Hexadecyl Treprostinil crystals and methods for preparation thereof
10781160 ยท 2020-09-22
Assignee
Inventors
Cpc classification
C07C69/736
CHEMISTRY; METALLURGY
C07C2603/14
CHEMISTRY; METALLURGY
C07C69/736
CHEMISTRY; METALLURGY
C07C67/52
CHEMISTRY; METALLURGY
International classification
C07C69/736
CHEMISTRY; METALLURGY
Abstract
There is provided stable crystalline Form I and Form II of Hexadecyl Treprostinil (C.sub.16TR) and processes for the preparation thereof. The stable crystalline Form I and Form II of Hexadecyl Treprostinil present advantages in storage, formulation, shipment and handling for commercially considerations.
Claims
1. A crystalline Form I of Hexadecyl Treprostinil, characterized by having an X-ray powder diffraction (XRPD) pattern comprising its six strongest characteristic peaks at the following 2 reflection angles: 3.30.2, 6.60.2, 14.20.2, 18.90.2, 21.30.2, and 22.50.2.
2. The crystalline Form I of Hexadecyl Treprostinil of claim 1, wherein the XRPD pattern further comprises characteristic peaks at the following 2 reflection angles: 13.80.2, 15.30.2, 16.90.2, 17.80.2, 19.80.2, 20.60.2, 20.90.2, 24.40.2, and 24.80.2.
3. The crystalline Form I of Hexadecyl Treprostinil of claim 1, wherein the XRPD pattern is substantially shown in
4. The crystalline Form I of Hexadecyl Treprostinil of claim 1, further having a differential scanning calorimetry (DSC) thermogram pattern comprising an endothermic peak with a peak onset temperature of approximately 52.21 C. and a peak maximum of approximately 54.51 C.
5. The crystalline Form I of Hexadecyl Treprostinil of claim 4, wherein the DSC thermogram pattern is substantially shown in
6. The crystalline Form I of Hexadecyl Treprostinil of claim 1, further having a 1% KBr Fourier transform infrared (FTIR) spectrum comprising peaks, in terms of cm.sup.1, at 34454 cm.sup.1, 34024 cm.sup.1, 29584 cm.sup.1, 29194 cm.sup.1, 28714 cm.sup.1, 28544 cm.sup.1, 17334 cm.sup.1, 16064 cm.sup.1, 15854 cm.sup.1, 14744 cm.sup.1, 14434 cm.sup.1, 14164 cm.sup.1, 13744 cm.sup.1, 13574 cm.sup.1, 13314 cm.sup.1, 13094 cm.sup.1, 12714 cm.sup.1, 12474 cm.sup.1, 12294 cm.sup.1, 12024 cm.sup.1, 11674 cm.sup.1, 11484 cm.sup.1, 11224 cm.sup.1, 10884 cm.sup.1, 10394 cm.sup.1, 10234 cm.sup.1, 10004 cm.sup.1, 9824 cm.sup.1, 9684 cm.sup.1, 9174 cm.sup.1, 8894 cm.sup.1, 7844 cm.sup.1, 7724 cm.sup.1, 7344 cm.sup.1, 7194 cm.sup.1, 7084 cm.sup.1.
7. The crystalline Form I of Hexadecyl Treprostinil of claim 6, wherein the FTIR spectrum is substantially shown in
8. A method for preparing the crystalline Form I of Hexadecyl Treprostinil according to claim 1, which comprises the steps of: dissolving Hexadecyl Treprostinil in a first solvent selected from the group consisting of ethyl ether, isopropyl ether, methyl tert-butyl ether, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, toluene, xylene, acetone, dichloromethane, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, propanol, butanol, benzyl alcohol, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, and mixtures thereof to form a homogenous solution, lowering the temperature and/or adding a second solvent selected from the group consisting of acetonitrile, water, and mixtures thereof to the homogenous solution; and stirring until a precipitate is formed.
9. The method of claim 8, further comprising the steps of: adding the second solvent or a mixture of the first solvent and the second solvent for rinsing the precipitate; filtering out the precipitate thereby isolating the crystalline Form I of Hexadecyl Treprostinil; and optionally drying the crystalline Form I of Hexadecyl Treprostinil.
10. A crystalline Form II of Hexadecyl Treprostinil, characterized by having an XRPD pattern comprising its six strongest characteristic peaks at the following 2 reflection angles: 3.40.2, 6.10.2, 9.40.2, 20.30.2, 21.60.2, and 23.40.2.
11. The crystalline Form II of Hexadecyl Treprostinil of claim 10, wherein the XRPD pattern further comprises characteristic peaks at the following 20 reflection angles: 7.00.2, 9.00.2, 12.20.2, 12.70.2, 17.50.2, 18.00.2, 18.50.2, 19.10.2, and 19.40.2.
12. The crystalline Form II of Hexadecyl Treprostinil of claim 10, wherein the XRPD pattern is substantially shown in
13. The crystalline Form II of Hexadecyl Treprostinil of claim 10, further having a DSC thermogram pattern comprising an endothermic peak with a peak onset temperature of approximately 54.61 C. and a peak maximum of approximately 56.91 C.
14. The crystalline Form II of Hexadecyl Treprostinil of claim 13, wherein the DSC thermogram pattern is substantially shown in
15. The crystalline Form II of Hexadecyl Treprostinil of claim 10, further having a 1% KBr FTIR spectrum comprising peaks, in terms of cm.sup.1, at 35154 cm.sup.1, 34434 cm.sup.1, 32914 cm.sup.1, 30344 cm.sup.1, 29534 cm.sup.1, 29224 cm.sup.1, 28514 cm.sup.1, 17694 cm.sup.1, 17304 cm.sup.1, 16054 cm.sup.1, 15844 cm.sup.1, 14694 cm.sup.1, 14564 cm.sup.1, 14374 cm.sup.1, 13954 cm.sup.1, 13714 cm.sup.1, 13474 cm.sup.1, 13304 cm.sup.1, 13114 cm.sup.1, 12954 cm.sup.1, 12864 cm.sup.1, 12714 cm.sup.1, 12594 cm.sup.1, 12354 cm.sup.1, 12184 cm.sup.1, 12094 cm.sup.1, 11894 cm.sup.1, 11714 cm.sup.1, 11484 cm.sup.1, 11154 cm.sup.1, 10704 cm.sup.1, 10534 cm.sup.1, 10304 cm.sup.1, 10194 cm.sup.1, 9894 cm.sup.1, 9464 cm.sup.1, 9264 cm.sup.1, 9094 cm.sup.1, 8934 cm.sup.1, 8784 cm.sup.1, 7904 cm.sup.1, 7654 cm.sup.1, 7264 cm.sup.1, 7044 cm.sup.1.
16. The crystalline Form II of Hexadecyl Treprostinil of claim 15, wherein the FTIR spectrum is substantially shown in
17. A method for preparing the crystalline Form II of Hexadecyl Treprostinil according to claim 10, which comprises the steps of: dissolving Hexadecyl Treprostinil in a third solvent selected from the group consisting of ethyl ether, isopropyl ether, methyl tert-butyl ether, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, toluene, xylene, acetone, dichloromethane, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, propanol, butanol, benzyl alcohol, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, and mixtures thereof to form a homogenous solution; lowering 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 to the homogenous solution; and stirring until a precipitate is formed.
18. The method of claim 17, further comprising the steps of: adding the fourth solvent or a mixture of the third solvent and the fourth solvent for rinsing the precipitate; filtering out the precipitate thereby isolating the crystalline Form II of Hexadecyl Treprostinil; and optionally drying the crystalline Form II of Hexadecyl Treprostinil.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
(1)
(2)
(3)
(4)
(5)
(6)
DETAILED DESCRIPTION OF THE INVENTION
(7) Hexadecyl Treprostinil Crystal Form I and Preparation Thereof
(8) In an embodiment of the present invention, the method for preparing Hexadecyl Treprostinil crystal Form I comprises the steps of: (a) dissolving crude Hexadecyl Treprostinil in a first solvent selected from the group consisting of ethyl ether, isopropyl ether, methyl tert-butyl ether, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, toluene, xylene, acetone, dichloromethane, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, propanol, butanol, benzyl alcohol, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, and mixtures thereof to form a homogenous solution; (b) lowering the temperature and/or adding a second solvent selected from the group consisting of acetonitrile, water, and mixtures thereof to the homogeneous solution; (c) stirring until a precipitate is formed; (d) filtering out the precipitate thereby isolating the Hexadecyl Treprostinil crystal Form I; and (e) optionally drying the Hexadecyl Treprostinil crystal Form I.
(9) In the present invention, the first solvent used to dissolve the crude Hexadecyl Treprostinil is selected from the group consisting of ethyl ether, isopropyl ether, methyl tert-butyl ether, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, toluene, xylene, acetone, dichloromethane, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, propanol, butanol, benzyl alcohol, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, and mixtures thereof, preferably ethanol and propanol. The volume of the first solvent depends on the types of the solvents used and may be about 0.5 ml to about 100 ml, preferably about 1 ml to about 50 ml, and more preferably about 2 ml to about 20 ml or about 5 ml to about 10 ml, per 1 g of the crude Hexadecyl Treprostinil. The crude Hexadecyl Treprostinil can be dissolved in the first solvent at a temperature ranging from about 0 C. to about 80 C., preferably from about 10 C. to so about 60 C., and more preferably from room temperature to about 40 C.
(10) In one embodiment of the present invention, the temperature of the homogenous solution is lowered to a temperature ranging from about 30 C. to about 50 C., preferably from about 20 C. to about 40 C., and more preferably from about 10 C. to about 30 C.
(11) The selection of the second solvent is the key to determine whether a Hexadecyl Treprostinil crystal Form I can be formed. In a preferred embodiment, the volume of the second solvent selected from the group consisting of acetonitrile, water, and mixtures thereof depends on the types of the solvents used and may be about 0.5 ml to about 200 ml, about 1 ml to about 150 ml, or about 2 ml to about 100 ml, per 1 ml of the first solvent. The second solvent can be added at a temperature ranging from about 30 C. to about 50 C., preferably from about 20 C. to about 40 C., and more preferably from about 10 C. to about 30 C.
(12) In one embodiment of the present invention, the precipitation of the crystal may be performed at a temperature ranging from about 30 C. to about 50 C., preferably from about 20 C. to about 40 C., and more preferably from about 10 C. to about 30 C.
(13) In one embodiment of the present invention, the step of filtering out the precipitate comprises using the second solvent or a mixture of the first solvent and the second solvent to wash the precipitate. In the mixing solvent, the ratio of the first solvent and the second solvent may be about 1:1 to about 1:100, preferably about 1:10 to about 1:50.
(14) In one embodiment of the present invention, the Hexadecyl Treprostinil crystal Form I has an X-ray powder diffraction (XRPD) pattern exhibiting its five strongest characteristic peaks at the following 2 reflection angles: 3.30.2, 6.60.2, 14.20.2, 18.90.2, 21.30.2, and 22.50.2. In a preferred embodiment, the XRPD pattern of Hexadecyl Treprostinil crystal Form I further comprises characteristic peaks at the following 2 reflection angles: 13.80.2, 15.30.2, 16.90.2, 17.80.2, 19.80.2, 20.60.2, 20.90.20, 24.40.2, and 24.80.2. More preferably, the XRPD pattern of Hexadecyl Treprostinil crystal Form I is consistent with
(15) TABLE-US-00001 TABLE 1 2 angle () d value () relative intensity (%) 3.3 26.6 100.0 6.6 13.4 40.1 9.8 9.0 4.5 13.1 6.8 2.8 13.8 6.4 7.9 14.2 6.2 46.0 15.3 5.8 11.3 16.3 5.4 6.7 16.9 5.2 19.7 17.8 5.0 16.0 18.9 4.7 92.8 19.8 4.5 14.5 20.6 4.3 8.2 20.9 4.2 20.2 21.3 4.2 32.2 22.5 4.0 27.8 24.4 3.6 27.7 24.8 3.6 19.4 26.2 3.4 4.5 27.3 3.3 2.3 27.8 3.2 2.1 28.8 3.1 1.5 29.9 3.0 1.6 31.2 2.9 1.2 32.5 2.8 1.5 34.0 2.6 2.5 36.2 2.5 1.8 36.8 2.4 3.4 39.7 2.3 2.7
(16) In one embodiment, the present invention provides a Hexadecyl Treprostinil crystal Form I having an XRPD pattern substantially as shown in
(17) In one embodiment, the present invention provides a Hexadecyl Treprostinil crystal Form I having a differential scanning calorimetry (DSC) thermogram pattern comprising an endothermic peak with a peak onset temperature of approximately 52.21 C. and a peak maximum of approximately 54.51 C. In a preferred embodiment, the present invention provides a Hexadecyl Treprostinil crystal Form I having a DSC thermogram pattern substantially as shown in
(18) In one embodiment, the present invention provides a Hexadecyl Treprostinil crystal Form I having a 1% KBr Fourier Transform Infrared (FTIR) spectrum comprising peaks, in terms of cm.sup.1, at 34454 cm.sup.1, 34024 cm.sup.1, 29584 cm.sup.1, 29194 cm.sup.1, 2871.4 cm.sup.1, 28544 cm.sup.1, 17334 cm.sup.1, 16064 cm.sup.1, 1585=4 cm.sup.1, 14744 cm.sup.1, 14434 cm.sup.1, 1416.4 cm.sup.1, 13744 cm.sup.1, 13574 cm.sup.1, 13314 cm.sup.1, 1309cm.sup.1, 12714 cm.sup.1, 12474 cm.sup.1, 12294 cm.sup.1, 120214 cm.sup.1, 11674 cm.sup.1, 11484 cm.sup.1, 11224 cm.sup.1, 10884 cm.sup.1, 10394 cm.sup.1, 10234 cm.sup.1, 10004 cm.sup.1, 9824 cm.sup.1, 9684 cm.sup.1, 9174 cm.sup.1, 8894 cm.sup.1, 7844 cm.sup.1, 7724 cm.sup.1, 7344 cm.sup.1, 7194 cm.sup.1, 7084 cm.sup.1. In a preferred embodiment, the present invention provides a Hexadecyl Treprostinil crystal Form I having a 1% KBr FTIR spectrum substantially as shown in
(19) Due to the organic solvent system used in the method of the present invention, the precipitated Hexadecyl Treprostinil crystal Form I possesses compact solid characteristics and thus is easy to be filtered out. The residual solvents can be easily removed under high vacuum at room temperature. Moreover, the dried Hexadecyl Treprostinil crystal Form I with granular characteristics is much easier to weight for commercially handling comparing with the waxy solid form of Hexadecyl Treprostinil with high viscosity.
(20) In addition, Hexadecyl Treprostinil crystal Form I is a stable crystalline form, which shows good stability, with no other crystalline forms or degraded products of impurities at room temperature for six months. Moreover, the assay of Hexadecyl Treprostinil crystal Form I can be kept between about 98.0% to about 102.0% even after thirty-six months of placement under normal storage temperature (about 5 C. to about 20 C.).
(21) Hexadecyl Treprostinil Crystal Form II and Preparation Thereof
(22) In an embodiment of the present invention, the method for preparing Hexadecyl Treprostinil crystal Form II comprises the steps of: (a) dissolving crude Hexadecyl Treprostinil in a third solvent selected from the group consisting of ethyl ether, isopropyl ether, methyl tert-butyl ether, methyl isobutyl so ketone, ethyl acetate, isopropyl acetate, toluene, xylene, acetone, dichloromethane, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, propanol, butanol, benzyl alcohol, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, and mixtures thereof to form a homogenous solution; (b) lowering 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 to the homogeneous solution; (c) stirring until a precipitate is formed; (d) filtering out the precipitate thereby isolating the Hexadecyl Treprostinil crystal Form II; and (e) optionally drying the Hexadecyl Treprostinil crystal Form II.
(23) In the present invention, the third solvent used to dissolve the crude Hexadecyl Treprostinil is selected from the group consisting of ethyl ether, isopropyl ether, methyl ten-butyl ether, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, toluene, xylene, acetone, dichloromethane, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, propanol, butanol, benzyl alcohol, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, and mixtures thereof, preferably ethyl acetate and toluene. The volume of the third solvent depends on the types of the solvents used and may be about 0.5 ml to about 100 ml, preferably about 1 ml to about 50 ml, and more preferably about 2 ml to about 20 ml or about 1 ml to about 10 ml, per 1 g of the crude Hexadecyl Treprostinil. The crude Hexadecyl Treprostinil can be dissolved in the third solvent at a temperature ranging from about 0 C. to about 80 C., preferably from about 10 C. to about 60 C., and more preferably from room temperature to about 40 C.
(24) In one embodiment of the present invention, the temperature of the homogenous solution is lowered to a temperature ranging from about 30 C. to about 50 C., preferably from about 20 C. to about 40 C., and more preferably from about 10 C. to about 30 C.
(25) The selection of the fourth solvent is the key to determine whether a Hexadecyl Treprostinil crystal Form II can be formed. In a preferred embodiment, the volume of the fourth solvent selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof depends on the types of the solvents used and may be about 0.5 ml to about 200 ml, about 1 ml to about 150 ml, or about 2 ml to about 100 ml, per 1 ml of so the third solvent. The fourth solvent can be added at a temperature ranging from about 30 C. to about 50 C., preferably from about 20 C. to about 40 C., and more preferably from about 10 C. to about 30 C.
(26) In one embodiment of the present invention, the precipitation of the crystal may be performed at a temperature ranging from about 30 C. to about 50 C., preferably from about 20 C. to about 40 C., and more preferably from about 10 C. to about 30 C.
(27) In one embodiment of the present invention, the step of filtering out the precipitate comprises using the fourth solvent or a mixture of the third solvent and the fourth solvent to wash the precipitate. In the mixing solvent, the ratio of the third solvent and the fourth solvent may be about 1:1 to about 1:100, preferably about 1:10 to about 1:50.
(28) In one embodiment of the present invention, the Hexadecyl Treprostinil crystal Form II has an XRPD pattern exhibiting its six strongest characteristic peaks at the following 2 reflection angles: 3.40.2, 6.10.2, 9.40.2, 20.30.2, 21.60.2, and 23.40.2. In a preferred embodiment, the XRPD pattern of Hexadecyl Treprostinil crystal Form II further comprises characteristic peaks at the following 2 reflection angles: 7.00.2, 9.00.2, 12.20.2, 12.70.2, 17.50.2, 18.00.2, 18.50.2, 19.10.2, and 19.40.2. More preferably, the XRPD pattern of Hexadecyl Treprostinil crystal Form II is consistent with
(29) TABLE-US-00002 TABLE 2 2 angle () d value () relative intensity (%) 3.4 26.0 100.0 4.5 19.6 2.2 6.1 14.5 45.1 7.0 12.6 22.0 7.7 11.5 3.9 9.0 9.8 27.8 9.4 9.4 85.5 10.0 8.8 3.6 10.6 8.3 13.9 17.2 7.7 22.6 12.7 7.0 29.9 13.9 6.4 3.8 14.2 6.2 3.9 14.9 5.9 5.2 15.5 5.7 17.2 16.1 5.5 18.1 16.7 5.3 6.2 17.5 5.1 25.4 18.0 4.9 30.8 18.5 4.8 79.3 19.1 4.6 33.8 19.4 4.6 30.3 20.3 4.4 39.9 20.9 4.2 19.8 71.6 4.1 40.6 22.6 3.9 9.4 23.4 3.8 81.9 25.4 3.5 9.3 27.7 3.2 3.6 28.8 3.1 3.1 30.9 2.9 2.3 37.3 2.4 2.1 40.0 2.3 2.8 43.3 2.1 2.1
(30) In one embodiment, the present invention provides a Hexadecyl Treprostinil crystal Form II having an XRPD pattern substantially as shown in
(31) In one embodiment, the present invention provides a Hexadecyl Treprostinil crystal Form II having a DSC thermogram pattern comprising an endothermic peak with a peak onset temperature of approximately 54.61 C. and a peak maximum of approximately 56.91 C. In a preferred embodiment, the present invention provides a Hexadecyl Treprostinil crystal Form II having a DSC thermogram pattern substantially as shown in
(32) In one embodiment, the present invention provides a Hexadecyl Treprostinil crystal Form II having a 1% KBr FTIR spectrum comprising peaks, in terms of cm.sup.1, at 35154 cm.sup.1, 34434 cm.sup.1, 32914 cm.sup.1, 30344 cm.sup.1, 29534 cm.sup.1, 29224 cm.sup.1, 28514 cm.sup.1, 17694 cm.sup.1, 17304 cm.sup.1, 16054 cm.sup.1, 15844 cm.sup.1, 14694 cm.sup.1, 14564 cm.sup.1, 14374 cm.sup.1, 13954 cm.sup.1, 13714 cm.sup.1, 3474 cm.sup.1, 13304 cm.sup.1, 13114 cm.sup.1, 12954 cm.sup.1, 12864 cm.sup.1, 12714 cm.sup.1, 12594 cm.sup.1, 12354 cm.sup.1, 12184 cm.sup.1, 12094 cm.sup.1, 11894 cm.sup.1, 11714 cm.sup.1, 11484 cm.sup.1, 11154 cm.sup.1, 10704 cm.sup.1, 10534 cm.sup.1, 10304 cm.sup.1, 10194 cm.sup.1, 9894 cm.sup.1, 9464 cm.sup.1, 9264 cm.sup.1, 9094 cm.sup.1, 8934 cm.sup.1, 8784 cm.sup.1, 7904 cm.sup.1, 7654 cm.sup.1, 7264 cm.sup.1, 7044 cm.sup.1. In a preferred embodiment, the present invention provides a Hexadecyl Treprostinil crystal Form II having a 1% KBr FTIR spectrum substantially as shown in
(33) Due to the organic solvent system used in the method of the present invention, the precipitated Hexadecyl Treprostinil crystal Form II possesses compact solid characteristics and thus is easy to be filtered out. The residual solvents can be easily removed under high vacuum at room temperature. Moreover, the dried Hexadecyl Treprostinil crystal Form II with granular characteristics is much easier to weight for commercially handling comparing with the waxy solid form of Hexadecyl Treprostinil with high viscosity.
(34) In addition, Hexadecyl Treprostinil crystal Form II is a stable crystalline form, which shows good stability, with no other crystalline forms or degraded products of impurities at room temperature for six months. Moreover, the assay of Hexadecyl Treprostinil crystal Form II can be kept between about 98.0 to about 102.0% even after thirty-six months of placement under normal storage temperature (about 5 C. to about 2 C.).
EXAMPLES
(35) X-ray Powder Diffraction (XRPD) Analysis: The XRPD patterns were collected on a Bruker D2 PHASER diffractometer with fixed divergence slits and 1D LYNXEYE detector. The samples (ca. 100 mg) were flatly placed on a sample holder. The prepared samples were analyzed over a 20 range from 20 to 50 with step size of 0.02 degrees and step time of 1 second using CuK.sub. radiation at a power of 10 mA and 30 kV. The CuK.sub. radiation was removed by a divergent beam nickel filter.
(36) Differential Scanning Calorimetry (DSC) Analysis: The DSC thermogram patterns were collected on a TA DISCOVERY DSC25 instrument. The samples (ca. 5 mg) were weighed into an aluminum pan with a crimping closed aluminum lid. The prepared samples were analyzed from 10 C. to 100 C. at scan rate of 10 C./min under a flow of nitrogen (ca. 50 ml/min). The melting temperature and heat of fusion were calibrated by indium (In) before measurement.
(37) Fourier Transform Infrared (FTIR) Analysis: The FTIR spectra were collected on a Perkin Elmer SPECTRUM 100 instrument. The samples were mixed with potassium bromide (KBr) in an approximately 1:100 ratio (w/w) using an agate mortar and pestle. The mixture was compressed in a pellet die at a pressure of about 10 to 13 tonnes for 2 minutes. The resulting disk was scanned 4 times versus a collected background from 4000 cm.sup.1 to 650 cm.sup.1 at a resolution of 4 cm.sup.1. The data was baseline corrected and normalized.
Example 1
(38) Preparation of Crude Hexadecyl Treprostinil
(39) 2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl)oxy)acetic acid (40.0 g, 102.4 mmol) was dissolved in 600 ml dimethylformamide and followed by addition of 42.0 g potassium carbonate with 72.0 g I-iodohexadecane, and stirred at 60 C. for 1 hour. Afterwards, the reaction mixture was slowly cooled to 10 C., and 650 ml water and 650 ml ethyl so acetate with 50.0 g magnesium sulfate were added to the reaction mixture for extraction. The extraction solution was evaporated off under vacuum at room temperature to get crude product. The crude product was then purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent to obtain 58.6 g off-white waxy solid (crude Hexadecyl Treprostinil).
Example 2
(40) Preparation of Hexadecyl Treprostinil Crystal Form I
(41) Crude Hexadecyl Treprostinil (1.00 g, from Example 1) and propanol (5 mil) were heated to 40 C. for dissolution and then cooled to room temperature. Water (5 ml) was added slowly dropwise and the mixture was stirred in ice water bath for 18 hours until solid precipitation occurred. Afterwards, the resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for 24 hours to give 0.92 g Hexadecyl Treprostinil crystal Form I. The XRPD, DSC and FTIR results are the same as shown in
Example 3
(42) Preparation of Hexadecyl Treprostinil Crystal Form I
(43) Crude Hexadecyl Treprostinil (1.01 g, from Example 1) and ethanol (6 mil) were heated to 40 C. for dissolution and then cooled to room temperature. Acetonitrile (30 ml) was added slowly dropwise and the mixture was stirred in ice water bath for 18 hours until solid precipitation occurred. Afterwards, the resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for 24 hours to give 0.90 g Hexadecyl Treprostinil crystal Form I. The XRPD, DSC and FTIR results are the same as shown in
Example 4
(44) Preparation of Hexadecyl Treprostinil Crystal Form I
(45) Crude Hexadecyl Treprostinil (1.0) g, from Example 1) and toluene (5 ml) were heated to 40 C. for dissolution. Acetonitrile (50 ml) was added slowly dropwise and the mixture was stirred in ice water bath for 20 hours until solid precipitation occurred. Afterwards, the resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for 24 hours to give 0.91 g Hexadecyl Treprostinil crystal Form I. The XRPD, DSC and FTIR results are the same as shown in
Example 5
(46) Preparation of Hexadecyl Treprostinil Crystal Form II
(47) Crude Hexadecyl Treprostinil (1.01 g, from Example 1) and ethyl acetate (1 ml) were heated to 40 C. for dissolution and then cooled to room temperature. N-hexane (30 ml) was added slowly dropwise and the mixture was stirred in ice water bath for 18 hours until solid precipitation occurred. Afterwards, the resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for 24 hours to give 0.88 g Hexadecyl Treprostinil crystal Form II. The XRPD, DSC and FTIR results are the same as shown in
Example 6
(48) Preparation of Hexadecyl Treprostinil Crystal Form II
(49) Crude Hexadecyl Treprostinil (1.00 g, from Example 1) and toluene (3 ml) were heated to 40 C. for dissolution and then cooled to room temperature. N-heptane (40 ml) was added slowly dropwise and the mixture was stirred in ice water bath for 24 hours until solid precipitation occurred. Afterwards, the resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for 24 hours to give 0.85 g Hexadecyl Treprostinil crystal Form II. The XRPD, DSC and FTIR results are the same as shown in
Example 7
(50) Preparation of Hexadecyl Treprostinil Crystal Form II
(51) Crude Hexadecyl Treprostinil (1.01 g, from Example 1) and methyl tert-butyl ether (3 ml) were heated to 40 C. for dissolution. N-pentane (30 ml) was added slowly dropwise and the mixture was stirred in ice water bath for 18 hours until solid precipitation occurred. Afterwards, the resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for 24 hours to give 0.85 g Hexadecyl Treprostinil crystal Form II. The XRPD, DSC and FTR results are the same as shown in