (0.84ml) (i.e. the solvent system for crystallization of US 2010/056808) and the mixture was stirred at 20 ℃ for 2 hours. The resulting suspension was filtered and washed, and then dried under high vacuum at room temperature to give lubiprostone crystals I. XRPD results are shown in fig. 12(a) and 12 (b).

As shown in fig. 12(a) and 12(b), the crystalline form of lubiprostone crystal V has completely converted to the crystalline form shown in fig. 1 and 3 (lubiprostone crystal I) within only two hours. This result demonstrates that the lubiprostone crystal II disclosed in US 2010/056808 does not contain any lubiprostone crystal V, since lubiprostone crystal V is unlikely to exist during the 18 hours of crystallization disclosed in US 2010/056808. Thus, the lubiprostone crystal V of the present invention is a novel crystalline form of lubiprostone, and the crystalline form shown in fig. 2 found by light microscopy in the unit cell of lubiprostone crystal II is the chiral isomer of lubiprostone, not lubiprostone crystal V.

Although the present invention has been described with reference to illustrative examples, it is to be understood that any modifications or alterations that may be readily accomplished by those skilled in the art will be within the scope of the disclosure of this specification and the appended claims.