Patent Application
20230355612
The present application claims priority to the following prior applications: the Chinese Patent Application for Invention with the application No. 202010870701.6 filed with China National Intellectual Property Administration on Aug. 26, 2020; the Chinese Patent Application for Invention with the application No. 202010869671.7 filed with China National Intellectual Property Administration on Aug. 26, 2020; the Chinese Patent Application for Invention with the application No. 202110324874.2 filed with China National Intellectual Property Administration on Mar. 26, 2021; and the Chinese Patent Application for Invention with the application No. 202110330670.X filed with China National Intellectual Property Administration on Mar. 26, 2021, which are incorporated herein by reference in their entirety.
The present disclosure relates to a pharmaceutical acceptable salt of cariprazine and crystalline forms thereof, a preparation method therefor and use thereof.
Cariprazine (formula I) is a novel atypical antipsychotic that has antagonistic effect on dopamine D3 receptor, dopamine D2 receptor and 5-hydroxytryptamine 2B receptor. It can be used for treating schizophrenia and bipolar I disorder. Cariprazine hydrochloride capsules are currently available on the market. This product is an oral preparation that should be taken daily to maintain its plasma concentration. However, the patient compliance is poor due to required frequent administration.
The patent reference CN101679315A discloses various salts of cariprazine, comprising monohydrochloride, dihydrochloride, monohydrobromide, maleate and mesylate. The patent CN105218484A discloses cariprazine tartrate, and provides the solubilities of cariprazine tartrate, cariprazine hydrochloride, cariprazine maleate, cariprazine benzenesulfonate and cariprazine phosphate, all of which are greater than 3 mg/mL. The patent WO2020056929A discloses a new crystalline form of cariprazine hydrochloride and mentions that cariprazine hydrochloride dissociates rapidly into a free base in a pH 6.5 buffer.
In view of the defect in the prior art, the search for a pharmaceutically acceptable salt of cariprazine and crystalline forms thereof which have low solubility, high stability and good clinical effect and are suitable for long-acting administration and commercialization is an urgent technical problem in need of solution in the art.
To ease the technical problem described above, the present disclosure provides a pharmaceutically acceptable salt of cariprazine, which is selected from a salt formed from cariprazine free base I and an organic acid having six or more carbon atoms:
According to an embodiment of the present disclosure, the organic acid having six or more carbon atoms comprises, but is not limited to: hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, nonanedioic acid, decanoic acid, decanedioic acid, undecanoic acid, lauric acid (dodecanoic acid), tridecanoic acid, myristic acid (tetradecanoic acid), pentadecanoic acid, palmitic acid (i.e., hexadecanoic acid), heptadecanoic acid, stearic acid (octadecanoic acid), nonadecanoic acid, eicosanoic acid (arachidic acid), oleic acid, heneicosanoic acid, docosanoic acid, tricosanoic acid, tetracosanoic acid, pentacosanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid, nonacosanoic acid, triacontanoic acid (melissic acid), triacetin, xylonic acid, embonic acid (palmitate), 1-hydroxy-2-naphthoic acid, pamoic acid and a naphthoic acid derivative (comprising but not limited to a naphthoate).
According to an embodiment of the present disclosure, the palmitate refers to a structure formed by esterification of palmitic acid with at least one hydroxy group of a compound that contains both carboxy and hydroxy (e.g., embonic acid); the naphthoate refers to a structure formed by esterification of naphthoic acid with at least one hydroxy group of a compound that contains both carboxy and hydroxy (e.g., embonic acid).
According to an embodiment of the present disclosure, the embonic acid is also known as pamoic acid, CAS No. 130-85-8.
According to an embodiment of the present disclosure, a molar ratio of cariprazine to organic acid in the pharmaceutically acceptable salt may be (1:0.5) to (1:2).
According to an embodiment of the present disclosure, the pharmaceutically acceptable salt of cariprazine may be cariprazine monopamoate, cariprazine hemipamoate, cariprazine 1-hydroxy-2-naphthoate, cariprazine laurate, cariprazine palmitate, cariprazine sebacate, cariprazine undecanoate or cariprazine heptanoate.
According to an embodiment of the present disclosure, the pamoic acid is also known as embonic acid, CAS No. 130-85-8.
According to an embodiment of the present disclosure, the pharmaceutically acceptable salt of cariprazine may be in crystalline, polymorphic or amorphous form.
According to an embodiment of the present disclosure, the term “polymorphic form” refers to a form of different crystalline forms and other solid state molecular forms of the same compound, for example, a solid comprising two or more crystalline forms and/or the amorphous form of the pharmaceutically acceptable salt of cariprazine.
According to an embodiment of the present disclosure, the pharmaceutically acceptable salt of cariprazine comprises a solvate thereof that are formed with a solvent. The solvate comprise a hydrate of the pharmaceutically acceptable salt of cariprazine and a solvate formed from the pharmaceutically acceptable salt of cariprazine and an organic solvent. The “organic solvent” in the “solvates formed from the pharmaceutically acceptable salt of cariprazine and an organic solvent” comprises, but are not limited to, a solvent selected from ethanol, acetone, dimethyl sulfoxide and mixtures thereof.
The present disclosure also provides a preparation method for the pharmaceutically acceptable salt of cariprazine, which comprises the following step: conducting a reaction (e.g., a neutralization reaction) of the cariprazine free base with the organic acid having six or more carbon atoms to give the pharmaceutical salt of cariprazine.
The preparation method for the pharmaceutically acceptable salt of cariprazine can be performed in a solvent or without solvent.
In the preparation method for the pharmaceutically acceptable salt of cariprazine, the organic acid having six or more carbon atoms may be a C6-C30 organic acid. The C6-C30 organic acid having six or more carbon atoms comprises, but is not limited to: hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, nonanedioic acid, decanoic acid, undecanoic acid, lauric acid (dodecanoic acid), tridecanoic acid, myristic acid (tetradecanoic acid), pentadecanoic acid, palmitic acid (hexadecanoic acid), heptadecanoic acid, stearic acid (octadecanoic acid), nonadecanoic acid, eicosanoic acid (arachidic acid), oleic acid, heneicosanoic acid, docosanoic acid, tricosanoic acid, tetracosanoic acid, pentacosanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid, nonacosanoic acid, triacontanoic acid (melissic acid), triacetin, xylonic acid, embonic acid (palmitate), 1-hydroxy-2-naphthoic acid and a naphthoic acid derivative (comprising but not limited to a naphthoate).
According to an embodiment of the present disclosure, the pharmaceutically acceptable salt of cariprazine is cariprazine embonate.
According to an embodiment of the present disclosure, the pharmaceutically acceptable salt of cariprazine is characterized in that the pharmaceutically acceptable salt of cariprazine is a cariprazine embonate formed from cariprazine free base and embonic acid in a molar ratio of 1:1 to 2:1.
According to an embodiment of the present disclosure, any one of the following methods is adopted as the preparation method for cariprazine embonate:
(1) dissolving cariprazine and embonic acid in a first solvent, and removing the solvent or adding a second solvent to obtain cariprazine embonate;
wherein the first solvent is methanol, ethanol, dichloromethane, acetone, dibutyl ketone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide or a mixture thereof, preferably methanol, ethanol, tetrahydrofuran, dimethyl sulfoxide or a mixture thereof;
the second solvent is isopropanol, methyl tert-butyl ether, n-heptane, toluene, isopropyl ether or a mixture thereof, preferably water;
(2) dissolving cariprazine in an aqueous solution of phosphoric acid to obtain solution A, dissolving embonic acid in an aqueous solution of sodium hydroxide to obtain solution B, adding solution B to solution A and stirring the mixture so cariprazine and embonic acid react to produce cariprazine embonate;
wherein the aqueous solution of phosphoric acid has a concentration of 1 mg/mL to 6 mg/mL;
preferably, the aqueous solution of sodium hydroxide has a concentration of 1 mg/mL to 8 mg/mL.
According to an embodiment of the present disclosure, the cariprazine embonate is in crystalline, polymorphic or amorphous form.
According to an embodiment of the present disclosure, the cariprazine embonate in crystalline form is an anhydrate, a hydrate or a solvate. The solvate comprises, but is not limited to, a solvate formed from cariprazine embonate and one or more of methanol, ethanol, acetonitrile, tetrahydrofuran and dimethyl sulfoxide.
According to an embodiment of the present disclosure, the cariprazine embonate is crystalline form A of cariprazine embonate.
According to an embodiment of the present disclosure, an X-ray powder diffraction graph of the crystalline form A of cariprazine embonate has characteristic peaks at 2θ values of 13.1°±0.2°, 18.7°±0.2°, 21.°±0.2°, etc.
Further, an X-ray powder diffraction graph of the crystalline form A of cariprazine embonate has characteristic peaks at 2θ values of 4.8°±0.2°, 13.1°±0.2°, 18.7°±0.2°, 20.1°±0.2°, 21.0°±0.2°, 26.1°±0.2°, etc.
Further, an X-ray powder diffraction graph of the crystalline form A of cariprazine embonate has characteristic peaks at 2θ values of 4.8°±0.2°, 9.7±0.2°, 12.3°±0.2°, 13.1°±0.2°, 18.7°±0.2°, 20.1°±0.2°, 21.0°±0.2°, 26.1°±0.2°, etc.
Furthermore, an X-ray powder diffraction graph of the crystalline form A of cariprazine embonate has absorption peaks at 2θvalues of 4.8°±0.2°, 8.2°±0.2°, 9.7±0.2°, 11.6°±0.2°, 12.3°±0.2°, 13.1°±0.2°, 14.7°±0.2°, 15.1°±0.2°, 16.6°±0.2°, 18.7°±0.2°, 20.1°±0.2°, 20.7°±0.2°, 21.0°±0.2°, 21.6°±0.2°, 22.1°±0.2°, 24.1°±0.2°, 26.1°±0.2°, etc.
Furthermore, an X-ray powder diffraction graph of the crystalline form A of the cariprazine embonate is substantially as shown in
A differential scanning calorimetry analysis graph of the crystalline form A of cariprazine embonate is substantially as shown in
A thermogravimetric analysis graph of the crystalline form A of cariprazine embonate is substantially as shown in
A nuclear magnetic resonance graph of the crystalline form A of cariprazine embonate is substantially as shown in
According to an embodiment of the present disclosure, a preparation method for the crystalline form A of cariprazine embonate is as follows:
(1) adding cariprazine embonate to a solvent, and stirring the mixture so cariprazine embonate crystallizes to form the crystalline form A of cariprazine embonate; wherein the solvent is methanol;
(2) dissolving cariprazine embonate in a good solvent, adding gradually an antisolvent, and stirring the mixture so cariprazine embonate crystallizes to form the crystalline form A of cariprazine embonate;
wherein the good solvent is dibutyl ketone;
the antisolvent is n-heptane.
According to an embodiment of the present disclosure, the cariprazine embonate is crystalline form F of cariprazine embonate.
According to an embodiment of the present disclosure, an X-ray powder diffraction graph of the crystalline form F of cariprazine embonate has characteristic peaks at 2θ values of 4.9°±0.2°, 19.2°±0.2°, 21.0°±0.2°, etc.
Further, an X-ray powder diffraction graph of the crystalline form F of cariprazine embonate has characteristic peaks at 2θ values of 4.9°±0.2°, 13.6°±0.2°, 19.2°±0.2°, 21.0°±0.2°, 24.0°±0.2°, 26.3°±0.2°, etc.
Further, an X-ray powder diffraction graph of the crystalline form F of cariprazine embonate has characteristic peaks at 2θ values of 4.9°±0.2°, 12.8°±0.2°, 13.6°±0.2°, 19.2°±0.2°, 20.3°±0.2°, 21.0°±0.2°, 24.0°±0.2°, 26.3 °±0.2°, etc.
Furthermore, according to an embodiment of the present disclosure, an X-ray powder diffraction graph of the crystalline form F of cariprazine embonate has characteristic peaks at 2θ values of 4.9°±0.2°, 8.4°±0.2°, 9.7±0.2°, 10.4°±0.2°, 11.6°±0.2°, 12.8°±0.2°, 13.3°±0.2°, 13.6°±0.2°, 15.0°±0.2°, 15.4°±0.2°, 16.8°±0.2°, 17.0°±0.2°, 18.5°±0.2°, 18.8°±0.2°, 19.2°±0.2°, 19.5°±0.2°, 20.3°±0.2°, 21.0°±0.2°, 21.9°±0.2°, 22.2°±0.2°, 22.5°±0.2°, 24.0°±0.2°, 25.1°±0.2°, 25.7°±0.2°, 26.3°±0.2°, 26.8°±0.2°, 28.8°±0.2°, 29.6°±0.2°, etc.
Furthermore, an X-ray powder diffraction graph of the crystalline form F of the cariprazine embonate is substantially as shown in
A differential scanning calorimetry analysis graph of the crystalline form F of cariprazine embonate is substantially as shown in
A thermogravimetric analysis graph of the crystalline form F of cariprazine embonate is substantially as shown in
A nuclear magnetic resonance graph of the crystalline form F of cariprazine embonate is substantially as shown in
According to an embodiment of the present disclosure, a preparation method for the crystalline form F of cariprazine embonate is as follows:
forming a slurry of crystalline form A of cariprazine embonate in a solvent, stirring the slurry so cariprazine embonate crystallizes to form the crystalline form F of cariprazine embonate;
wherein the solvent is ethyl acetate, isopropyl acetate, methyl tert-butyl ether or n-heptane.
According to an embodiment of the present disclosure, the cariprazine embonate is crystalline form D of cariprazine embonate.
According to an embodiment of the present disclosure, an X-ray powder diffraction graph of the crystalline form D of cariprazine embonate has characteristic peaks at 2θ values of 9.6°±0.2°, 11.9°±0.2°, 20.4°±0.2°, etc.
Further, an X-ray powder diffraction graph of the crystalline form D of cariprazine embonate has characteristic peaks at 2θ values of 9.6°±0.2°, 11.9°±0.2°, 16.6°±0.2°, 20.4°±0.2°, 24.5°±0.2°, 25.3°±0.2°, etc.
Further, an X-ray powder diffraction graph of the crystalline form D of cariprazine embonate has characteristic peaks at 2θ values of 9.6°±0.2°, 11.9°±0.2°, 15.2°±0.2°, 16.6°±0.2°, 20.4°±0.2°, 20.7°±0.2°, 24.5°±0.2°, 25.3°±0.2°, etc.
Furthermore, according to an embodiment of the present disclosure, an X-ray powder diffraction graph of the crystalline form D of cariprazine embonate has characteristic peaks at 2θ values of 9.6°±0.2°, 10.1°±0.2°, 10.5±0.2°, 11.9°±0.2°, 13.2°±0.2°, 14.5°±0.2°, 15.2°±0.2°, 16.6°±0.2°, 20.4°±0.2°, 20.7°±0.2°, 21.1°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 18.8°±0.2°, 19.2°±0.2°, 19.5°±0.2°, 20.3°±0.2°, 21.0°±0.2°, 24.5°±0.2°, 25.3°±0.2°, etc.
Furthermore, an X-ray powder diffraction graph of the crystalline form D of the cariprazine embonate is substantially as shown in
A differential scanning calorimetry analysis graph of the crystalline form D of cariprazine embonate is substantially as shown in
A thermogravimetric analysis graph of the crystalline form D of cariprazine embonate is substantially as shown in
A nuclear magnetic resonance graph of the crystalline form D of cariprazine embonate is substantially as shown in
According to an embodiment of the present disclosure, a preparation method for the crystalline form D of cariprazine embonate is as follows:
stirring cariprazine embonate in ethanol so cariprazine embonate crystallizes to form the crystalline form D of cariprazine embonate.
According to an embodiment of the present disclosure, the cariprazine embonate is crystalline form B of cariprazine embonate.
According to an embodiment of the present disclosure, an X-ray powder diffraction pattern of the crystalline form B of cariprazine embonate has characteristic peaks at 2θ values of 5.2°±0.2°, 10.5°±0.2°, 14.0°±0.2°, 14.4°±0.2°, 17.5°±0.2°, 21.3°±0.2°, 21.9°±0.2°, 22.9°±0.2°, 26.2°±0.2°, etc.
Further, an X-ray powder diffraction graph of the crystalline form B of the cariprazine embonate is substantially as shown in
According to an embodiment of the present disclosure, the cariprazine embonate is crystalline form C of cariprazine embonate.
According to an embodiment of the present disclosure, an X-ray powder diffraction pattern of the crystalline form C of cariprazine embonate has characteristic peaks at 2θ values of 8.6°±0.2°, 13.0°±0.2°, 16.8°±0.2°, 17.3°±0.2°, 18.2°±0.2°, 18.5°±0.2°, 19.8°±0.2°, 22.1°±0.2°, 23.5°±0.2°, etc.
Further, an X-ray powder diffraction graph of the crystalline form C of the cariprazine embonate is substantially as shown in
According to an embodiment of the present disclosure, the cariprazine embonate is crystalline form E of cariprazine embonate.
According to an embodiment of the present disclosure, an X-ray powder diffraction pattern of the crystalline form E of cariprazine embonate has characteristic peaks at 2θ values of 11.0°±0.2°, 12.8°±0.2°, 13.8°±0.2°, 15.5°±0.2°, 15.9°±0.2°, 17.9°±0.2°, 18.4°±0.2°, 20.7°±0.2°, 23.4°±0.2°, etc.
Further, an X-ray powder diffraction graph of the crystalline form E of the cariprazine embonate is substantially as shown in
According to an embodiment of the present disclosure, the cariprazine embonate is crystalline form G of cariprazine embonate.
According to an embodiment of the present disclosure, an X-ray powder diffraction pattern of the crystalline form G of cariprazine embonate has characteristic peaks at 2θ values of 8.7°±0.2°, 10.0°±0.2°, 13.6°±0.2°, 14.3°±0.2°, 17.5°±0.2°, 18.0°±0.2°, 20.3°±0.2°, 23.2°±0.2°, 25.1°±0.2°, etc.
Further, an X-ray powder diffraction graph of the crystalline form G of the cariprazine embonate is substantially as shown in
According to an embodiment of the present disclosure, the cariprazine embonate is crystalline form I of cariprazine embonate.
According to an embodiment of the present disclosure, an X-ray powder diffraction pattern of the crystalline form I of cariprazine embonate has characteristic peaks at 2θ values of 10.0°±0.2°, 14.9°±0.2°, 16.3°±0.2°, 17.7°±0.2°, 18.5°±0.2°, 19.0°±0.2°, 21.1°±0.2°, 22.1°±0.2°, 24.5°±0.2°, etc.
Further, an X-ray powder diffraction graph of the crystalline form I of the cariprazine embonate is substantially as shown in
According to an embodiment of the present disclosure, the term “solvate”refers to a molecular complex comprising the drug and a stoichiometric or non-stoichiometric amount of one or more kinds of solvent molecules (such as ethanol). When the solvent is closely associated with the drug, the resulting complex will have a well-defined stoichiometry independent of humidity. However, when the solvent is weakly associated with the drug, the solvent content will depend on humidity and drying conditions, as in channel solvates and hygroscopic compounds. In such a case, the complex will typically be non-stoichiometric.
According to an embodiment of the present disclosure, the term “hydrate”describes a solvate comprising the drug and a stoichiometric or non-stoichiometric amount of water. The term “relative humidity”refers to the ratio of the amount of water vapor at a given temperature to the maximum amount of water vapor that can be maintained at that temperature and pressure, expressed as a percentage.
The preferred conditions described above may be combined arbitrarily to obtain preferred embodiments of the present disclosure without departing from the general knowledge in the art. The reagents and starting materials used in the present disclosure are commercially available. According to an embodiment of the present disclosure, the room temperature refers to an ambient temperature of 10-35° C.
The inventors surprisingly found that the pharmaceutically acceptable salts of cariprazine disclosed in the prior art were too soluble and cariprazine hydrochloride had the disadvantages of being not very stable in aqueous solution, dissociating rapidly into a free base in a slightly acidic or alkaline environment and so on. Accordingly, these types of salts are not suitable for use in long-acting sustained-release preparations. The pharmaceutically acceptable salt of cariprazine of the present disclosure eases the problems described above, and its properties such as low solubility, good crystalline form stability, good storage stability, no dissociation, being easy to process and the like, are more favorable for the preparation of long-acting sustained-release preparations. The pharmaceutically acceptable salt of cariprazine of the present disclosure has a good marketing prospect.
The present disclosure is further illustrated by the following examples; however, these examples should not be construed as limiting the present disclosure. Experimental procedures without specified conditions in the following examples are conducted in accordance with conventional procedures and conditions, or in accordance with the manufacturer's manual.
Unless otherwise indicated, the starting materials and reagents in the examples below are either commercially available or prepared by one skilled in the art according to methods known in the art. The salt compounds of the examples were tested by nuclear magnetic resonance (1H-NMR), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage polarized light microscopy (PLM) and high performance liquid chromatography (HPLC), and the test parameters are as follows:
Content method:
Content gradient elution program table:
Related substances method:
Related gradient elution program table:
Unless otherwise indicated, the aqueous suspensions of the pharmaceutical composition of cariprazine in the context of the present disclosure were measured on a particle size analyzer under the following conditions:
4000 mg (9.36 mmol) of cariprazine was dissolved in 200 mL of a phosphoric acid solution (5.4 mg/mL) to give solution A. 3634 mg (9.36 mmol) of embonic acid was dissolved in 100 mL of a sodium hydroxide solution (7.5 mg/mL) to give solution B. 100 mL of solution B was added to 200 mL of solution A over 30 min under stirring. The product was isolated by filtration, washed with water and dried in vacuo at 40° C. for 12 h to give a pale yellow solid (5840 mg, 76% yield (calculated based on free base)).
The structure and molar ratio of the cariprazine embonate of the present disclosure were confirmed by hydrogen nuclear magnetic resonance.
1H-NMR (400 MHz, DMSO-d6): δ8.38 (s, 2H), 8.16 (d, 2H), 8.80 (d, 2H), 7.39-7.13 (m, 7H), 5.86 (d, 1H), 4.76 (s, 2H), 3.40-3.32 (m, 3H), 3.22-3.18 (m, 4H), 2.75 (s, 6H), 1.76 (t, 4H), 1.63-1.57 (m, 2H), 1.25-1.16 (m, 3H), 1.04-0.96 (m, 2H).
The nuclear magnetic resonance result shows that cariprazine and embonic acid formed the salt in a molar ratio of 1:1.
The sample described above was analyzed by solid-state characterization. The XRPD graph is shown in
20 g (46.8 mmol) of cariprazine and 18.17 g (46.8 mmol) of embonic acid were dissolved in 170 mL of a mixed solvent of THF:MeOH (2:1) at 60° C. The mixture was filtered and concentrated under reduced pressure to remove the solvent, and then 300 mL of methanol was added to dissolve the residue at 60° C. The solution was concentrated under reduced pressure to remove the solvent, and the residue was dried in vacuo at 40° C. for 12 h to give amorphous cariprazine embonate (36.6 g).
200 mg (0.468 mmol) of cariprazine was dissolved in 10 mL of a phosphoric acid solution (5.4 mg/mL) to give solution A. 90.85 mg (0.234 mmol) of embonic acid was dissolved in 2.5 mL of a sodium hydroxide solution (7.5 mg/mL) to give solution B. 2.5 mL of solution B was added to 10 mL of solution A over 30 min under stirring. The product was isolated by filtration, washed with water and dried in vacuo at 40° C. for 12 h to give a pale yellow solid (204 mg, 70% yield).
The structure and molar ratio of the cariprazine embonate of the present disclosure were confirmed by hydrogen nuclear magnetic resonance.
1H-NMR (400 MHz, DMSO-d6): δ8.25 (s, 1H), 8.18 (d, 1H), 7.69 (d, 1H), 7.38-7.31 (m, 2H), 7.22-7.14 (m, 2H), 7.05 (t, 1H), 5.86 (d, 1H), 4.71 (s, 1H), 3.39-3.22 (m, 5H), 2.75 (s, 6H), 1.75 (t, 4H), 1.59-1.54 (m, 2H), 1.25-1.15 (m, 3H), 1.04-0.95 (m, 2H).
The nuclear magnetic resonance result shows that cariprazine and embonic acid formed the salt in a molar ratio of 2:1.
The sample described above was analyzed by PLM, and the result shows that the sample was an amorphous solid without light polarization.
100 mg (0.234 mmol) of cariprazine and 45 mg (0.234 mmol) of 1-hydroxy-2-naphthoic acid were added to 8 mL of methanol, completely dissolved by stirring and filtered. Three volumes of n-heptane were added. The solvent was evaporated at room temperature to give an oil. The oil was dried in vacuo at 40° C. for 4 h to give a solid.
PLM analysis showed that the solid had light polarization and started to melt at about 200° C. 1H-NMR (400 MHz, DMSO-d6): 68.23 (d, 1H), 7.80-7.74 (m, 2H), 7.57-7.53 (m, 1H), 7.48-7.44 (m, 1H), 7.38-7.31 (m, 2H), 7.20-7.16 (m, 2H), 5.86 (d, 1H), 3.36-3.09 (m, 10H), 2.75 (s, 6H), 1.74 (t, 4H), 1.61-1.56 (m, 2H), 1.33-1.15 (m, 5H), 1.02-0.83 (m, 3H).
The nuclear magnetic resonance result shows that cariprazine and 1-hydroxy-2-naphthoic acid formed the salt in a molar ratio of 1:1.
50 mg (0.117 mmol) of cariprazine and 23.7 mg (0.118 mmol) of lauric acid were added to 5 mL of methanol and dissolved at 50° C. The solution was stirred at room temperature for 12 h. Two volumes of water were added. The mixture was filtered. The solid was dried in vacuo at 40° C. for 12 h to give cariprazine laurate.
50 mg (0.117 mmol) of cariprazine and 30.3 mg (0.118 mmol) of palmitic acid were added to 5 mL of methanol and dissolved at 50° C. The solution was stirred at room temperature for 12 h. One volume of water was added. The mixture was filtered. The solid was dried in vacuo at 40° C. for 12 h to give cariprazine palmitate.
Cariprazine and acid were measured out in a molar ratio of 1:1.1. Each acid was dissolved in methanol solvent, and the resulting acidic reagent was added to a solution of cariprazine in methanol at room temperature to start a salt formation reaction. After 12 h of stirring at room temperature, the solvent was left to volatilize at room temperature, and the residue was dried to give the corresponding salt of cariprazine.
2000 mg of the cariprazine embonate prepared in Example 1 was measured out and added to 20 mL of methanol. The mixture was stirred at room temperature for 24 h to crystallize cariprazine embonate. The solid was collected by filtration and dried in vacuo at 55° C. to give crystalline form A of cariprazine embonate (1900 mg, 95% yield).
Its X-ray powder diffraction graph is shown in
Its differential scanning calorimetry graph is shown in
Its thermogravimetric analysis graph is shown in
Its nuclear magnetic resonance graph is shown in
A 30 g sample of the amorphous solid of cariprazine embonate prepared in Example 2 was measured out and added to 300 mL of methanol. The mixture was stirred at 10° C. for 24 h to crystallize cariprazine embonate. The solid was collected by filtration and dried in vacuo at 55° C. to give crystalline form A of cariprazine embonate (28.5 g).
200 mg of the crystalline form A of cariprazine embonate obtained in Example 9 was measured out and a slurry of it was formed in methanol solvent. In the slurry, the weight-to-volume ratio of crystalline form A of cariprazine embonate to solvent was 40 mg/mL. The slurry was stirred for 3 days so cariprazine embonate crystallized to form crystalline form B of cariprazine embonate (180 mg).
Its X-ray powder diffraction graph is shown in
Its nuclear magnetic resonance result shows that it was a methanol solvate.
2 g of the crystalline form A of cariprazine embonate prepared in Example 9 was measured out and added to 50 mL of methanol. The mixture was stirred at room temperature for 72 h to crystallize cariprazine embonate. The solid was collected by filtration and dried in vacuo at 55° C. to give crystalline form B of cariprazine embonate (1.9 mg).
The crystalline form A of cariprazine embonate obtained in Example 8 was measured out and a slurry of it was formed in acetone solvent. In the slurry, the weight-to-volume ratio of crystalline form A of cariprazine embonate to solvent was 40 mg/mL. The slurry was stirred for 3 days so cariprazine embonate crystallized to form crystalline form C of cariprazine embonate.
Its X-ray powder diffraction graph is shown in
Its nuclear magnetic resonance result shows that it was an acetone solvate.
200 mg of the crystalline form A cariprazine embonate prepared in Example 8 was measured out and added to 2 mL of ethanol. The mixture was stirred at room temperature for 48 h to crystallize cariprazine embonate. The solid was collected by filtration and dried in vacuo at 55° C. to give crystalline form D of cariprazine embonate (190 mg, 95% yield).
Its X-ray powder diffraction graph is shown in
Its differential scanning calorimetry graph is shown in
Its thermogravimetric analysis graph is shown in
Its nuclear magnetic resonance graph is shown in
The crystalline form A of cariprazine embonate obtained in Example 8 was measured out and a slurry of it was formed in acetonitrile solvent. In the slurry, the weight-to-volume ratio of crystalline form A of cariprazine embonate to solvent was 40 mg/mL. The slurry was stirred for 3 days so cariprazine embonate crystallized to form crystalline form E of cariprazine embonate.
Its X-ray powder diffraction graph is shown in
2 g of the crystalline form A of cariprazine embonate prepared in Example 9 was measured out and added to 50 mL of acetonitrile. The mixture was stirred at room temperature for 72 h to crystallize cariprazine embonate. The solid was collected by filtration and dried in vacuo at 55° C. to give crystalline form E of cariprazine embonate (1.8 g).
200 mg of the crystalline form A cariprazine embonate prepared in Example 8 was measured out and added to 20 mL of isopropyl acetate. The mixture was stirred at room temperature for 12 h to crystallize cariprazine embonate. The solid was collected by filtration and dried in vacuo at 55° C. to give crystalline form F of cariprazine embonate (180 mg, 90% yield).
Its X-ray powder diffraction graph is shown in
Its differential scanning calorimetry graph is shown in
Its thermogravimetric analysis graph is shown in
Its nuclear magnetic resonance graph is shown in
200 mg of the crystalline form A of cariprazine embonate obtained in Example 8 was measured out and added to 5 mL of acetonitrile to form a slurry. The slurry was stirred for 5 days so cariprazine embonate crystallized to form crystalline form G of cariprazine embonate.
Its X-ray powder diffraction graph is shown in
Its nuclear magnetic resonance result shows that it was an acetonitrile solvate.
A 15 mg sample of the amorphous solid of cariprazine embonate obtained in Example 1 was measured out and illuminated for 10 days to give crystalline form I of cariprazine embonate.
Its X-ray powder diffraction graph is shown in
Preparation of a sample of crystalline form I of cariprazine hydrochloride according to the original cariprazine hydrochloride patent:
1 g of commercially available cariprazine free base was added to a 25 mL round-bottom flask. 2 mL of methanol and 8 mL of water were added. The mixture was stirred in an oil bath at 70° C. for 0.5 h. A mixed solution of 0.226 mL of concentrated hydrochloric acid and 0.35 mL of water was added. After complete dissolution, the solution was filtered while hot. Heating was stopped and the solution was naturally cooled overnight to give an off-white solid (0.8 g).
Its X-ray powder diffraction graph is shown in
The amorphous cariprazine embonate prepared in Example 1, the crystalline form A of cariprazine embonate prepared in Example 8, the crystalline form B of cariprazine embonate prepared in Example 10, the crystalline form F of cariprazine embonate prepared in Example 16, the crystalline form G of cariprazine embonate prepared in Example 17 and the crystalline form I of cariprazine hydrochloride prepared in Example 19 were left to stand under high-temperature (60°C.) conditions, high-humidity (25° C./90% RH) conditions, accelerated (40°C./75% RH) conditions and illuminated (1.2×106 Lux·h) conditions, and samples were taken on day 0, day 5, day 7 and day 10 and tested by HPLC or XRPD.
The related substances results are shown in Table 1, indicating that the crystalline form A of cariprazine embonate, crystalline form B of cariprazine embonate, crystalline form G of cariprazine embonate and crystalline form A of cariprazine embonate of the present disclosure are relatively stable—the total related substances remained substantially unchanged when they were left to stand under these conditions for 10 days, while amorphous cariprazine embonate was unstable and showed a bigger increase in impurities under high-temperature conditions.
The crystalline form stability results are shown in Table 2, indicating that the crystalline form A of cariprazine embonate of the present disclosure had more excellent crystalline form stability than the crystalline form I of cariprazine hydrochloride that is known—when crystalline form A was left to stand under these conditions for 10 days, its crystalline form did not change and its crystallinity also did not change significantly; and that the crystalline form F of cariprazine embonate of the present disclosure was relatively stable under high-temperature conditions and illuminated conditions—its crystalline form did not change—and would change into crystalline form A of cariprazine embonate under high-humidity conditions and accelerated conditions.
The amorphous cariprazine embonate prepared in Example 1, the amorphous cariprazine hemiembonate prepared in Example 3, the amorphous cariprazine laurate prepared in Example 5, the cariprazine palmitate prepared in Example 6, the cariprazine sebacate, cariprazine succinate, cariprazine malate, cariprazine lactate, cariprazine undecanoate and cariprazine heptanoate prepared in Example 7, the crystalline form A of cariprazine embonate prepared in Example 8, the crystalline form B of cariprazine embonate prepared in Example 10, the crystalline form F of cariprazine embonate prepared in Example 16, the crystalline form G of cariprazine embonate prepared in Example 17, the crystalline form I of cariprazine hydrochloride prepared in Example 19 and cariprazine were each added to a corresponding medium. The mixtures were shaken at 37° C. for 24 h and filtered through 0.45 μm aqueous-phase filter membranes. The filtrates were collected and the solubility was determined by high performance liquid chromatography. pH3, pH4, pH5 and pH6 represent acetate buffer solutions, and pH7, pH7.4, pH8 and pH9 represent phosphate buffer solutions.
The results are shown in Table 3, indicating that the solubilities of the cariprazine embonate and crystalline forms thereof and cariprazine hemiembonate prepared in the present disclosure were all significantly lower—the solubility of cariprazine embonate in water was 3-10 μg/mL, which is equivalent to one eighteenth to one sixtieth of the cariprazine's solubility (about 180 μg/mL) and one thousandth to one thirty-six hundredth of the cariprazine hydrochloride's solubility (about 11 mg/mL)—and were all relatively low in media having different pH values. As they have sustained-release effects, their equivalent solubilities in media having different pH values enable the rate of release to be least dependent on pH, so that influence on their rates of drug release in pH environments of different areas in the body is avoided, burst releases or excessive plasma concentrations in local areas in the body are avoided, and the difference in drug release between individuals is reduced. In addition, as cariprazine embonate has relatively good crystalline form stability, it is suitable for use in long-acting preparations so fewer doses can be used and therefore patient compliance is improved. Cariprazine embonate has a good marketing prospect.
The amorphous cariprazine embonate prepared in Example 1, the crystalline form A of cariprazine embonate prepared in Example 8, the crystalline form B of cariprazine embonate prepared in Example 10 and the crystalline form G of cariprazine embonate prepared in Example 17 were each added to a phosphate buffer solution medium having a pH of 7.4. The mixtures were shaken at 37° C. Point samples were taken at 1 h, 3 h, 5 h, 7 h and 24 h and the solubility was determined. The results are shown in Table 4 and
The crystalline form A of cariprazine embonate prepared in Example 8 and the crystalline form I of cariprazine hydrochloride prepared in Example 19 were each added to corresponding media such as pH6, pH7, pH7.4, pH8, pH9, etc. The mixtures were shaken at 37° C. for 4 h and centrifuged. The residues were tested by XRPD, and the results show that crystalline form A of cariprazine embonate did not change while crystalline form I of cariprazine hydrochloride dissociated into cariprazine free base. The pH7.4 comparison results are shown in
Preparation process:
The syringeability, suspendibility, settling ratio and redispersibility of the formula samples prepared in Examples 20-25 were investigated, and the investigation revealed that the suspension samples described above could all pass through 0.45×15 mm syringe needles and had good suspendibility, and that the samples of Examples 22-25 had good 24-hour settling ratios and redispersibility.
Preparation process:
The syringeability, suspendibility, settling ratio and wettability of the formula samples prepared in Examples 26-30 were investigated, and the investigation revealed that the suspension samples described above could all pass through 0.45×15 mm syringe needles and had good suspendibility, settling ratios and wettability.
Preparation process:
From the results in the table above, it can be seen that in aqueous suspensions of the same formula, aqueous suspensions of particles of different particle sizes (Dv90) can be prepared by controlling the grinding parameters.
Preparation process:
The syringeability, suspendibility, settling ratio and wettability of the formula samples prepared in
Examples 35-37 were investigated, and the investigation revealed that the suspension samples described above could all pass through 0.45×15 mm syringe needles and had good suspendibility, settling ratios and wettability.
According to the results in the table above and the investigation of syringeability, suspendibility, settling ratio and wettability, aqueous suspensions of the same formula and the same grinding parameters apply to different crystalline forms of cariprazine embonate.
Preparation process:
The 0-day, 5-day and 10-day particle size and related substances of the cariprazine embonate prepared in Example 33 and the aqueous suspension of cariprazine hydrochloride prepared in Example 38 were measured at 60° C., and the results are shown in the table below.
From the results in the table above, it can be seen that in aqueous suspensions of the same formula, the aqueous suspension of cariprazine embonate was significantly more stable than the aqueous suspension of cariprazine hydrochloride with respect to impurity and particle size.
1. Process of preparing injectable suspensions of Examples 40-43:
2. Process of preparing oral suspension of Example 44:
An in vivo experiment was conducted on rats with the different concentrations of formula samples of cariprazine embonate prepared in Examples 40-44 as follows:
15 male SD rats were divided into five groups, of which four groups were given single doses of formula samples of different crystalline forms of cariprazine embonate by intramuscular injection at 9 mg/kg and plasma was collected 0 h, 1 h, 3 h, 7 h, 24 h, 4 d, 7 d, 11 d, 15 d, 20 d, 25 d and 30 d after administration; the remaining group was orally intragastrically given single doses of the formula sample of crystalline form A of cariprazine embonate at 0.3 mg/kg and plasma was collected 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h and 24 h after administration. In the whole experiment, the animals from the intramuscular injection group were given ad libitum access to food and water, and those from the oral intragastrical group were fasted overnight before administration and given access to food 4 h after administration.
Plasma sample collection: about 150 μL of blood was collected from the jugular vein (whole blood was centrifuged within 30 min to isolate plasma) and placed in a tube containing anticoagulant EDTA-K2, and after treatment, plasma was stored in a freezer at −70° C. before use.
Pretreatment of plasma sample: to 30 μL of plasma sample was added 200 μL of internal standard solution (40 ng/mL Glipizide acetonitrile solution); the mixture was vortexed for 1 min and centrifuged at 5800 rpm at 4° C. for 10 min; 100 μL of supernatant was transferred to a new plate and 1 μL of solution was taken for LC-MS/MS analysis.
Chromatographic conditions:
Mobile phase composition: mobile phase A: 0.025% formic acid in water-1 mM ammonium acetate mobile phase B: 0.025% methanoic acid in methanol-1 mM ammonium acetate
Gradient elution:
As can be seen from
From the experimental results of the present disclosure, it can be seen that after the injectable preparations of cariprazine embonate provided by the present disclosure were formulated into aqueous suspensions, cariprazine embonate had relatively small granularity and was evenly distributed, having good injectability and also the characteristic of continuously releasing the drug over a long time (at least one week in SD rats).
| Number | Date | Country | Kind |
|---|---|---|---|
| 202010869671.7 | Aug 2020 | CN | national |
| 202010870701.6 | Aug 2020 | CN | national |
| 202110324874.2 | Mar 2021 | CN | national |
| 202110330670.X | Mar 2021 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2021/114756 | 8/26/2021 | WO |
