NOVEL SALTS, CRYSTALS, AND CO-CRYSTALS
20230312573 · 2023-10-05
Assignee
Inventors
Cpc classification
C07C309/30
CHEMISTRY; METALLURGY
C07C229/26
CHEMISTRY; METALLURGY
A61P25/18
HUMAN NECESSITIES
International classification
Abstract
The disclosure provides 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-HT.sub.2A receptor, serotonin transporter (SERT), and/or dopamine D.sub.1/D.sub.2 receptor signaling pathways.
Claims
1. 2,2-d.sub.2-1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-one (d.sub.2-lumateperone), in the form of a salt selected from a hydrochloride, mono-tosylate, or bis-tosylate salt, or in the form of a co-crystal between d.sub.2-lumateperone free base and isonicotinamide or between d.sub.2-lumateperone tosylate and lysine free base (e.g., L-lysine), wherein said salt or co-crystal is in solid crystalline form.
2. The salt or co-crystal according to claim 1, wherein the salt or co-crystal is substantially free of other forms of d.sub.2-lumateperone.
3. The salt or co-crystal according to claim 1 which is a hydrochloride salt crystal, e.g., having an X-ray diffraction pattern substantially corresponding to
4. The salt or co-crystal according to claim 1 which is a mono-tosylate salt crystal, e.g., having an X-ray diffraction pattern substantially corresponding to
5. The salt or co-crystal according to claim 1 which is a bis-tosylate salt crystal, e.g., having an X-ray diffraction pattern substantially corresponding to
6. The salt or co-crystal according to claim 1 which is a co-crystal between d.sub.2-lumateperone free base and isonicotinamide, e.g., having an X-ray diffraction pattern substantially corresponding to
7. The salt or co-crystal according to claim 1 which is a co-crystal between d.sub.2-lumateperone mono-tosylate and lysine free base (e.g., L-lysine), e.g., having an X-ray diffraction pattern substantially corresponding to
8. A salt according to claim 1, wherein the salt comprises a 1:1 molar ratio of d.sub.2-lumateperone and hydrochloric acid.
9. A co-crystal according to claim 1, wherein the co-crystal comprises a 1:1 or 2:1 molar ratio of d.sub.2-lumateperone free base and isonicotinamide.
10. A method making a salt according to claim 1, comprising (a) reacting free base d.sub.2-lumateperone with an acid selected from hydrochloric acid and toluenesulfonic acid, e.g., together with an organic solvent, and (b) recovering the salt thus formed.
11. A method making a co-crystal according to claim 1, comprising (a) combining free base d.sub.2-lumateperone with isonicotinamide, or d.sub.2-lumateperone mono-tosylate with lysine free base (e.g., L-lysine), e.g., together with an organic solvent, and (b) recovering the salt thus formed.
12. A method of purifying 2,2-d.sub.2-1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-one (d.sub.2-lumateperone) in free or salt form, comprising reacting d.sub.2-lumateperone with an acid selected from hydrochloric acid and toluenesulfonic acid, or combining free base d.sub.2-lumateperone with isonicotinamide, or d.sub.2-lumateperone mono-tosylate with lysine free base (e.g., L-lysine), recovering the salt or co-crystal thus formed, and optionally converting the salt or co-crystal back to d.sub.2-lumateperone free base or to another salt form.
13. A method for the prophylaxis or treatment of a human suffering from a disease or abnormal condition involving or mediated by the 5-HT.sub.2A receptor, serotonin transporter (SERT), and/or dopamine D.sub.1/D.sub.2 receptor signaling pathways comprising administering to said human an effective amount of a salt according to claim 1.
14. A pharmaceutical composition comprising a salt according to claim 1, in combination or association with a pharmaceutically acceptable diluent or carrier.
15. A salt according to claim 1, wherein the salt is a mono-tosylate salt.
16. A salt according to claim 1, wherein the salt is a bis-tosylate salt.
17. A co-crystal according to claim 1, wherein the co-crystal comprises a 1:1 molar ratio of d.sub.2-lumateperone mono-tosylate and L-lysine free base.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] The present invention will become more fully understood from the detailed description and the accompanying drawings, wherein:
[0026]
[0027]
[0028]
[0029]
[0030]
DETAILED DESCRIPTION
[0031] 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.
[0032] 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. In addition, all references cited herein are hereby incorporated by referenced in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls.
[0033] 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.
Hydrochloride Salts
[0034] In a first embodiment, the invention provides d.sub.2-lumateperone in hydrochloride salt form (Salt 1). The invention therefore provides the following: [0035] 1.1. Salt 1 in solid form. [0036] 1.2. Salt 1 or 1.1 in crystalline form, e.g., dry crystalline form. [0037] 1.3. Salt 1.2 in a homogeneous crystal form, free or substantially free of other forms, 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 amorphous forms. [0038] 1.4. Any foregoing form of Salt 1 in crystalline form, when crystallized from a mixture of hydrochloric acid and d.sub.2-lumateperone, e.g., in an organic solvent, e.g., comprising toluene, ethyl acetate, CPME, or mixtures thereof; e.g., wherein the hydrochloric acid and d.sub.2-lumateperone are in a molar ratio of about 1:1, and the solvent is toluene or CPME, optionally the concentration of d.sub.2-lumateperone is at least 150 g/L or at least 200 g/L. [0039] 1.5. Any foregoing form of Salt 1 which is a solvate, e.g., an ethyl acetate, CPME or toluene solvate. [0040] 1.6. Any foregoing form of Salt 1 which is not a solvate. [0041] 1.7. Any foregoing form of Salt 1 which is a hydrate. [0042] 1.8. Any foregoing form of Salt 1 which is not a hydrate. [0043] 1.9. Any foregoing form of Salt 1 formed by combining hydrochloric acid and d.sub.2-lumateperone free base in about a 1:1 molar ratio. [0044] 1.10. Any foregoing form of Salt 1 wherein a DSC analysis shows (A) two endothermic events, at about 111° C. and about 290° C.; e.g. wherein a DSC/TGA analysis shows the first endothermic event at T.sub.onset=101.9° C., T.sub.peak=110.9° C. and ΔE=−18.4 J/g and the second at T.sub.onset=278.7° C., T.sub.peak=290.0° C. and ΔE=−148.6 J/g; or (B) two endothermic events, at about 108° C. and about 290° C.; e.g. wherein a DSC/TGA analysis shows the first endothermic event at T.sub.onset=93.6° C., T.sub.peak=108.0° C. and ΔE=−30.0 J/g and the second at T.sub.onset=277.5° C., T.sub.peak=289.9° C. and ΔE=−146.3 J/g. [0045] 1.11. Any foregoing form of Salt 1, 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 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, e.g., at least 0.5, e.g., at least 0.6, e.g., comprising peaks 9, 13, 15, 22, 23, and 25 of Table (A) or peaks 6, 10, 17, 18, 20, and 21 of Table (B):
TABLE-US-00001 # Angle d Value Rel. Intensity (A) XRPD (Cu anode, Ni filter) for HCl Salt Crystal (polymorph 1) 1 5.242 16.84554 11.70% 2 5.709 15.46731 23.70% 3 6.39 13.82049 2.20% 4 10.274 8.60283 9.70% 5 10.512 8.40867 39.70% 6 10.948 8.0746 15.50% 7 11.678 7.57202 34.90% 8 12.044 7.34265 53.50% 9 12.948 6.83174 99.10% 10 13.203 6.70037 26.00% 11 14.084 6.28299 15.50% 12 14.972 5.91243 37.80% 13 15.764 5.61708 92.20% 14 16.237 5.45446 37.00% 15 16.501 5.36799 86.20% 16 16.773 5.28161 22.30% 17 17.662 5.01769 23.20% 18 18.135 4.88772 20.70% 19 18.649 4.75428 9.80% 20 18.941 4.68146 23.70% 21 19.714 4.49969 36.50% 22 20.974 4.23205 93.20% 23 21.595 4.11178 100.00% 24 22.154 4.00926 70.10% 25 23.91 3.71867 82.00% 26 24.458 3.63659 33.00% 27 25.059 3.55076 11.50% 28 25.788 3.45193 10.90% 29 26.703 3.33577 30.30% 30 28.054 3.17806 10.60% 31 28.883 3.08873 6.40% 32 29.867 2.98912 7.70% 33 30.262 2.95102 6.90% 34 30.932 2.8886 4.10% 35 31.483 2.83933 4.50% 36 32.911 2.71932 4.70% 37 33.831 2.6474 8.80% 38 34.03 2.63242 8.00% 39 37.892 2.37252 3.60% 40 41.864 2.15613 3.20% or (B): XRPD (Cu anode, Ni filter) for HCI Salt Crystal (polymorph 2) 1 5.095 17.32919 26.50% 2 5.499 16.0584 4.30% 3 7.127 12.39353 1.80% 4 10.432 8.47297 15.00% 5 11.376 7.7719 35.40% 6 11.938 7.40728 100.00% 7 13.074 6.76632 55.90% 8 14.411 6.14116 9.80% 9 14.992 5.90451 57.80% 10 16.128 5.49129 99.40% 11 17.974 4.93126 10.20% 12 18.547 4.78015 18.30% 13 19.193 4.62066 18.60% 14 19.576 4.53115 32.60% 15 20.716 4.28417 21.80% 16 21.134 4.20047 52.10% 17 21.408 4.14722 64.70% 18 22.246 3.99285 68.80% 19 23.331 3.80966 19.80% 20 23.977 3.70847 64.90% 21 23.993 3.70596 64.40% 22 24.495 3.63124 33.30% 23 25.389 3.50533 10.10% 24 26.589 3.34979 21.50% 25 27.113 3.28615 18.10% 26 27.413 3.2509 9.50% 27 28.664 3.11178 4.70% 28 30.464 2.9319 8.60% 29 30.795 2.90113 7.60% 30 31.987 2.79576 3.00% 31 32.145 2.78232 3.00% 32 33.114 2.7031 4.20% 33 34.461 2.60047 4.60% 34 39.594 2.27438 2.70% [0046] 1.12. Any foregoing form of Salt 1, in the form of a crystal having an X-ray powder diffraction pattern corresponding to
[0055] In another embodiment, the invention provides a process (Process 1) for the production of Salt 1, comprising [0056] (a) reacting free base d.sub.2-lumateperone with hydrochloric acid, e.g., together with an organic solvent, e.g., comprising toluene, ethyl acetate, CPME, or mixtures thereof; e.g., wherein the hydrochloric acid and the d.sub.2-lumateperone free base are in a molar ratio of about 1:1, and the solvent is toluene or CPME, optionally wherein the concentration of d.sub.2-lumateperone is at least 150 g/L or at least 200 g/L; and [0057] (b) recovering the hydrochloride salt thus formed, e.g., recovering a hydrochloride salt according to any of Salt 1, et seq. above.
[0058] In another embodiment, the invention provides a method of purifying d.sub.2-lumateperone in free or salt form, comprising reacting a crude solution of d.sub.2-lumateperone with hydrochloric acid, and recovering the hydrochloride salt thus formed, e.g., in accordance with Process 1, and optionally converting the hydrochloride salt back to d.sub.2-lumateperone free base or to another salt form.
[0059] In another embodiment, the invention provides the use of hydrochloric acid in a method of isolating and/or purifying d.sub.2-lumateperone.
[0060] In another embodiment, the invention provides a pharmaceutical composition comprising Salt 1, e.g., any of Salt 1.1-1.21, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier.
[0061] In another embodiment, the invention provides pharmaceutical composition comprising Salt 1, e.g., any of Salt 1.1-1.21, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, wherein the Salt 1 is predominantly, or is entirely or substantially entirely, in dry crystalline form.
[0062] In a particular embodiment, the invention provides a pharmaceutical composition comprising Salt 1, e.g., any of Salt 1.1-1.21, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, in the form of an injectable depot form, to provide extended release of d.sub.2-lumateperone.
[0063] In another embodiment, the invention provides Salt 1, e.g., any of Salt 1.1-1.21, or a pharmaceutical composition comprising Salt 1, e.g., any of Salt 1.1-1.21, for use in treating a disease or abnormal condition involving or mediated by the 5-HT.sub.2A receptor, serotonin transporter (SERT), and/or dopamine D.sub.1/D.sub.2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression (such as bipolar depression or major depressive disorder), anxiety, psychosis, schizophrenia (especially the residual symptoms and/or negative symptoms of schizophrenia), migraine, obsessive-compulsive disorder, sexual disorders, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, social phobias, dementia (e.g., Alzheimer's disease), symptoms or disorders associated with dementia (e.g., associated with Alzheimer's disease), acute anxiety, and acute depression. Particular symptoms or disorders associated with dementia (e.g., Alzheimer's disease) include anxiety, agitation, aggression, cognitive dysfunction, and memory impairment.
[0064] In another embodiment, the invention provides a method for the prophylaxis or treatment of a human suffering from a disease or abnormal condition involving or mediated by the 5-HT.sub.2A receptor, serotonin transporter (SERT), and/or dopamine D.sub.1/D.sub.2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression (such as bipolar depression or major depressive disorder), anxiety, psychosis, schizophrenia (especially the residual symptoms and/or negative symptoms of schizophrenia), migraine, obsessive-compulsive disorder, sexual disorders, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, social phobias, dementia, disorders associated with dementia, acute anxiety, and acute depression, comprising administering to a patient in need thereof a therapeutically effective amount of any of Salt 1, et seq.
Mono-Tosylate Salts
[0065] In another embodiment, the invention provides d.sub.2-lumateperone in monotosylate salt form (Salt 2). The invention therefore provides the following:
[0066] 2.1. Salt 2 in solid form. [0067] 2.2. Salt 2 or 2.1 in crystalline form, e.g., dry crystalline form. [0068] 2.3. Salt 2.2 in a homogeneous crystal form, free or substantially free of other forms, 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 amorphous forms. [0069] 2.4. Any foregoing form of Salt 2 in crystalline form, when crystallized from a mixture of toluenesulfonic acid and d.sub.2-lumateperone, e.g., in an organic solvent, e.g., comprising 2-butanone; e.g., wherein the toluenesulfonic acid and d.sub.2-lumateperone are in a molar ratio of about 1:1, the solvent is 2-butanone, and the concentration of d.sub.2-lumateperone is at least 50 g/L, or at least 65 g/L, or at least 100 g/L. [0070] 2.5. Any foregoing form of Salt 2 which is a solvate, e.g., a 2-butanone solvate. [0071] 2.6. Any foregoing form of Salt 2 which is not a solvate. [0072] 2.7. Any foregoing form of Salt 2 which is a hydrate. [0073] 2.8. Any foregoing form of Salt 2 which is not a hydrate. [0074] 2.9. Any foregoing form of Salt 2 formed by combining toluenesulfonic acid and d.sub.2-lumateperone free base in about a 1:1 molar ratio. [0075] 2.10. Any foregoing form of Salt 2, wherein a DSC analysis shows one endothermic event, at about 181° C.; e.g., wherein a DSC/TGA analysis shows the endothermic event at T.sub.onset=179.2° C., T.sub.peak=180.9° C. and ΔE=−77.1 J/g; optionally wherein the DSC analysis further shows an exothermic event at about 277° C.; e.g., wherein a DSC/TGA analysis shows the exothermic event at T.sub.onset=277.1° C., T.sub.peak=285.3° C. and ΔE=+151.5 J/g. [0076] 2.11. Any foregoing form of Salt 2, in the form of a crystal having an X-ray powder diffraction pattern corresponding to the d-spacing and/or angle (2-theta) values from the following table, for example 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 0.3, e.g., at least 0.35, e.g., at least 0.4, e.g., comprising peaks 3, 6, 14, 19 and 28:
TABLE-US-00002 XRPD (Cu anode, Ni filter) for Mono-Tosylate Salt Crystal # Angle d Value Rel. Intensity 1 2.851 30.96656 17.10% 2 5.127 17.2226 0.90% 3 5.678 15.55363 42.70% 4 8.513 10.37781 6.20% 5 11.376 7.77174 19.70% 6 12.104 7.30617 44.60% 7 13.332 6.63591 21.30% 8 14.211 6.22737 2.50% 9 15.037 5.88696 3.30% 10 15.388 5.75362 2.60% 11 15.808 5.60166 16.60% 12 16.041 5.52094 20.20% 13 16.445 5.38617 13.70% 14 17.048 5.19683 100.00% 15 17.533 5.05418 9.00% 16 18.173 4.87762 20.60% 17 19.002 4.66654 19.00% 18 19.278 4.60039 6.00% 19 19.947 4.44764 52.60% 20 20.763 4.27468 4.50% 21 21.668 4.09818 10.20% 22 21.841 4.06605 4.80% 23 22.589 3.93303 29.30% 24 22.815 3.89464 23.60% 25 23.018 3.86072 14.50% 26 23.48 3.78575 23.60% 27 23.757 3.74234 11.10% 28 24.314 3.65785 44.50% 29 25.687 3.46536 5.90% 30 25.999 3.42447 8.70% 31 26.978 3.30231 2.80% 32 27.264 3.26836 5.30% 33 29.69 3.00656 3.90% 34 30.864 2.89488 2.00% 35 31.61 2.82821 5.10% 36 32.314 2.76819 2.10% 37 34.559 2.59334 3.10% 38 34.85 2.5723 4.30% 39 37.55 2.39331 1.60% [0077] 2.12. Any foregoing form of Salt 2, in the form of a crystal having an X-ray powder diffraction pattern corresponding to
[0087] In another embodiment, the invention provides a process for the production of Salt 2 (Process 2), comprising [0088] (a) reacting free base d.sub.2-lumateperone with toluenesulfonic acid, e.g., together with an organic solvent, e.g., comprising 2-butanone; e.g., wherein the toluenesulfonic acid and the d.sub.2-lumateperone free base are in a molar ratio of about 1:1, and the solvent is 2-butanone, and optionally wherein the concentration of d.sub.2-lumateperone is at least 50 g/L, or at least 65 g/mL, or at least 100 g/L; [0089] (b) recovering the mono-tosylate salt thus formed, e.g., recovering a mono-tosylate salt according to any of Salt 2, et seq. above.
[0090] In another embodiment, the invention provides a method of purifying d.sub.2-lumateperone in free or salt form, comprising reacting a crude solution of d.sub.2-lumateperone with toluenesulfonic acid, and recovering the toluenesulfonic salt thus formed, e.g., in accordance with Process 2, and optionally converting the toluenesulfonic salt back to d.sub.2-lumateperone free base or to another salt form.
[0091] In another embodiment, the invention provides the use of toluenesulfonic acid in a method of isolating and/or purifying d.sub.2-lumateperone, wherein the molar ratio of toluenesulfonic acid to d.sub.2-lumateperone free base is about 1:1.
[0092] In another embodiment, the invention provides a pharmaceutical composition comprising Salt 2, e.g., any of Salt 2.1-2.21, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier.
[0093] In another embodiment, the invention provides pharmaceutical composition comprising Salt 2, e.g., any of Salt 2.1-2.21, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, wherein the Salt 2 is predominantly, or is entirely or substantially entirely, in dry crystalline form.
[0094] In a particular embodiment, the invention provides a pharmaceutical composition comprising Salt 2, e.g., any of Salt 2.1-2.21, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, in the form of an injectable depot form, to provide extended release of d.sub.2-lumateperone.
[0095] In another embodiment, the invention provides Salt 2, e.g., any of Salt 2.1-2.21, or a pharmaceutical composition comprising Salt 2, e.g., any of Salt 2.1-2.21, for use in treating a disease or abnormal condition involving or mediated by the 5-HT.sub.2A receptor, serotonin transporter (SERT), and/or dopamine D.sub.1/D.sub.2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression (such as bipolar depression or major depressive disorder), anxiety, psychosis, schizophrenia (especially the residual symptoms and/or negative symptoms of schizophrenia), migraine, obsessive-compulsive disorder, sexual disorders, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, social phobias, dementia (e.g., Alzheimer's disease), disorders associated with dementia (e.g., Alzheimer's disease), acute anxiety, and acute depression. Particular symptoms or disorders associated with dementia (e.g., Alzheimer's disease) include anxiety, agitation, aggression, cognitive dysfunction, and memory impairment.
[0096] In another embodiment, the invention provides a method for the prophylaxis or treatment of a human suffering from a disease or abnormal condition involving or mediated by the 5-HT.sub.2A receptor, serotonin transporter (SERT), and/or dopamine D.sub.1/D.sub.2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression (such as bipolar depression or major depressive disorder), anxiety, psychosis, schizophrenia (especially the residual symptoms and/or negative symptoms of schizophrenia), migraine, obsessive-compulsive disorder, sexual disorders, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, social phobias, dementia, disorders associated with dementia, acute anxiety, and acute depression, comprising administering to a patient in need thereof a therapeutically effective amount of any of Salt 2, et seq.
Bis-Tosylate Salts
[0097] In another embodiment, the invention provides d.sub.2-lumateperone in bis-tosylate salt form (Salt 3). The invention therefore provides the following: [0098] 3.1. Salt 3 in solid form. [0099] 3.2. Salt 3 or 3.1 in crystalline form, e.g., in dry crystalline form. [0100] 3.3. Salt 3.2 in a homogeneous crystal form, free or substantially free of other forms, 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 amorphous forms. [0101] 3.4. Any foregoing form of Salt 3 in crystalline form, when crystallized from a mixture of toluenesulfonic acid and d.sub.2-lumateperone, e.g., in an organic solvent, e.g., comprising 2-butanone; e.g., wherein the toluenesulfonic acid and d.sub.2-lumateperone are in a molar ratio of about 1:2, the solvent is 2-butanone, and the concentration of d.sub.2-lumateperone is at least 50 g/L, or at least 65 g/L, or at least 100 g/L. [0102] 3.5. Any foregoing form of Salt 3 which is a solvate, e.g., a 2-butanone solvate. [0103] 3.6. Any foregoing form of Salt 3 which is not a solvate. [0104] 3.7. Any foregoing form of Salt 3 which is a hydrate. [0105] 3.8. Any foregoing form of Salt 3 which is not a hydrate. [0106] 3.9. Any foregoing form of Salt 3 formed by combining toluenesulfonic acid and d.sub.2-lumateperone free base in a 2:1 molar ratio. [0107] 3.10. Any foregoing form of Salt 3 wherein a DSC analysis shows one endothermic event, at about 187° C.; e.g., wherein a DSC/TGA analysis shows the endothermic event at T.sub.onset=181.6° C., T.sub.peak=186.6° C. and ΔE=−84.4 J/g; optionally wherein the DSC analysis further shows an exothermic event at about 261° C.; e.g., wherein a DSC/TGA analysis shows the exothermic event at T.sub.onset=235.0° C., T.sub.peak=261.1° C. and ΔE=+331.5 J/g. [0108] 3.11. Any foregoing form of Salt 3, in the form of a crystal having an X-ray powder diffraction pattern corresponding to the d-spacing and/or angle (2-theta) values from the following table, for example 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 0.2, e.g., at least 0.3, e.g., at least 0.4, e.g., comprising peaks 10, 13, 19, and 20:
TABLE-US-00003 XRPD (Cu anode, Ni filter) for Bis-tosylate Salt Crystal # Angle d Value Rel. Intensity 1 4.146 21.29319 19.30% 2 6.223 14.19209 1.10% 3 8.306 10.63621 3.10% 4 10.401 8.49836 14.30% 5 12.209 7.24368 1.60% 6 13.675 6.47004 7.90% 7 14.16 6.24983 30.80% 8 14.513 6.09848 25.00% 9 14.905 5.93889 33.40% 10 15.375 5.75839 43.40% 11 15.901 5.56892 35.90% 12 16.473 5.37695 24.20% 13 17.093 5.1833 66.90% 14 17.836 4.96894 13.50% 15 17.941 4.94014 22.10% 16 18.675 4.74767 23.10% 17 19.193 4.62071 6.10% 18 19.802 4.47986 6.10% 19 20.399 4.35002 100.00% 20 20.73 4.28143 58.50% 21 21.301 4.16792 16.90% 22 21.568 4.11697 11.70% 23 22.437 3.95936 11.40% 24 22.921 3.8769 11.60% 25 23.198 3.83126 4.50% 26 23.968 3.7098 22.40% 27 24.586 3.61791 4.30% 28 25.135 3.54015 12.60% 29 25.895 3.43789 5.70% 30 26.033 3.42 3.90% 31 26.813 3.32231 6.40% 32 27.336 3.25991 22.90% 33 27.649 3.22376 15.80% 34 28.582 3.12061 3.30% 35 28.945 3.08226 4.40% 36 29.285 3.04721 4.10% 37 30.134 2.96327 5.80% 38 31.612 2.82804 1.40% 39 32.161 2.78099 2.40% 40 33.495 2.67321 1.60% 41 34.567 2.59273 1.30% 42 35.452 2.52998 2.70% 43 39.727 2.26707 2.30% 44 42.643 2.11854 1.60% [0109] 3.12. Any foregoing form of Salt 3, in the form of a crystal having an X-ray powder diffraction pattern corresponding to
[0119] In another embodiment, the invention provides a process (Process 3) for the production of Salt 3, comprising: [0120] (a) reacting free base d.sub.2-lumateperone with toluenesulfonic acid, e.g., together with an organic solvent, e.g., comprising 2-butanone; e.g., wherein the toluenesulfonic acid and the d.sub.2-lumateperone free base are in a molar ratio of about 1:1 or of about 2:1, and the solvent is 2-butanone, and optionally wherein the concentration of d.sub.2-lumateperone is at least 50 g/L, or at least 65 g/mL, or at least 100 g/L; and [0121] (b) recovering the bis-tosylate salt thus formed, e.g., recovering a bis-tosylate salt according to any of Salt 3, et seq. above.
[0122] In another embodiment, the invention provides a method of purifying d.sub.2-lumateperone in free or salt form, comprising reacting a crude solution of d.sub.2-lumateperone with toluenesulfonic acid, and recovering the bis-tosylate salt thus formed, e.g., in accordance with Process 3, and optionally converting the toluenesulfonic salt back to d.sub.2-lumateperone free base or to another salt form.
[0123] In another embodiment, the invention provides the use of toluenesulfonic acid in a method of isolating and/or purifying d.sub.2-lumateperone, wherein the molar ratio of toluenesulfonic acid to d.sub.2-lumateperone free base is about 1:1 or about 2:1.
[0124] In another embodiment, the invention provides a pharmaceutical composition comprising Salt 3, e.g., any of Salt 3.1-3.21, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier.
[0125] In another embodiment, the invention provides a pharmaceutical composition comprising Salt 3, e.g., any of Salt 3.1-3.21, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, wherein the Salt 3 is predominantly, or is entirely or substantially entirely, in dry crystalline form.
[0126] In a particular embodiment, the invention provides a pharmaceutical composition comprising Salt 3, e.g., any of Salt 3.1-3.21, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, in the form of an injectable depot form, to provide extended release of d.sub.2-lumateperone.
[0127] In another embodiment, the invention provides Salt 3, e.g., any of Salt 3.1-3.21, or a pharmaceutical composition comprising Salt 3, e.g., any of Salt 3.1-3.21, for use in treating a disease or abnormal condition involving or mediated by the 5-HT.sub.2A receptor, serotonin transporter (SERT), and/or dopamine D.sub.1/D.sub.2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression (such as bipolar depression or major depressive disorder), anxiety, psychosis, schizophrenia (especially the residual symptoms and/or negative symptoms of schizophrenia), migraine, obsessive-compulsive disorder, sexual disorders, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, social phobias, dementia (e.g., Alzheimer's disease), disorders associated with dementia (e.g., Alzheimer's disease), acute anxiety, and acute depression. Particular symptoms or disorders associated with dementia (e.g., Alzheimer's disease) include anxiety, agitation, aggression, cognitive dysfunction, and memory impairment.
[0128] In another embodiment, the invention provides a method for the prophylaxis or treatment of a human suffering from a disease or abnormal condition involving or mediated by the 5-HT.sub.2A receptor, serotonin transporter (SERT), and/or dopamine D.sub.1/D.sub.2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression (such as bipolar depression or major depressive disorder), anxiety, psychosis, schizophrenia (especially the residual symptoms and/or negative symptoms of schizophrenia), migraine, obsessive-compulsive disorder, sexual disorders, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, social phobias, dementia, disorders associated with dementia, acute anxiety, and acute depression, comprising administering to a patient in need thereof a therapeutically effective amount of any of Salt 3, et seq.
Free Base-Isonicotinamide Co-Crystal
[0129] In another embodiment, the invention provides d.sub.2-lumateperone free base in the form of a co-crystal with isonicotinamide (Co-Crystal 1). The invention therefore provides the following: [0130] 1.1. Co-Crystal 1 in solid form. [0131] 1.2. Co-Crystal 1 or 1.1 in crystalline form, e.g., in dry crystalline form. [0132] 1.3. Co-Crystal 1.2 in a homogeneous crystal form, free or substantially free of other forms, 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 amorphous forms. [0133] 1.4. Any foregoing form of Co-Crystal 1, when crystallized from a mixture of isonicotinamide and d.sub.2-lumateperone free base, e.g., in an organic solvent, e.g., comprising methanol; e.g., wherein the isonicotinamide and d.sub.2-lumateperone are in a molar ratio of about 1:1 or 1:2, the solvent is methanol, and the concentration of d.sub.2-lumateperone is at least 50 g/L, or at least 100 g/L, or at least 200 g/L, and optionally wherein the Co-Crystal is crystallized from methanol. [0134] 1.5. Any foregoing form of Co-Crystal 1 which is a solvate, e.g., a methanol solvate. [0135] 1.6. Any foregoing form of Co-Crystal 1 which is not a solvate. [0136] 1.7. Any foregoing form of Co-Crystal 1 which is a hydrate. [0137] 1.8. Any foregoing form of Co-Crystal 1 which is not a hydrate. [0138] 1.9. Any foregoing form of Co-Crystal 1 formed by combining isonicotinamide and d.sub.2-lumateperone free base in a 1:1 or 2:1 molar ratio. [0139] 1.10. Any foregoing form of Co-Crystal 1 wherein a DSC analysis shows one endothermic event, at about 151° C.; e.g., wherein a DSC/TGA analysis shows the endothermic event at T.sub.onset=143.2° C., T.sub.peak=150.7° C. and ΔE=−55.3 J/g. [0140] 1.11. Any foregoing form of Co-Crystal 1, in the form of a crystal having an X-ray powder diffraction pattern corresponding to the d-spacing and/or angle (2-theta) values from the following table, for example 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 0.5, e.g., at least 0.7, e.g., at least 0.9, e.g., comprising peak 7:
TABLE-US-00004 XRPD (Cu anode, Ni filter) for Free Base-Isonicotinamide Co-Crystal # Angle d Value Rel. Intensity 1 11.358 7.78412 0.80% 2 14.476 6.11379 1.90% 3 18.419 4.81292 1.90% 4 20.66 4.29569 2.80% 5 21.928 4.05007 1.60% 6 22.099 4.01919 2.60% 7 22.912 3.87828 100.00% 8 24.214 3.67263 1.90% 9 28.509 3.12837 1.30% 10 28.526 3.12655 1.30% 11 29.856 2.99023 0.70% 12 32.096 2.78645 0.90% 13 32.121 2.78437 0.90% 14 34.737 2.58043 0.60% 15 34.811 2.57513 0.60% 16 36.547 2.45668 1.30% 17 36.572 2.45506 1.30% [0141] 1.12. Any foregoing form of Co-Crystal 1, in the form of a crystal having an X-ray powder diffraction pattern corresponding to
[0151] In another embodiment, the invention provides a process (Process 4) for the production of Co-Crystal 1, comprising [0152] (a) combining free base d.sub.2-lumateperone with isonicotinamide, e.g., together with an organic solvent, e.g., comprising 2-butanone; e.g., wherein the isonicotinamide and the d.sub.2-lumateperone free base are in a molar ratio of about 1:1 or 2:1, and the solvent is methanol, and optionally wherein the concentration of d.sub.2-lumateperone is at least 50 g/L, or at least 100 g/mL, or at least 200 g/L; and [0153] (b) removing the solvent and recovering the Co-Crystal thus formed, e.g., recovering an isonicotinamide Co-Crystal according to any of Co-Crystal 1, et seq. above.
[0154] In another embodiment, the invention provides a method of purifying d.sub.2-lumateperone in free or salt form, comprising combining d.sub.2-lumateperone free base with isonicotinamide, and recovering the Co-Crystal thus formed, e.g., in accordance with Process 4, and optionally converting the Co-Crystal back to d.sub.2-lumateperone free base or to another salt form.
[0155] In another embodiment, the invention provides the use of isonicotinamide in a method of isolating and/or purifying d.sub.2-lumateperone.
[0156] In another embodiment, the invention provides a pharmaceutical composition comprising Co-Crystal 1, e.g., any of Co-Crystal 1.1-1.21, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier.
[0157] In another embodiment, the invention provides a pharmaceutical composition comprising Co-Crystal 1, e.g., any of Co-Crystal 1.1-1.21, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, wherein the Co-Crystal 1 is predominantly, or is entirely or substantially entirely, in dry crystalline form.
[0158] In a particular embodiment, the invention provides a pharmaceutical composition comprising Co-Crystal 1, e.g., any of Co-Crystal 1.1-1.21, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, in the form of an injectable depot form, to provide extended release of d.sub.2-lumateperone.
[0159] In another embodiment, the invention provides Co-Crystal 1, e.g., any of Co-Crystal 1.1-1.21, or a pharmaceutical composition comprising Co-Crystal 1, e.g., any of Co-Crystal 1.1-1.21, for use in treating a disease or abnormal condition involving or mediated by the 5-HT.sub.2A receptor, serotonin transporter (SERT), and/or dopamine D.sub.1/D.sub.2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression (such as bipolar depression or major depressive disorder), anxiety, psychosis, schizophrenia (especially the residual symptoms and/or negative symptoms of schizophrenia), migraine, obsessive-compulsive disorder, sexual disorders, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, social phobias, dementia (e.g., Alzheimer's disease), disorders associated with dementia (e.g., Alzheimer's disease), acute anxiety, and acute depression. Particular symptoms or disorders associated with dementia (e.g., Alzheimer's disease) include anxiety, agitation, aggression, cognitive dysfunction, and memory impairment.
[0160] In another embodiment, the invention provides a method for the prophylaxis or treatment of a human suffering from a disease or abnormal condition involving or mediated by the 5-HT.sub.2A receptor, serotonin transporter (SERT), and/or dopamine D.sub.1/D.sub.2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression (such as bipolar depression or major depressive disorder), anxiety, psychosis, schizophrenia (especially the residual symptoms and/or negative symptoms of schizophrenia), migraine, obsessive-compulsive disorder, sexual disorders, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, social phobias, dementia, disorders associated with dementia, acute anxiety, and acute depression, comprising administering to a patient in need thereof a therapeutically effective amount of any of Co-Crystal 1, et seq.
Tosylate-Lysine Co-Crystal
[0161] In another embodiment, the invention provides d.sub.2-lumateperone tosylate in the form of a co-crystal with L-lysine free base (Co-Crystal 2). The invention therefore provides the following: [0162] 2.1. Co-Crystal 2 in solid form. [0163] 2.2. Co-Crystal 2 or 2.1 in crystalline form, e.g., in dry crystalline form. [0164] 2.3. Co-Crystal 2.2 in a homogeneous crystal form, free or substantially free of other forms, 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 amorphous forms. [0165] 2.4. Any foregoing form of Co-Crystal 2, when crystallized from a mixture of L-lysine free base and d.sub.2-lumateperone tosylate (e.g., mono-tosylate), e.g., in an organic solvent, e.g., comprising methanol; e.g., wherein the lysine free base and d.sub.2-lumateperone are in a molar ratio of about 1:1, the solvent is methanol, and the concentration of d.sub.2-lumateperone is at least 50 g/L, or at least 80 g/L, and optionally wherein the Co-Crystal is crystallized from methanol. [0166] 2.5. Any foregoing form of Co-Crystal 2 which is a solvate, e.g., a methanol solvate. [0167] 2.6. Any foregoing form of Co-Crystal 2 which is not a solvate. [0168] 2.7. Any foregoing form of Co-Crystal 2 which is a hydrate. [0169] 2.8. Any foregoing form of Co-Crystal 2 which is not a hydrate. [0170] 2.9. Any foregoing form of Co-Crystal 2 formed by combining L-lysine free base and d.sub.2-lumateperone tosylate (e.g., mono-tosylate) in a 1:1 molar ratio. [0171] 2.10. Any foregoing form of Co-Crystal 2 wherein a DSC analysis shows two endothermic events, at about 204° C. and 222° C.; e.g., wherein a DSC/TGA analysis shows a first endothermic event at T.sub.onset=193.1° C., T.sub.peak=203.1° C. and ΔE=−72.2 J/g, and a second endothermic event at T.sub.onset=188.8° C., T.sub.peak=221.7° C. and ΔE=−109.3 J/g. [0172] 2.11. Any foregoing form of Co-Crystal 2, in the form of a crystal having an X-ray powder diffraction pattern corresponding to the d-spacing and/or angle (2-theta) values from the following table, for example 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 0.2, e.g., at least 0.3, e.g., at least 0.4, e.g., comprising peaks 2, 11, 14, and 20:
TABLE-US-00005 XRPD (Cu anode, Ni filter) for Tosylate-Lysine Co-Crystal # Angle d Value Rel. Intensity 1 7.471 11.82319 5.90% 2 9.541 9.26261 44.60% 3 11.149 7.92974 3.30% 4 11.522 7.67421 11.80% 5 12.469 7.09293 8.10% 6 14.969 5.9137 10.30% 7 15.437 5.73524 12.70% 8 17.543 5.05147 3.20% 9 18.184 4.87469 22.40% 10 19.14 4.63327 10.60% 11 20 4.43594 100.00% 12 20.177 4.39754 18.60% 13 20.781 4.27107 13.90% 14 22.386 3.96821 64.10% 15 22.708 3.91277 21.00% 16 23.152 3.83863 7.30% 17 24.535 3.6254 8.30% 18 24.857 3.57907 12.80% 19 25.405 3.50311 2.10% 20 25.913 3.43555 82.20% 21 28.025 3.18128 1.40% 22 28.91 3.08591 1.70% 23 29.73 3.00261 7.90% 24 30.211 2.95595 22.20% 25 30.655 2.91408 4.30% 26 30.901 2.8915 6.60% 27 32.121 2.78434 4.10% 28 33.567 2.66765 5.10% 29 33.892 2.64284 4.70% 30 34.195 2.62011 3.30% 31 35.017 2.56045 2.90% 32 35.857 2.50239 4.20% 33 37.319 2.4076 4.70% 34 39.287 2.29144 2.40% 35 39.712 2.26788 1.20% 36 40.68 2.2161 1.60% 37 42.856 2.10851 1.00% 38 43.764 2.06684 1.50% [0173] 2.12. Any foregoing form of Co-Crystal 2, in the form of a crystal having an X-ray powder diffraction pattern corresponding to
[0183] In another embodiment, the invention provides a process (Process 5) for the production of Co-Crystal 2, comprising [0184] (a) combining d.sub.2-lumateperone tosylate (e.g., mono-tosylate) with L-lysine free base, e.g., together with an organic solvent, e.g., comprising methanol; e.g., wherein the d.sub.2-lumateperone tosylate (e.g., mono-tosylate) and the L-lysine free base are in a molar ratio of about 1:1, and the solvent is methanol, and optionally wherein the concentration of d.sub.2-lumateperone is at least 50 g/L, or at least 80 g/L; and [0185] (b) removing the solvent and recovering the Co-Crystal thus formed, e.g., recovering a lysine Co-Crystal according to any of Co-Crystal 2, et seq. above.
[0186] In another embodiment, the invention provides a method of purifying d.sub.2-lumateperone in free or salt form, comprising combining d.sub.2-lumateperone tosylate (e.g., mono-tosylate) with L-lysine free base, and recovering the Co-Crystal thus formed, e.g., in accordance with Process 5, and optionally converting the Co-Crystal back to d.sub.2-lumateperone free base or to another salt form.
[0187] In another embodiment, the invention provides the use of L-lysine free base in a method of isolating and/or purifying d.sub.2-lumateperone.
[0188] In another embodiment, the invention provides a pharmaceutical composition comprising Co-Crystal 2, e.g., any of Co-Crystal 2.1-2.21, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier.
[0189] In another embodiment, the invention provides a pharmaceutical composition comprising Co-Crystal 2, e.g., any of Co-Crystal 2.1-2.21, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, wherein the Co-Crystal 2 is predominantly, or is entirely or substantially entirely, in dry crystalline form.
[0190] In a particular embodiment, the invention provides a pharmaceutical composition comprising Co-Crystal 2, e.g., any of Co-Crystal 2.1-2.21, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, in the form of an injectable depot form, to provide extended release of d.sub.2-lumateperone.
[0191] In another embodiment, the invention provides Co-Crystal 2, e.g., any of Co-Crystal 2.1-2.21, or a pharmaceutical composition comprising Co-Crystal 2, e.g., any of Co-Crystal 2.1-2.21, for use in treating a disease or abnormal condition involving or mediated by the 5-HT.sub.2A receptor, serotonin transporter (SERT), and/or dopamine D.sub.1/D.sub.2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression (such as bipolar depression or major depressive disorder), anxiety, psychosis, schizophrenia (especially the residual symptoms and/or negative symptoms of schizophrenia), migraine, obsessive-compulsive disorder, sexual disorders, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, social phobias, dementia (e.g., Alzheimer's disease), disorders associated with dementia (e.g., Alzheimer's disease), acute anxiety, and acute depression. Particular symptoms or disorders associated with dementia (e.g., Alzheimer's disease) include anxiety, agitation, aggression, cognitive dysfunction, and memory impairment.
[0192] In another embodiment, the invention provides a method for the prophylaxis or treatment of a human suffering from a disease or abnormal condition involving or mediated by the 5-HT.sub.2A receptor, serotonin transporter (SERT), and/or dopamine D.sub.1/D.sub.2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression (such as bipolar depression or major depressive disorder), anxiety, psychosis, schizophrenia (especially the residual symptoms and/or negative symptoms of schizophrenia), migraine, obsessive-compulsive disorder, sexual disorders, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, social phobias, dementia, disorders associated with dementia, acute anxiety, and acute depression, comprising administering to a patient in need thereof a therapeutically effective amount of any of Co-Crystal 2, et seq.
Other Salts and Co-Crystals
[0193] In another embodiment, the invention provides: [0194] (1) 1-(4-fluorophenyl)-4-((6bR,10aS)-3-(d.sub.3-methyl)-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-one (d.sub.3-lumateperone), [0195] (2) 2-2-d.sub.2-1-(4-fluorophenyl)-4-((6bR,10aS)-3-(d.sub.3-methyl)-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-one (d.sub.5-lumateperone), [0196] (3) 1,1,2,2-d.sub.4-1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-one (d.sub.4-lumateperone), or [0197] (4) 1,1,2,2-d.sub.4-1-(4-fluorophenyl)-4-((6bR,10aS)-3-(d.sub.3-methyl)-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-one (d.sub.7-lumateperone), in the form of a stable salt or co-crystal (Salt or Co-Crystal 4). The invention further provides the following: [0198] 4.1. Salt or Co-Crystal 4 in solid form. [0199] 4.2. Salt or Co-Crystal 4 in crystalline form, e.g., in dry crystalline form. [0200] 4.3. Salt or Co-Crystal 4 in a homogeneous crystal form, free or substantially free of other forms, 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 amorphous forms. [0201] 4.4. Salt or Co-Crystal 4, wherein the Salt or Co-Crystal is a salt selected from the group consisting of hydrochloride salt, mono-tosylate salt, and bis-tosylate salt; [0202] 4.5. Salt or Co-Crystal 4.4, when crystallized from a mixture of hydrochloride acid, or toluenesulfonic acid and d.sub.3-lumateperone, d.sub.5-lumateperone, d.sub.4-lumateperone, or d.sub.7-lumateperone, e.g., in an organic solvent, e.g., comprising methanol, ethyl acetate, toluene, CPME, or 2-butanone; e.g., wherein the acid and deuterated lumateperone are in a molar ratio of about 1:1 or 1:2, and the concentration of d.sub.2-lumateperone is at least 50 g/L, or at least 65 g/L, or at least 100 g/L, or at least 200 g/L. [0203] 4.6. Salt or Co-Crystal 4, wherein the Salt or Co-Crystal is a free base-isonicotinamide co-crystal or a tosylate salt-lysine co-crystal. [0204] 4.7. Salt or Co-Crystal 4.6, when crystallized from a mixture of lysine free base and d.sub.3-lumateperone, d.sub.5-lumateperone, d.sub.4-lumateperone, or d.sub.7-lumateperone, free base or tosylate (e.g., mono-tosylate), e.g. in an organic solvent, e.g., comprising methanol; e.g., wherein the lysine free base or isonicotinamide and the deuterated lumateperone are in a molar ratio of about 1:1, the solvent is methanol, and the concentration of the deuterated lumateperone is at least 50 g/L, or at least 65 g/L, or at least 100 g/L, or at least 200 g/L. [0205] 4.8. Any foregoing form of Salt or Co-Crystal 4 which is a solvate. [0206] 4.9. Any foregoing form of Salt or Co-Crystal 4 which is not a solvate. [0207] 4.10. Any foregoing form of Salt or Co-Crystal 4 which is a hydrate. [0208] 4.11. Any foregoing form of Salt or Co-Crystal 4 which is not a hydrate. [0209] 4.12. Any foregoing form of Salt or Co-Crystal 4, wherein the Salt or Co-Crystal has a diastereomeric excess of greater than 70%, preferably greater than 80%, more preferably greater than 90% and most preferably greater than 95%. [0210] 4.13. Any foregoing form of Salt or Co-Crystal 4, wherein the Salt or Co-Crystal has greater than natural incorporation of deuterium at the indicated deuterium positions of the structure (i.e., greater than 0.0156%). [0211] 4.14. Any foregoing form of Salt or Co-Crystal 4, wherein the Salt or Co-Crystal has substantially greater than natural incorporation of deuterium at the indicated deuterium positions of the structure (e.g., greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%). [0212] 4.15. Any foregoing form of Salt or Co-Crystal 4, wherein the Salt or Co-Crystal has greater than 50% incorporation of deuterium at the indicated deuterated positions of the structure (i.e., greater than 50 atom % D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90% or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%. [0213] 4.16. Any foregoing form of Salt or Co-Crystal 4 exhibiting any combination of characteristics as described in 4.1-4.15.
[0214] In another embodiment, the invention provides a process (Process 6) for the production of Salt or Co-Crystal 4, comprising [0215] (a) reacting d.sub.3-lumateperone, d.sub.5-lumateperone, d.sub.4-lumateperone, or d.sub.7-lumateperone, free base or tosylate (e.g., mono-tosylate), with hydrochloric acid, toluenesulfonic acid, lysine free base (e.g., L-lysine), or isonicotinamide, e.g., together with an organic solvent, e.g., comprising methanol, ethyl acetate, CPME, toluene, or 2-butanone; e.g., wherein the acid or the co-former and the deuterated lumateperone in a molar ratio of about 1:1 or 2:1, and optionally wherein the concentration of the deuterated lumateperone is at least 50 g/L, or at least 65 g/L, or at least 100 g/L, or at least 200 g/L; and [0216] (b) recovering the salt or co-crystal thus formed, e.g., recovering Salt or Co-Crystal 4 or any of 4.1-4.15.
[0217] In another embodiment, the invention provides a method of purifying d.sub.3-lumateperone, d.sub.5-lumateperone, d.sub.4-lumateperone, or d.sub.7-lumateperone, in free or salt form, comprising reacting a crude solution of the deuterated lumateperone with hydrochloric acid, toluenesulfonic acid, lysine free base (e.g., L-lysine), or isonicotinamide, and recovering the salt or co-crystal thus formed, e.g., in accordance with Process 6, and optionally converting the salt or co-crystal back to d.sub.3-lumateperone, d.sub.5-lumateperone, d.sub.4-lumateperone, or d.sub.7-lumateperone free base or to another salt form.
[0218] In another embodiment, the invention provides the use of hydrochloric acid, toluenesulfonic acid, lysine free base (e.g., L-lysine), or isonicotinamide, in a method of isolating and/or purifying d.sub.3-lumateperone, d.sub.5-lumateperone, d.sub.4-lumateperone, or d.sub.7-lumateperone, wherein the molar ratio of the acid or co-former to the deuterated lumateperone free base or salt is about 1:1 or 2:1.
[0219] In another embodiment, the invention provides a pharmaceutical composition comprising Salt or Co-Crystal 4 or any of 4.1-4.15, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier.
[0220] In another embodiment, the invention provides a pharmaceutical composition comprising Salt or Co-Crystal 4 or any of 4.1-4.15, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, wherein the Salt or Co-Crystal 4 is predominantly, or is entirely or substantially entirely, in dry crystalline form.
[0221] In a particular embodiment, the invention provides a pharmaceutical composition comprising Salt or Co-Crystal 4 or any of 4.1-4.15, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, in the form of an injectable depot form, to provide extended release of the deuterated lumateperone.
[0222] In another embodiment, the invention provides Salt or Co-Crystal 4 or any of 4.1-4.15, or a pharmaceutical composition comprising Salt or Co-Crystal 4 or any of 4.1-4.15, for use in treating a disease or abnormal condition involving or mediated by the 5-HT.sub.2A receptor, serotonin transporter (SERT), and/or dopamine D.sub.1/D.sub.2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression (such as bipolar depression or major depressive disorder), anxiety, psychosis, schizophrenia (especially the residual symptoms and/or negative symptoms of schizophrenia), migraine, obsessive-compulsive disorder, sexual disorders, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, social phobias, dementia (e.g., Alzheimer's disease), disorders associated with dementia (e.g., Alzheimer's disease), acute anxiety, and acute depression. Particular symptoms or disorders associated with dementia (e.g., Alzheimer's disease) include anxiety, agitation, aggression, cognitive dysfunction, and memory impairment.
[0223] In another embodiment, the invention provides a method for the prophylaxis or treatment of a human suffering from a disease or abnormal condition involving or mediated by the 5-HT.sub.2A receptor, serotonin transporter (SERT), and/or dopamine D.sub.1/D.sub.2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression (such as bipolar depression or major depressive disorder), anxiety, psychosis, schizophrenia (especially the residual symptoms and/or negative symptoms of schizophrenia), migraine, obsessive-compulsive disorder, sexual disorders, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, social phobias, dementia, disorders associated with dementia, acute anxiety, and acute depression, comprising administering to a patient in need thereof a therapeutically effective amount of any of Salt or Co-Crystal 4 or any of 4.1-4.15, et seq.
[0224] All salts and co-crystals described herein are preferably stable, meaning that they retain physical and chemical identity (as shown by, e.g., 1H-NMR, LCMS) over a period of at least 1 month, e.g., at least 3 months, or at least 6 months, or at least 9 months.
EXAMPLES
[0225] The following equipment and methods are used to isolate and characterize the exemplified salt forms:
[0226] 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 30 kV, 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 Soller 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° 20, sample rotation 5 rpm, 0.5 s/step, 0.010°/step, 3.0 mm 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.
[0227] 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.
[0228] 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, 1-8 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 check 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.
[0229] 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 was used with a beam splitter of KBr. Experiment setup of the collected sample is used number of scans 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.
[0230] Thermogravimetric analysis (TGA) with infrared spectroscopy (TGA-IR): In TGA-IR, the off-gassing materials are directed through a transfer line to a gas cell, where the infrared light interacts with the gases. The temperature ramp and first derivative weight loss information from the TGA is shown as a Gram-Schmidt (GS) profile; the GS profile essentially shows the total change in the IR signal relative to the initial state. In most cases, the GS and the derivative weight loss will be similar in shape, although the intensity of the two can differ. For this experiment are two devices coupled to each other. The TGA studies are performed using a Mettler Toledo TGA/DSC1 STARe System with a 34-position auto sampler, equipment #1547. The samples are made using Al crucibles (100 μl; pierced). Typically, 20-50 mg of sample is loaded into 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. A nitrogen purge of 40 ml/min is maintained over the sample. The TGA-IR module of the Nicolet iS50 is coupled to the TGA/DSC1. The IR studies were performed using a Thermo Scientific Nicolet iS50, equipment #2357. Experiment setup of the collected series, the profile Gram-Schmidt is used number of scans 10 with a resolution of 4. The software OMNIC version 9.2 is used for data collection and evaluation.
[0231] High performance liquid chromatography (HPLC): The high performance liquid chromatography analyses are performed on 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.
[0232] During previous studies, the salt crystals and co-crystals formed by lumateperone (non-deuterated) were found to include only oxalate salt, cyclamate salt, 4-aminosalicylate salt, HCl salt (different forms), mono-tosylate salt, bis-tosylate salt, free base-nicotinamide co-crystal, free base-isonicotinamide co-crystal, tosylate-lysine co-crystal, and tosylate-piperazine co-crystal. The salt crystals were identified after extensive experimentation conducted using a salt screen with 90 different counter ions, various ratios between lumateperone free base and the selected acid, six different solvents, and including four different crystallization methods (slurry experiments, cooling crystallization, evaporation and precipitation experiments). The lumateperone co-crystals were similarly identified after extensive experimentation involving 26 candidate co-formers (including sugar alcohols, amino acids, and other compounds identified as having potential to for co-crystals, various ratios between the lumateperone and the co-former, various solvent, and three different experimental conditions (adding solutions stepwise, slurry experiments and cooling crystallization experiments).
[0233] It was therefore expected that deuterated lumateperone would be similarly difficult to form crystalline salts and co-crystals from. Unlike lumateperone, d.sub.2-lumateperone failed to form a stable and reproducible salt with oxalic acid. Instead, it was found that an oxalate salt forms in very poor yield and over time (<3 months) it changes from a yellow powder to a sticky brown solid. XRPD confirmed that while the yellow powder was a crystalline oxalate salt, the sticky brown solid was not. Similar experiments using cyclamic acid produced green and yellow powders in very low yield, analysis of which did not suggest formation of a d.sub.2-lumateperone cyclamate salt. Analysis suggested the formation of coordination complexes with a ratio of free base to cyclamate of about 1:10. Attempts to form a crystalline 4-aminosalicylate salt also failed, as either no solid material was obtained or only amorphous material was obtained. Attempts to form a free base-nicotinamide co-crystal or a tosylate-piperazine co-crystal failed as well. XRPD of the solids obtained in the former experiments showed only nicotinamide. The powder obtained from the latter attempt was a crystal by XRPD, but NMR indicated something have a 1:20 ratio of tosylate salt to piperazine.
[0234] Thus, it was unexpected that d.sub.2-lumateperone would not form the same crystalline salts and co-crystals as lumateperone did. Due to these unexpected difference, additional salt and co-crystal screening was performed with d.sub.2-lumateperone.
Example 1: Hydrochloride Salt Crystals
[0235] Hydrogen chloride in CPME solvent was added to a solution of d.sub.2-lumateperone free base in ethyl acetate, toluene or CPME, at a 1:1 molar ratio of free base to HCl. Then the solution was heated to 50° C., kept at this temperature for an hour and cooled to room temperature. The HCl formation experiments are summarized in the table below:
TABLE-US-00006 TGA FT-IR FT-IR DSC mass correlation correlation LC T.sub.peak loss with FB with CI purity Expt. # Appearance XRPD (° C.) (%) (%) (%) (area-%) .sup.1H-NMR 1-1 Clear N/A N/A N/A N/A N/A N/A N/A solution 1-2 Clear N/A N/A N/A N/A N/A N/A N/A solution 1-3 Yellowish N/A N/A N/A N/A N/A N/A N/A suspension 1-4 Clear N/A N/A N/A N/A N/A N/A N/A solution 1-5 Off-white Crystal N/A N/A N/A N/A N/A N/A solid 1-6 Off-white Crystal N/A N/A N/A N/A N/A N/A solid 1-7 Yellowish Crystal 110.9 2.4 60 6 98 Shifts; powder salt formation 1-8 Off-white Crystal 108.0 2.6 59 7 98 Shifts; powder salt formation
[0236] Experiments 1-1, 1-2 and 1-3 were performed at 100 mg scale with a d.sub.2-lumateperone free base concentration of 100 mg/mL. A clear solution was obtained for experiment 1-1 (ethyl acetate) and 1-2 (toluene), and a yellowish suspension was formed of experiment 1-3 (CPME), but the yield of solid was very low. Therefore, in experiments 1-4, 1-5 and 1-6, a 100 mg scale was used, with the concentration of d.sub.2-lumateperone free base increased to 200 mg/mL. Experiment 1-4 (ethyl acetate) still produced as a clear solution, and experiment 1-5 (toluene) and 1-6 (CPME) both showed a yellowish slurry upon cooling and an off-white powder upon isolation. Both solids showed suggestive crystalline patterns. These two experiments were then repeated at a 600 mg scale with a concentration of 200 mg/mL, as Experiments 1-7 (toluene) and 1-8 (CPME). Two new crystalline patterns were observed which were not the same as that seen in Experiments 1-5 and 1-6. Analysis of the TGA data showed that 2.4 wt-% and 2.6 wt-% solvent residual were recorded respectively, potentially accounting for the difference in crystalline pattern.
[0237] The XRPD patterns for the salts obtained in Experiments 1-7 and 1-8 are shown in
TABLE-US-00007 TABLE 1 (A). XRPD (Cu anode, Ni filter) for HCl Salt Crystal (polymorph 1) # Angle d Value Rel. Intensity 1 5.242 16.84554 11.70% 2 5.709 15.46731 23.70% 3 6.39 13.82049 2.20% 4 10.274 8.60283 9.70% 5 10.512 8.40867 39.70% 6 10.948 8.0746 15.50% 7 11.678 7.57202 34.90% 8 12.044 7.34265 53.50% 9 12.948 6.83174 99.10% 10 13.203 6.70037 26.00% 11 14.084 6.28299 15.50% 12 14.972 5.91243 37.80% 13 15.764 5.61708 92.20% 14 16.237 5.45446 37.00% 15 16.501 5.36799 86.20% 16 16.773 5.28161 22.30% 17 17.662 5.01769 23.20% 18 18.135 4.88772 20.70% 19 18.649 4.75428 9.80% 20 18.941 4.68146 23.70% 21 19.714 4.49969 36.50% 22 20.974 4.23205 93.20% 23 21.595 4.11178 100.00% 24 22.154 4.00926 70.10% 25 23.91 3.71867 82.00% 26 24.458 3.63659 33.00% 27 25.059 3.55076 11.50% 28 25.788 3.45193 10.90% 29 26.703 3.33577 30.30% 30 28.054 3.17806 10.60% 31 28.883 3.08873 6.40% 32 29.867 2.98912 7.70% 33 30.262 2.95102 6.90% 34 30.932 2.8886 4.10% 35 31.483 2.83933 4.50% 36 32.911 2.71932 4.70% 37 33.831 2.6474 8.80% 38 34.03 2.63242 8.00% 39 37.892 2.37252 3.60% 40 41.864 2.15613 3.20%
TABLE-US-00008 TABLE 1 (B). XRPD (Cu anode, Ni filter) for HCl Salt Crystal (polymorph 2) # Angle d Value Rel. Intensity 1 5.095 17.32919 26.50% 2 5.499 16.0584 4.30% 3 7.127 12.39353 1.80% 4 10.432 8.47297 15.00% 5 11.376 7.7719 35.40% 6 11.938 7.40728 100.00% 7 13.074 6.76632 55.90% 8 14.411 6.14116 9.80% 9 14.992 5.90451 57.80% 10 16.128 5.49129 99.40% 11 17.974 4.93126 10.20% 12 18.547 4.78015 18.30% 13 19.193 4.62066 18.60% 14 19.576 4.53115 32.60% 15 20.716 4.28417 21.80% 16 21.134 4.20047 52.10% 17 21.408 4.14722 64.70% 18 22.246 3.99285 68.80% 19 23.331 3.80966 19.80% 20 23.977 3.70847 64.90% 21 23.993 3.70596 64.40% 22 24.495 3.63124 33.30% 23 25.389 3.50533 10.10% 24 26.589 3.34979 21.50% 25 27.113 3.28615 18.10% 26 27.413 3.2509 9.50% 27 28.664 3.11178 4.70% 28 30.464 2.9319 8.60% 29 30.795 2.90113 7.60% 30 31.987 2.79576 3.00% 31 32.145 2.78232 3.00% 32 33.114 2.7031 4.20% 33 34.461 2.60047 4.60% 34 39.594 2.27438 2.70%
[0238] The hydrochloride salts are also analyzed by DSC/TGA, HPLC, .sup.1H-NMR and FT-IR. DSC/TGA analysis of polymorph 1 (Exp. 1-7) shows a first endothermic event at T.sub.onset=101.9° C., T.sub.peak=110.9° C. and ΔE=−18.4 J/g and a second at T.sub.onset=278.7° C., T.sub.peak=290.0° C. and ΔE=−148.6 J/g. TGA indicates a 2.4 wt % solvent residual.
[0239] DSC/TGA analysis of polymorph 2 (Exp. 1-8) shows a first endothermic event at T.sub.onset=93.6° C., T.sub.peak=108.0° C. and ΔE=−30.0 J/g and a second at T.sub.onset=277.5° C., T.sub.peak=289.9° C. and ΔE=−146.3 J/g. TGA indicates a 2.6 wt % solvent residual.
[0240] Analysis of the HPLC data shows a purity of 98-area % for both polymorphs. Analysis of the .sup.1H-NMR data shows some shifts compared to the free base, which confirms the salt formation in both cases. FT-IR analysis confirms the chemical structure.
Example 2: Mono-Tosylate Salt Crystal
[0241] p-Toluenesulfonic acid was added in a 1:1 molar ratio to a solution of d.sub.2-lumateperone free base in 2-butanone. The solution was heated to 50° C., and kept at this temperature for 1 hour, then cooled to room temperature. Scale up experiments were analyzed by XRPD, TGA, DSC, FT-IR, LC and 1H-NMR. The results are summarized in the table below:
TABLE-US-00009 TGA FT-IR FT-IR DSC mass correlation correlation LC T.sub.peak loss with FB with CI purity Expt. # Appearance XRPD (° C.) (%) (%) (%) (area-%) .sup.1H-NMR 2-1 Greenish Crystal N/A N/A N/A N/A N/A N/A solid 2-2 Off-white Crystal 180.9 <0.1 28 15 90.9 Ratio 1:1 powder 2-3 Off-white Crystal N/A N/A N/A N/A N/A N/A powder
[0242] Experiment 2-1 was performed at 100 mg scale (100 mg/mL), and a greenish slurry was obtained which was isolated as a greenish solid. XRPD showed mono-tosylate salt formation (spectrum not shown). Scale up of this experiment was performed at 1000 mg scale (66.7 mg/mL) (Exp. 2-2). The product was isolated as an off-white powder. Salt formation is confirmed by 1H-NMR. An additional experiment (Exp. 2-3) was performed at 2000 mg scale with a concentration of 50 mg/mL. This material is used for the tosylate co-crystal formation experiments. The mixture of d.sub.2-lumateperone free base, p-toluenesulfonic acid and 2-butanone was heated to 50° C. for 1 hour, then cooled to room temperature and precipitation occurred after 3 hours. The product was isolated as an off-white powder. The XRPD from Exp. 2-3 is shown in
[0243] The peak list corresponding to
TABLE-US-00010 TABLE 2 XRPD (Cu anode, Ni filter) for Mono-Tosylate Salt Crystal # Angle d Value Rel. Intensity 1 2.851 30.96656 17.10% 2 5.127 17.2226 0.90% 3 5.678 15.55363 42.70% 4 8.513 10.37781 6.20% 5 11.376 7.77174 19.70% 6 12.104 7.30617 44.60% 7 13.332 6.63591 21.30% 8 14.211 6.22737 2.50% 9 15.037 5.88696 3.30% 10 15.388 5.75362 2.60% 11 15.808 5.60166 16.60% 12 16.041 5.52094 20.20% 13 16.445 5.38617 13.70% 14 17.048 5.19683 100.00% 15 17.533 5.05418 9.00% 16 18.173 4.87762 20.60% 17 19.002 4.66654 19.00% 18 19.278 4.60039 6.00% 19 19.947 4.44764 52.60% 20 20.763 4.27468 4.50% 21 21.668 4.09818 10.20% 22 21.841 4.06605 4.80% 23 22.589 3.93303 29.30% 24 22.815 3.89464 23.60% 25 23.018 3.86072 14.50% 26 23.48 3.78575 23.60% 27 23.757 3.74234 11.10% 28 24.314 3.65785 44.50% 29 25.687 3.46536 5.90% 30 25.999 3.42447 8.70% 31 26.978 3.30231 2.80% 32 27.264 3.26836 5.30% 33 29.69 3.00656 3.90% 34 30.864 2.89488 2.00% 35 31.61 2.82821 5.10% 36 32.314 2.76819 2.10% 37 34.559 2.59334 3.10% 38 34.85 2.5723 4.30% 39 37.55 2.39331 1.60%
[0244] The mono-tosylate salt (Exp. 2-2) is also analyzed by DSC/TGA and HPLC, the results are summarized in table 4. DSC/TGA analysis shows an endothermic event at T.sub.onset=179.2° C., T.sub.peak=180.9° C. and ΔE=−77.1 J/g, and an exothermic event at T.sub.onset=277.1° C., T.sub.peak=285.3° C. and ΔE=+151.5 J/g. Analysis of the HPLC data shows a purity of 91-area %. Analysis of the .sup.1H-NMR data shows shift compared to the free base, both the free base and toluenesulfonic acid are present in a 1:1 molar ratio, which confirms the salt formation.
Example 3: Bis-Tosylate Salt Crystal
[0245] Toluenesulfonic acid was added in a 1:2 molar ratio to a solution of d.sub.2-lumateperone free base in 2-butanone. The solution was heated to 50° C., kept at this temperature for 1 hour, then cooled to room temperature. A greenish/brownish slurry was obtained which was isolated as an off-white solid. The experiment was performed at 1000 mg scale with a concentration of 50 mg/mL. The off-white solid is characterized by XRPD, DSC, TGA, FT-IR, LC and 1H-NMR, and the results are summarized in the table below:
TABLE-US-00011 TGA FT-IR FT-IR DSC mass correlation correlation LC T.sub.peak loss with FB with CI purity Sample # Appearance XRPD (° C.) (%) (%) (%) (area-%) .sup.1H-NMR 3-1 Off-white Crystal 186.6 1.0 6 18 94 Ratio 1:2 solid
[0246] The XRPD pattern for the salt is shown in
TABLE-US-00012 TABLE 3 XRPD (Cu anode, Ni filter) for Bis-tosylate Salt Crystal # Angle d Value Rel. Intensity 1 4.146 21.29319 19.30% 2 6.223 14.19209 1.10% 3 8.306 10.63621 3.10% 4 10.401 8.49836 14.30% 5 12.209 7.24368 1.60% 6 13.675 6.47004 7.90% 7 14.16 6.24983 30.80% 8 14.513 6.09848 25.00% 9 14.905 5.93889 33.40% 10 15.375 5.75839 43.40% 11 15.901 5.56892 35.90% 12 16.473 5.37695 24.20% 13 17.093 5.1833 66.90% 14 17.836 4.96894 13.50% 15 17.941 4.94014 22.10% 16 18.675 4.74767 23.10% 17 19.193 4.62071 6.10% 18 19.802 4.47986 6.10% 19 20.399 4.35002 100.00% 20 20.73 4.28143 58.50% 21 21.301 4.16792 16.90% 22 21.568 4.11697 11.70% 23 22.437 3.95936 11.40% 24 22.921 3.8769 11.60% 25 23.198 3.83126 4.50% 26 23.968 3.7098 22.40% 27 24.586 3.61791 4.30% 28 25.135 3.54015 12.60% 29 25.895 3.43789 5.70% 30 26.033 3.42 3.90% 31 26.813 3.32231 6.40% 32 27.336 3.25991 22.90% 33 27.649 3.22376 15.80% 34 28.582 3.12061 3.30% 35 28.945 3.08226 4.40% 36 29.285 3.04721 4.10% 37 30.134 2.96327 5.80% 38 31.612 2.82804 1.40% 39 32.161 2.78099 2.40% 40 33.495 2.67321 1.60% 41 34.567 2.59273 1.30% 42 35.452 2.52998 2.70% 43 39.727 2.26707 2.30% 44 42.643 2.11854 1.60%
[0247] DSC/TGA analysis shows an endothermic event at T.sub.onset=181.6° C., T.sub.peak=186.6° C. and ΔE=−84.4 J/g; and an exothermic event at T.sub.onset=235.0° C., T.sub.peak=261.1° C. and ΔE=+331.5 J/g. Analysis of the HPLC data shows a purity of 94-area %. Analysis of the 1H-NMR data shows shift compared to the free base, both the free base and toluenesulfonic acid are present in a 1:2 molar ratio, which confirms the salt formation.
Example 4: Free Base-Isonicotinamide Co-Crystal
[0248] d.sub.2-lumateperone free base and isonicotinamide were mixed in methanol at a concentration of 100 mg/ml of d.sub.2-lumateperone free base (Exp. 4-1). A clear solution was formed which was shaken overnight, then the solution was evaporated to dryness and a sticky oily solid was obtained. The experiment was repeated using at a concentration of 200 mg/mL, and a similar procedure, resulting in a sticky brown solid (Exp. 4-2). The solid was confirmed as the free base-isonicotinamide co-crystal based on XRPD, TGA, DSC, FT-IR, LC and 1H-NMR. A third experiment was conducted using a concentration of 200 mg/mL, but in a 5:2 v/v mixture of methanol and water. The results are summarized in the table below:
TABLE-US-00013 TGA FT-IR FT-IR DSC mass correlation correlation LC T.sub.peak loss with FB with CI purity Expt. # Appearance XRPD (° C.) (%) (%) (%) (area-%) .sup.1H-NMR 4-1 Sticky/oily N/A N/A N/A N/A N/A N/A N/A 4-2 Sticky Co- 150.7 N/A 80 11 64 Ratio 1:2 brown solid Crystal 4-3 Sticky Co- 150.0 1.8 10 25 67 N/A brown/ Crystal yellowish solid
[0249] The XRPD patterns for the salt (Exp. 4-2) is shown in
TABLE-US-00014 TABLE 4 XRPD (Cu anode, Ni filter) for Free Base-Isonicotinamide Co-Crystal # Angle d Value Rel. Intensity 1 11.358 7.78412 0.80% 2 14.476 6.11379 1.90% 3 18.419 4.81292 1.90% 4 20.66 4.29569 2.80% 5 21.928 4.05007 1.60% 6 22.099 4.01919 2.60% 7 22.912 3.87828 100.00% 8 24.214 3.67263 1.90% 9 28.509 3.12837 1.30% 10 28.526 3.12655 1.30% 11 29.856 2.99023 0.70% 12 32.096 2.78645 0.90% 13 32.121 2.78437 0.90% 14 34.737 2.58043 0.60% 15 34.811 2.57513 0.60% 16 36.547 2.45668 1.30% 17 36.572 2.45506 1.30%
[0250] DSC/TGA analysis (Exp. 4-2) shows an endothermic event at T.sub.onset=143.2° C., T.sub.peak=150.7° C. and ΔE=−55.3 J/g. Analysis of the HPLC data shows a purity of 64-area %. Analysis of the .sup.1H-NMR data shows free base and isonicotinamide are present in a 1:2 molar ratio, which confirms the co-crystal formation.
Example 5: Tosylate-Lysine Co-Crystal
[0251] d.sub.2-lumateperone mono-tosylate (Exp. 2-3) and L-lysine free base were mixed in methanol. The solution turned into a gel overnight and additional methanol was added in order to create a slurry. The product was isolated as a yellowish powder and characterized by XRPD, DSC, TGA, FT-IR, LC and 1H-NMR. The results are summarized in the table below:
TABLE-US-00015 TGA FT-IR FT-IR DSC mass correlation correlation LC T.sub.peak loss with FB with CF purity Sample # Appearance XRPD (° C.) (%) (%) (%) (area-%) .sup.1H-NMR 5-1 Yellowish Co- 203.1 20.6 N/A N/A 93.0 Free base, powder Crystal 221.7 tosylate and lysine
[0252] The XRPD patterns for the co-crystal is shown in
TABLE-US-00016 TABLE 5 XRPD (Cu anode, Ni filter) for Tosylate-Lysine Co-Crystal # Angle d Value Rel. Intensity 1 7.471 11.82319 5.90% 2 9.541 9.26261 44.60% 3 11.149 7.92974 3.30% 4 11.522 7.67421 11.80% 5 12.469 7.09293 8.10% 6 14.969 5.9137 10.30% 7 15.437 5.73524 12.70% 8 17.543 5.05147 3.20% 9 18.184 4.87469 22.40% 10 19.14 4.63327 10.60% 11 20 4.43594 100.00% 12 20.177 4.39754 18.60% 13 20.781 4.27107 13.90% 14 22.386 3.96821 64.10% 15 22.708 3.91277 21.00% 16 23.152 3.83863 7.30% 17 24.535 3.6254 8.30% 18 24.857 3.57907 12.80% 19 25.405 3.50311 2.10% 20 25.913 3.43555 82.20% 21 28.025 3.18128 1.40% 22 28.91 3.08591 1.70% 23 29.73 3.00261 7.90% 24 30.211 2.95595 22.20% 25 30.655 2.91408 4.30% 26 30.901 2.8915 6.60% 27 32.121 2.78434 4.10% 28 33.567 2.66765 5.10% 29 33.892 2.64284 4.70% 30 34.195 2.62011 3.30% 31 35.017 2.56045 2.90% 32 35.857 2.50239 4.20% 33 37.319 2.4076 4.70% 34 39.287 2.29144 2.40% 35 39.712 2.26788 1.20% 36 40.68 2.2161 1.60% 37 42.856 2.10851 1.00% 38 43.764 2.06684 1.50%
[0253] DSC/TGA analysis shows a first endothermic event at T.sub.onset=193.1° C., T.sub.peak=203.1° C. and ΔE=−72.2 J/g, and a second endothermic event at T.sub.onset=188.8° C., T.sub.peak=221.7° C. and ΔE=−109.3 J/g. Analysis of the HPLC data shows a purity of 93-area %. Analysis of the .sup.1H-NMR data shows d.sub.2-lumateperone free base, toluenesulfonic acid, and lysine, which confirms the co-crystal formation.