HK40025629B - Novel salts and crystals - Google Patents
Novel salts and crystals Download PDFInfo
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- HK40025629B HK40025629B HK62020015410.7A HK62020015410A HK40025629B HK 40025629 B HK40025629 B HK 40025629B HK 62020015410 A HK62020015410 A HK 62020015410A HK 40025629 B HK40025629 B HK 40025629B
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- toluenesulfonic acid
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Description
This disclosure relates to certain salts and crystal forms of a substituted heterocycle fused gamma-carboline, the manufacture thereof, pharmaceutical compositions thereof, and use thereof, e.g., in the treatment of diseases or abnormal conditions involving or mediated by the 5-HT2A receptor, serotonin transporter (SERT), and/or dopamine D1/D2 receptor signaling pathways.
1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (sometimes referred to as 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone, and also known as Lumateperone or as ITI-007), has the following structure:
ITI-007 is a potent 5-HT2A receptor ligand (Ki=0.5 nM) with a strong affinity for the dopamine (DA) D2 receptor (Ki=32 nM) and the serotonin transporter (SERT) (Ki=62 nM), but negligible binding to receptors associated with cognitive and metabolic side effects of antipsychotic drugs (e.g., H1 histaminergic, 5-HT2C, and muscarinic). ITI-007 is also active at the dopamine D1 receptor (Ki=52 nM), and indirectly via this interaction, ITI-007 has been found to result in enhanced NMDA and AMPA signaling in the brain, especially in the medial prefrontal cortex (mPFC). ITI-007 is currently in clinical trials, e.g., for the treatment of schizophrenia, depression, and other psychological disorders. While ITI-007 is a promising drug, its production and formulation present challenges. In free base form, ITI-007 is an oily, sticky solid, with poor aqueous solubility. Making salts of the compound has proven to be unusually difficult. A hydrochloride salt form of ITI-007 was disclosed in U.S. Patent 7,183,282 , but this particular salt form was hygroscopic and showed poor stability. It was obtained by precipitation from diethyl ether. A toluenesulfonic acid addition salt (tosylate) of ITI-007 was finally identified and described in WO 2009/114181 and US 2011/0112105 ( U.S. Patent 8,648,077 ). ITI-007 (Lumateperone) salt forms are further discussed in WO 2018/031535 A1 and WO 2019/102240 A1 .
There is a need for alternative stable and pharmaceutically acceptable salts and polymorphs of ITI-007.
The invention relates to a method of making a stable bis-tosylate salt of 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007), comprising the steps of:
- (a) reacting 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) free base with toluenesulfonic acid, together with an organic solvent, wherein the organic solvent is 2-butanone wherein the ITI-007 free base and toluenesulfonic acid are in a molar ratio of 1:1, wherein the reaction temperature is room temperature, wherein the reaction time is 25 hours, and wherein the concentration of the ITI-007 free base is about 1 g per 20 mL of 2-butanone solvent; and
- (b) recovering the salt thus formed by filtration.
In an effort to find new salts and polymorphs of ITI-007, an extensive salt screen was undertaken. ITI-007 does not readily form salts with other common, pharmaceutically acceptable acids, despite the good solubility of the free base in a variety of organic solvents. Initially, a toluenesulfonic acid addition salt (tosylate) was prepared, as described in WO 2009/114181 and US 2011/0112105 , but no other stable salts were found. Finally, a major salt screen was carried out, wherein the free base compound was studied in different solvent systems and under different conditions, and then systematically screened using a selection of over 100 acids under different conditions and with different solvent, cosolvent and anti-solvent systems, to identify new possible salt forms. Following extensive screening and experimentation, a new bis-tosylate salt polymorph was discovered. This new bistosylate salt form is crystalline and stable.
The present disclosure thus provides a new bis-tosylate salt form of ITI-007, which is especially advantageous for use in the preparation of galenic formulations, together with methods of making and using the same. The bi-tosylate salt form of ITI-007 is not part of the invention, which is solely defined in the appended claim. This disclosure shows that this new bis-tosylate salt form of ITI-007 can be prepared under various conditions, including from the free base form of ITI-007, as well as from the mono-tosylate salt form of ITI-007. Only the method as defined in the appended claim is according to the invention.
Further areas of applicability of the present invention will become apparent from the detailed description provided hereinafter
The present invention will become more fully understood from the detailed description and the accompanying drawings.
- Figure 1 depicts overlaid X-ray powder diffraction (XRPD) patterns for the ITI-007 bis-tosylate salt crystal obtained from Example 1 (from a 1:1 molar mixture of ITI-007 free base and toluenesulfonic acid) (upper curve), with reference to the known XRPD pattern for ITI-007 mono-tosylate salt crystal (lower curve).
- Figure 2 depicts the TGA-DSC thermogram of the ITI-007 bis-tosylate salt crystal obtained from Example 1.
- Figure 3 depicts the 1H-NMR spectrum of the ITI-007 bis-tosylate salt crystal obtained from Example 1.
- Figure 4 depicts the FTIR spectrum of the ITI-007 bis-tosylate salt crystal obtained from Example 1.
- Figure 5 depicts overlaid X-ray powder diffraction (XRPD) patterns for the ITI-007 mono-tosylate salt crystal obtained from Example 2 (from a 2:1 molar mixture of ITI-007 free base and toluenesulfonic acid) (upper curve), with reference to the known XRPD pattern for ITI-007 mono-tosylate salt crystal (lower curve).
- Figure 6 depicts the TGA-DSC thermogram of the ITI-007 bis-tosylate salt crystal obtained from Example 2.
- Figure 7 depicts the 1H-NMR spectrum of the ITI-007 bis-tosylate salt crystal obtained from Example 2.
The following description of the preferred embodiment(s) is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses.
As used throughout, ranges are used as shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range.
Unless otherwise specified, all percentages and amounts expressed herein and elsewhere in the specification should be understood to refer to percentages by weight. The amounts given are based on the active weight of the material.
The invention relates to a method of making a stable bis-tosylate salt of 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007), comprising the steps of:
- (a) reacting 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) free base with toluenesulfonic acid, together with an organic solvent, wherein the organic solvent is 2-butanone wherein the ITI-007 free base and toluenesulfonic acid are in a molar ratio of 1:1, wherein the reaction temperature is room temperature, wherein the reaction time is 25 hours, and wherein the concentration of the ITI-007 free base is about 1 g per 20 mL of 2-butanone solvent; and
- (b) recovering the salt thus formed by filtration.
The disclosure further provides 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) in stable bis-tosylate salt form (Salt 1), which is not part of the invention. Also disclosed, but not part of the invention, are the following aspects 1.1. to 1.27.
1.1. Salt 1, wherein the salt is in solid form.
1.2. Salt 1 or 1.1, wherein the salt is in crystalline form, e.g., dry crystalline form.
1.3. Salt 1.2, wherein the salt is in a homogeneous crystal form, e.g., free or substantially free of other forms of ITI-007, e.g., free or substantially free, e.g., less than 10 wt. %, preferably less than about 5 wt. %, more preferably less than about 2 wt. %, still preferably less than about 1 wt. %, still preferably less than about 0.1 %, most preferably less than about 0.01 wt. %, of any amorphous forms.
1.4. Any foregoing form of Salt 1, wherein the salt is in crystalline form, crystallized from 2-butanone solvent.
1.5. Any foregoing form of Salt 1, wherein the salt is a solvate, e.g., a 2-butanone solvate.
1.6. Any foregoing form of Salt 1, wherein the salt is not a solvate.
1.7. Any foregoing form of Salt 1, wherein the salt is a hydrate.
1.8. Any foregoing form of Salt 1, wherein the salt is not a hydrate.
1.9. Any foregoing form of Salt 1, wherein the salt is formed by combining free ITI-007 free base and toluenesulfonic acid in a molar ratio from 1:1 to 1:3, e.g., a molar ratio from 1:1 to 1:2.2, or from 1:1 to 1:2, or from 1:1 to 1:1.5, or a molar ratio of about 1:1, or about 1:1.5, or about 1:2, or about 1:2.2.
1.10. Any foregoing form of Salt 1, wherein the salt is formed from a slurry of ITI-007 free base and toluenesulfonic acid in 2-butanone solvent.
1.11. Any foregoing form of Salt 1, wherein a DSC/TGA analysis of the salt shows one endothermic event at about 184 ºC, and one exothermic event at about 258 ºC, e.g. wherein a DSC/TGA analysis shows the first endothermic event at about Tonset= 178 °C, Tpeak= 184 °C and ΔE= -88 J/g, and the second exothermic event at about Tonset= 242 °C, Tpeak= 258 °C and ΔE= 122 J/g, for example, wherein the first endothermic event is a melt and the second exothermic event is a recrystallization.
1.12. Any foregoing form of Salt 1, wherein the salt is in the form of a crystal having an X-ray powder diffraction pattern corresponding to the d-spacing and/or angle (2-theta) values of the following table, for example, wherein the pattern comprises at least five, or at least six, or at least seven, or at least eight of said values, e.g., taking into account potential variations due to sample purity and instrument variation, for example 2θ shifts due to variation in X-ray wavelength, e.g., wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer with a copper anode and a nickel filter, e.g., comprising at least those peaks having a relative intensity of at least 0.4, at least 0.5, or at least 0.6, or comprising peaks 1, 2, 6, 7, 8, and 9:
XRPD (Cu anode, Ni filter) for Bis-tosylate Salt Crystal Polymorph 1
1.13. Any foregoing form of Salt 1, wherein the salt is in the form of a crystal having an X-ray powder diffraction pattern corresponding to Figure 1 (upper curve), e.g., taking into account potential variations due to sample purity and instrument variation, for example 2θ shifts due to variation in X-ray wavelength, e.g., an X-ray powder diffraction pattern corresponding to Figure 1 generated using an X-ray diffractometer with a copper anode and a nickel filter.
1.14. Any foregoing form of Salt 1, wherein the salt is in the form of a crystal having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8, peaks having angle (2-theta) values selected from the group consisting of about 6.35, 8.39, 10.45, 13.79, 14.26, 14.66, 14.92, 15.40, 15.93, 16.51, 17.11, 17.90, 18.65, 19.20, 20.49, 20.67, 20.86, 22.47, 22.90, 23.97, 25.11, 25.92, 27.03, 27.42, 28.74, 29.14, 30.13, 31.65, 33.43, 35.41, 36.48, 39.67, 42.62, and 43.56, taking into account potential variations due to sample purity and instrument variation, e.g., wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer with a copper anode and a nickel filter.
1.15. Any foregoing form of Salt 1, in the form of a crystal having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8, peaks having d-spacing values selected from the group consisting of about 13.91, 10.53, 8.46, 6.42, 6.21, 6.04, 5.93, 5.75, 5.56, 5.37, 5.18, 4.95, 4.75, 4.62, 4.33, 4.29, 4.26, 3.95, 3.88, 3.71, 3.54, 3.44, 3.30, 3.25, 3.10, 3.06, 2.96, 2.83, 2.68, 2.53, 2.46, 2.27, 2.12, and 2.07, taking into account potential variations due to sample purity and instrument variation, wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer with a copper anode and a nickel filter.
1.16. Any foregoing form of Salt 1, wherein the salt is in the form of a crystal having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8, peaks having angle (2-theta) values and/or d-spacing values as provided in Salts 1.14 and/or 1.15.
1.17. Any foregoing form of Salt, wherein the salt is in the form of a crystal having an X-ray powder diffraction pattern having at least a peak of 25% relative intensity at an angle (2-theta) value of 10.2-10.5 (e.g., 10.3-10.5, or about 10.3, or about 10.4 or about 10.45, or about 10.5), optionally, wherein said peak has a relative intensity of at least 30% or at least 40% or at least 50%, or about 25% or about 30%, or about 35%.
1.18. Any foregoing form of Salt 1, wherein the salt is in the form of a crystal having an X-ray powder diffraction powder having relative angle (2-theta) values as provided in the table of embodiment 1.12, wherein the values are shifted by up to +/- 0.2 degrees, e.g., wherein the values are substantially uniformly shifted by up to +/- 0.2 degrees.
1.19. Any foregoing form of Salt 1, wherein the salt is in the form of a crystal having an X-ray diffraction pattern as shown, or substantially as shown, in the upper curve of Figure 1 .
1.20. Any foregoing form of Salt 1, wherein the salt is in the form of a crystal having a DSC/TGA thermogram as shown, or substantially as shown, in Figure 2 .
1.21. Any foregoing form of Salt 1, wherein the salt has a proton NMR spectrum as shown, or substantially as shown, in Figure 3 .
1.22. Any foregoing form of Salt 1, wherein the salt has a proton NMR spectrum indicating the presence of about two toluenesulfonic acid moieties per ITI-007 base moiety, e.g., as demonstrated by the NMR proton peaks at (i.e., the multiplets centered at) about 7.11 ppm, 7.36 ppm, 7.49 ppm and 8.03 ppm at about an integral ratio of 4:2:4:2 (when the spectrum is taken at 400 MHz in DMSO-d6 solvent).
1.23. Any foregoing form of Salt 1, wherein the salt has an FTIR spectrum as shown, or substantially as shown, in Figure 4 .
1.24. Any foregoing form of Salt 1, wherein the salt contains less than 10 wt% of any other ITI-007 tosylate salt form (e.g., mono-tosylate salt or tri-tosylate salt), e.g., less than 5%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, by weight of Salt 1.
1.25. Any foregoing form of Salt 1, wherein the salt contains less than 10 wt% of ITI-007 free base form, e.g., less than 5%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, by weight of Salt 1.
1.26. Any foregoing form of Salt 1, wherein the ITI-007 is deuterated, e.g., wherein the deuterium:protium ratio at one or more specified positions in the molecule is significantly higher, e.g., at least 2x, for example at least 10x higher, than the natural isotope ratios or the isotope ratios at other positions in the molecule; for example, any foregoing form of Salt 1 wherein the -CH2- adjacent to the methylated nitrogen moiety and/or adjacent to the carbonyl moiety of ITI-007 is deuterated, e.g., is in the form of -CHD- or -CD2- at levels which are significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule, and/or wherein the methyl group is deuterated, e.g., is CD3-, e.g., at levels which are significantly higher than the natural deuterium:protium isotope ratio or the deuterium:protium isotope ratio at other positions in the molecule, e.g., as described in WO 2015/154025 (and U.S. Pat. Pub. 2017/0183350 ) or as described in WO 2017/165843 (equivalent to U.S. Applic. No. 16/088,397 ).
1.27. Any foregoing form of Salt 1, wherein the salt exhibits any combination of characteristics as described in 1.1-1.26.
| # | |||
| 1 | 6.347 | 13.9139 | 1.70% |
| 2 | 8.389 | 10.53127 | 18.20% |
| 3 | 10.453 | 8.45646 | 36.00% |
| 4 | 13.794 | 6.41449 | 6.60% |
| 5 | 14.26 | 6.20595 | 24.30% |
| 6 | 14.661 | 6.03727 | 25.20% |
| 7 | 14.916 | 5.93459 | 25.20% |
| 8 | 15.397 | 5.75029 | 31.10% |
| 9 | 15.925 | 5.56057 | 27.10% |
| 10 | 16.51 | 5.36504 | 18.60% |
| 11 | 17.106 | 5.1793 | 54.00% |
| 12 | 17.895 | 4.95287 | 21.80% |
| 13 | 18.65 | 4.75399 | 14.70% |
| 14 | 19.198 | 4.61939 | 3.10% |
| 15 | 20.488 | 4.33151 | 100.00% |
| 16 | 20.67 | 4.29368 | 75.70% |
| 17 | 20.857 | 4.25564 | 68.10% |
| 18 | 22.468 | 3.95398 | 15.00% |
| 19 | 22.9 | 3.88029 | 11.80% |
| 20 | 23.973 | 3.709 | 24.60% |
| 21 | 25.114 | 3.54305 | 12.80% |
| 22 | 25.919 | 3.43479 | 7.90% |
| 23 | 27.032 | 3.29588 | 10.80% |
| 24 | 27.416 | 3.25062 | 27.80% |
| 25 | 28.738 | 3.10393 | 3.90% |
| 26 | 29.14 | 3.06208 | 3.40% |
| 27 | 30.128 | 2.96386 | 6.10% |
| 28 | 31.645 | 2.82511 | 3.00% |
| 29 | 33.432 | 2.67815 | 1.50% |
| 30 | 35.412 | 2.53276 | 5.30% |
| 31 | 36.475 | 2.46136 | 2.30% |
| 32 | 39.667 | 2.27035 | 3.90% |
| 33 | 42.624 | 2.11941 | 2.50% |
| 34 | 43.595 | 2.07446 | 1.80% |
In one embodiment, the invention provides a process (Process 1) for the production of Salt 1, comprising
- (a) reacting 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) free base with toluenesulfonic acid, e.g., together with an organic solvent wherein the organic solvent is 2-butanone, for example, wherein the ITI-007 free base and toluenesulfonic acid are in a molar ratio of 1:1; wherein the reaction temperature is room temperature, wherein the reaction time is 25 hours, and wherein the concentration of the ITI-007 free base is about 1 g per 20 mL of 2-butanone solvent; and
- (b) recovering the salt thus formed by filtration, e.g., recovering Salt 1.
In another embodiment of Process 1, the reaction step (a) comprises dissolving or suspending the ITI-007 free base in 2-butanone, and adding thereto the toluenesulfonic acid. In another embodiment of Process 1, the reaction step (a) comprises combining the ITI-007 free base with the toluenesulfonic acid and adding thereto 2-butanone.
In some embodiments of Process 1, the process step (a) is carried out as a batch process, and in other embodiments the process step (a) is carried out as a continuous (flow) process.
Also disclosed, but not part of the invention, is a pharmaceutical composition comprising Salt 1, or any of Salts 1.1-1.27, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier.
Also disclosed, but not part of the invention, is a pharmaceutical composition comprising Salt 1, or any of Salts 1.1-1.27, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, wherein the salt is predominantly, or is entirely or substantially entirely, in dry crystalline form.
Also disclosed, but not part of the invention, is a pharmaceutical composition comprising Salt 1, or any of Salts 1.1-1.27, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, wherein the composition is in the form of an injectable depot, e.g., to provide extended release of ITI-007.
Also disclosed, but not part of the invention, is a pharmaceutical composition (Composition 2) comprising:
- (1) (a) 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) free base or (b) an acid addition salt of 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) free base, and
- (2) at least 1 molar equivalent of toluenesulfonic acid based on the amount of 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) present.
Also disclosed, but not part of the invention, is a method of making Composition 2 comprising the steps of:
- (1) Combining either (a) 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) free base or (b) an acid addition salt of 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) free base, with
- (2) at least 1 molar equivalent of toluenesulfonic acid based on the amount of 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) present, and
- (3) mixing the components with at least one pharmaceutically acceptable diluent or carrier to form the Composition.
Also disclosed, but not part of the invention, are Salt 1, or any of Salts 1.1-1.27, or a pharmaceutical composition comprising Salt 1, or any of Salts 1.1-1.27, for use in treating a disease or abnormal condition involving or mediated by the 5-HT2A receptor, serotonin transporter (SERT), and/or dopamine D1/D2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorders, bipolar depression, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, social phobias, and/or dementia.
Also disclosed, but not part of the invention, is a method for the prophylaxis or treatment of a human suffering from a disease or abnormal condition involving or mediated by the 5-HT2A receptor, serotonin transporter (SERT), and/or dopamine D1/D2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorders, bipolar depression, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, social phobias, and/or dementia, the method comprising administering to a patient in need thereof a therapeutically effective amount of Salt 1, or any of Salts 1.1-1.27.
The following equipment and methods are used to isolate and characterize the exemplified salt forms:
X-ray powder diffraction (XRPD): The X-ray powder diffraction studies are performed using a Bruker AXS D2 PHASER in Bragg-Brentano configuration, equipment #1549 / #2353. The equipment uses a Cu anode at 30kV, 10 mA; sample stage standard rotating; monochromatization by a Kβ-filter (0.5% Ni). Slits: fixed divergence slits 1.0 mm (=0.61°), primary axial Soller slit 2.5°, secondary axial Seller slit 2.5°. Detector: Linear detector LYNXEYE with receiving slit 5° detector opening. The standard sample holder (0.1 mm cavity in (510) silicon wafer) has a minimal contribution to the background signal. Measurement conditions: scan range 5 - 45° 2θ, sample rotation 5 rpm, 0.5s/step, 0.010°/step, 3.0mm detector slit; and all measuring conditions are logged in the instrument control file. As system suitability, corundum sample A26-B26-S (NIST standard) is measured daily. The software used for data collection is Diffrac.Commander v2.0.26. Data analysis is done using Diffrac.Eva v1.4. No background correction or smoothing is applied to the patterns.
Simultaneous thermogravimetry (TGA) and differential scanning calorimetry (DSC) or TGA/DSC analysis: The TGA/DSC studies are performed using a Mettler Toledo TGA/DSC1 Stare System, equipment #1547, auto-sampler equipped, using pin-holed Al-crucibles of 40 µl. Measurement conditions: 5 min 30.0 °C, 30.0 - 350.0 °C with 10 °C/min., N2 flow of 40 ml/min. The software used for instrument control and data analysis is STARe v12.10.
Differential scanning calorimetry (DSC): The DSC studies are performed using a Mettler Toledo DSC1 STARe System, equipment #1564. The samples are made using Al crucibles (40 µl; pierced). Typically, 1 to 8 mg of sample is loaded onto a pre-weighed Al crucible and is kept at 30°C for 5 minutes, after which it is heated at 10°C/min from 30°C to 350 °C and kept at 350°C for 1 minute. A nitrogen purge of 40 ml/min is maintained over the sample. As system suitability checks, Indium and Zinc are used as references. The software used for data collection and evaluation is STARe Software v12.10 build 5937. No corrections are applied to the thermogram.
Fourier transform infrared spectroscopy (FT-IR): The FT-IR studies are performed using a Thermo Scientific Nicolet iS50, equipment # 2357. An attenuated total reflectance (ATR) technique is used with a beam splitter of KBr. Number of scans is 16 with a resolution of 4, from 400 cm-1 to 4000 cm-1. The software OMNIC version 9.2 is used for data collection and evaluation.
High performance liquid chromatography (HPLC): The high performance liquid chromatography analyses are performed on an LC-31, equipped with an Agilent 1100 series G1322A degasser equipment #1894, an Agilent 1100 series G1311A quaternary pump equipment #1895, an Agilent 1100 series G1313A ALS equipment #1896, an Agilent 1100 series G1318A column equipment #1897 and an Agilent 1100 series G1314A VWD equipment #1898 / LC-34, equipped with an Agilent 1200 series G1379B degasser equipment #2254, an Agilent 1100 series G1311A quaternary pump equipment #2255, Agilent 1100 series G1367A WPALS equipment #1656, an Agilent 1100 series G1316A column equipment #2257 and an Agilent 1100 series G1315B DAD equipment #2258. Data is collected and evaluated using Agilent ChemStation for LC systems Rev. B.04.02[96]. Solutions are prepared as follows: Mobile phase A: Add 800 ml of MilliQ water to a 1L volumetric flask Add 1 ml of TFA and homogenize. Fill up to the mark with MilliQ. Mobile phase B: Add 800 ml of Acetonitrile to a 1L volumetric flask Add 1 ml of TFA and homogenize. Fill up to the mark with Acetonitrile; Diluent: 50/50 MeOH/ACN.
Proton Nuclear Magnetic Resonance (NMR): Samples are prepared in DMSO-d6 solvent, and spectra are collected on an Agilent Inova400 at room temperature, and at a frequency of 399.9 MHz, with a sweep width of 6398 Hz, and spin of 20 Hz.
Approximately one gram of ITI-007 free base and one molar equivalent of toluenesulfonic acid is combined and mixed with 2-butanone solvent (20 mL). The mixture is stirred at 500 rpm at room temperature for 25 hours. The mixture is then filtered and dried to give a white/brown solid. The solid is analyzed by XRPD, DSC/TGA, HPLC, FTIR and proton NMR. The solid is found to be soluble in methanol and acetic acid (> 30 mg/mL), and sparingly soluble in dichloromethane (10-30 mg/mL).
XRPD analysis shows the obtained solid to be a crystalline solid. The XRPD pattern is shown in Figure 1 (upper curve) with reference to the XRPD pattern obtained from a previously made ITI-007 mono-tosylate salt crystal (lower curve). The reference crystal was obtained from a 1:1 molar mixture of ITI-007 and toluenesulfonic acid using ethyl acetate or toluene as solvent. The results show clear differences in the XPRD pattern between the solid obtained by Example 1 and the reference ITI-007 mono-tosylate salt. One key distinguishing peak that is believed to signal formation of the bis-tosylate salt appears at an angle (2-theta) of about 10.45. The peaks for the compound of Example 1 are identified in tabular form in table 1:
Table 1. XRPD peak list for ITI-007 Bis-tosylate Salt of Example 1
| 1 | 6.347 | 13.9139 | 1.70% |
| 2 | 8.389 | 10.53127 | 18.20% |
| 3 | 10.453 | 8.45646 | 36.00% |
| 4 | 13.794 | 6.41449 | 6.60% |
| 5 | 14.26 | 6.20595 | 24.30% |
| 6 | 14.661 | 6.03727 | 25.20% |
| 7 | 14.916 | 5.93459 | 25.20% |
| 8 | 15.397 | 5.75029 | 31.10% |
| 9 | 15.925 | 5.56057 | 27.10% |
| 10 | 16.51 | 5.36504 | 18.60% |
| 11 | 17.106 | 5.1793 | 54.00% |
| 12 | 17.895 | 4.95287 | 21.80% |
| 13 | 18.65 | 4.75399 | 14.70% |
| 14 | 19.198 | 4.61939 | 3.10% |
| 15 | 20.488 | 4.33151 | 100.00% |
| 16 | 20.67 | 4.29368 | 75.70% |
| 17 | 20.857 | 4.25564 | 68.10% |
| 18 | 22.468 | 3.95398 | 15.00% |
| 19 | 22.9 | 3.88029 | 11.80% |
| 20 | 23.973 | 3.709 | 24.60% |
| 21 | 25.114 | 3.54305 | 12.80% |
| 22 | 25.919 | 3.43479 | 7.90% |
| 23 | 27.032 | 3.29588 | 10.80% |
| 24 | 27.416 | 3.25062 | 27.80% |
| 25 | 28.738 | 3.10393 | 3.90% |
| 26 | 29.14 | 3.06208 | 3.40% |
| 27 | 30.128 | 2.96386 | 6.10% |
| 28 | 31.645 | 2.82511 | 3.00% |
| 29 | 33.432 | 2.67815 | 1.50% |
| 30 | 35.412 | 2.53276 | 5.30% |
| 31 | 36.475 | 2.46136 | 2.30% |
| 32 | 39.667 | 2.27035 | 3.90% |
| 33 | 42.624 | 2.11941 | 2.50% |
| 34 | 43.595 | 2.07446 | 1.80% |
The DSC/TGA thermogram is shown in Figure 2 . DSC/TGA analysis shows one endothermic event at about 184ºC, and one exothermic event at about 258 ºC. The first endothermic event occurs at about Tonset= 178 °C, with a Tpeak= 184 °C and a ΔE= -88 J/g. The second exothermic event occurs at about Tonset= 242 °C, with a Tpeak= 258 °C and a ΔE= 122 J/g. The endothermic event is a melt, while the exothermic event is a recrystallization. The TGA profile shows a mass loss of 1.7% from 40 °C to 190 °C, and a mass loss of 3.4% from 210 °C to 270 °C. It is noted that the recrystallization event occurs at a temperature about 25 °C lower than that previously observed for the reference ITI-007 mono-tosylate salt crystal.
LC-MS analysis shows a purity of 92 area% for the obtained solid.
Proton NMR is shown in Figure 3 . Proton NMR analysis shows that the compound is the bis-tosylate salt of ITI-007. Specifically, the proton NMR spectrum shows the presence of about two toluenesulfonic acid moieties per ITI-007 base moiety. This is demonstrated by the NMR protons at about 7.11 ppm, 7.36 ppm, 7.49 ppm and 8.03 ppm, which are present at an integral ratio of about 4:2:4:2. The 7.11 and 7.49 ppm peaks represent protons from the aromatic tosylate ring of the toluene sulfonate moiety, while the 7.36 and 8.03 peaks represent protons from the aromatic 4-fluorophenyl ring of the ITI-007 moiety. The remaining aromatic peaks between 6.4 and 7.0 ppm represent the aromatic protons of the quinoxaline core of ITI-007 and their integral is consistent with one molar unit of ITI-007 free base. The alkyl peak at about 2.3 ppm represents the methyl group of the tosylate rings and its integral is also consistent with two molar units of toluenesulfonic acid.
The FTIR spectrum is shown in Figure 4 , and it is also consistent with a bis-tosylate structure of the salt.
Dynamic vapor sorption (DVS) analysis shows a stepwise sorption with a total mass uptake at 95 RH% of 2%. This salt is thus slightly hygroscopic. Analysis results are summarized in Table 2 below. Table 2. Analytical results for ITI-007 Bis-tosylate Salt of Example 1
| 2-Butanone | White/brown solid | 2 | 184 | -88 | 1.7 | 92 |
| 258 | +121 | 3.4 |
In direct comparison to the analytical data obtained on the mono-tosylate salt of Example 2, it is apparent that the salt of Example 1 is a distinct crystalline salt form comprising a 1:2 molar ratio of ITI-007 free base to toluene sulfonic acid. Without being bound by theory, it is believed that the lower solubility of ITI-007 free base in 2-butanone solvent, compared to other solvents, result in the effective concentration of free base being lower, and the effective ratio of free base to toluenesulfonic acid being higher. As a result, the bis-tosylate salt forms and unreacted free base remains in solution after filtration of the product.
Additional experiments demonstrate that at a 1:2 molar ratio of ITI-007 free base to toluenesulfonic acid in 2-butanone solvent, conducted substantially as described above, the solid collected after filtration is the same bis-tosylate salt as described above in high to quantitative yield.
Approximately one gram of ITI-007 free base and one-half molar equivalent of toluenesulfonic acid is added mixed with 2-butanone solvent (15 mL). The mixture is stirred at 500 rpm at room temperature for 25 hours. The mixture is then filtered and dried to give a white solid. The solid is analyzed by XRPD, DSC/TGA, HPLC, FTIR and proton NMR. The analysis demonstrates that this salt is a mono-tosylate salt of ITI-007 and it is distinctly different from the bis-tosylate salt obtained from Example 1.
XRPD analysis shows the obtained solid to be a crystalline solid. The XRPD pattern is shown in Figure 5 (upper curve) with reference to the XRPD pattern obtained from a previously made ITI-007 mono-tosylate salt crystal (lower curve). The reference crystal was obtained from a 1:1 molar mixture of ITI-007 and toluenesulfonic acid using ethyl acetate or toluene as solvent. The results show substantially the same XPRD pattern between the solid obtained by Example 2 and the reference ITI-007 mono-tosylate salt. The peaks for the compound of Example 2 are identified in tabular form in table 3:
Table 3. XRPD peak list for ITI-007 Mono-tosylate Salt of Example 2
| # | |||
| 1 | 8.463 | 10.43945 | 9.70% |
| 2 | 11.331 | 7.80275 | 15.20% |
| 3 | 12.059 | 7.33324 | 47.30% |
| 4 | 13.285 | 6.65902 | 23.70% |
| 5 | 14.142 | 6.25762 | 1.00% |
| 6 | 14.987 | 5.90646 | 3.20% |
| 7 | 15.802 | 5.6038 | 21.50% |
| 8 | 15.929 | 5.55918 | 18.40% |
| 9 | 16.381 | 5.40706 | 13.20% |
| 10 | 16.993 | 5.21366 | 100.00% |
| 11 | 17.432 | 5.08331 | 7.80% |
| 12 | 18.096 | 4.89827 | 18.90% |
| 13 | 18.938 | 4.68221 | 16.60% |
| 14 | 19.218 | 4.61464 | 6.30% |
| 15 | 19.854 | 4.46835 | 29.10% |
| 16 | 20.686 | 4.29037 | 4.00% |
| 17 | 21.612 | 4.10869 | 9.40% |
| 18 | 22.557 | 3.93865 | 35.70% |
| 19 | 22.757 | 3.90439 | 26.00% |
| 20 | 23.442 | 3.79192 | 24.90% |
| 21 | 23.642 | 3.7602 | 11.20% |
| 22 | 24.263 | 3.66543 | 39.40% |
| 23 | 25.727 | 3.46008 | 6.50% |
| 24 | 25.912 | 3.43574 | 7.40% |
| 25 | 27.162 | 3.28038 | 4.30% |
| 26 | 29.604 | 3.01515 | 3.30% |
| 27 | 30.804 | 2.90033 | 1.60% |
| 28 | 31.551 | 2.83332 | 3.10% |
| 29 | 32.265 | 2.77228 | 2.30% |
| 30 | 34.662 | 2.58583 | 3.60% |
| 31 | 36.82 | 2.43906 | 1.60% |
| 32 | 37.497 | 2.39657 | 1.60% |
| 33 | 39.386 | 2.28588 | 1.30% |
The DSC/TGA thermogram is shown in Figure 6 . DSC/TGA analysis shows one endothermic event at about 179 ºC, and one exothermic event at about 285 ºC. The first endothermic event occurs at about Tonset= 175 °C, with a Tpeak= 179 °C and a ΔE= -81 J/g. The second exothermic event occurs at about Tonset= 278 °C, with a Tpeak= 285 °C and a ΔE= 255 J/g. The endothermic event is a melt, while the exothermic event is a recrystallization. The TGA profile shows a mass loss of 0.4% from 40 °C to 220 °C, and a mass loss of 9.4% from 220 °C to 290 °C.
LC-MS analysis shows a purity of 93 area% for the obtained solid.
Proton NMR is shown in Figure 7 . Proton NMR analysis shows that the compound is the mono-tosylate salt of ITI-007. Specifically, the spectrum proton NMR spectrum shows the presence of one toluenesulfonic acid moiety per ITI-007 base moiety. This is demonstrated by the NMR protons at about 7.11 ppm, 7.36 ppm, 7.52 ppm and 8.05 ppm, which are present at an integral ratio of about 2:2:2:2. The 7.11 and 7.52 ppm peaks represent protons from the aromatic tosylate ring, while the 7.36 and 8.05 peaks represent protons from the aromatic 4-fluorophenyl ring of the ITI-007 free base. The remaining aromatic peaks between 6.4 and 7.0 ppm represent the aromatic protons of the quinoxaline core of ITI-007 and their integral is consistent with one molar unit of ITI-007 free base (integrals in a 1:1:1 ratio of clearly distinct peaks). The alkyl peak at about 2.3 ppm represents the methyl group of the tosylate ring and its integral is also consistent with one molar unit of toluenesulfonic acid.
Analytical results are summarized in Table 4 below.
Table 4. Analytical results for ITI-007 Mono-tosylate Salt of Example 2
| 2-Butanone | White solid | 179 | -81 | 0.4 | 93 |
| 285 | +255 | 9.4 |
Claims (1)
- A method of making a stable bis-tosylate salt of 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007), comprising the steps of:(a) reacting 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) free base with toluenesulfonic acid, together with an organic solvent, wherein the organic solvent is 2-butanone wherein the ITI-007 free base and toluenesulfonic acid are in a molar ratio of 1:1, wherein the reaction temperature is room temperature, wherein the reaction time is 25 hours, and wherein the concentration of the ITI-007 free base is about 1 g per 20 mL of 2-butanone solvent; and(b) recovering the salt thus formed by filtration.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201862681534P | 2018-06-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK40025629A HK40025629A (en) | 2020-12-24 |
| HK40025629B true HK40025629B (en) | 2023-12-08 |
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