STABLE CRYSTALLINE NORIBOGAINE SALT ANSOLVATES
20170022194 ยท 2017-01-26
Assignee
Inventors
Cpc classification
A61P29/00
HUMAN NECESSITIES
C07D471/22
CHEMISTRY; METALLURGY
International classification
Abstract
Stable noribogaine salt ansolvates are useful for preparing pharmaceutical compositions and for alleviating nociceptive pain in a patient. Such ansolvates can be prepared by slurrying solvated forms, preferably MeOH solvated noribogaine hydrochloride in EtOH/water.
Claims
1. A stable pharmaceutically acceptable salt of noribogaine ansolvate.
2. The stable salt of noribogaine ansolvate of claim 1, wherein the salt is a hydrochloride salt.
3. The salt of claim 2, which is crystalline.
4. The crystalline salt of claim 3, characterized by at least one X-ray powder diffraction peak (Cu K radiation) selected from 11.6, 12.1, 13.5, 13.9, 14.9, 15.7, 17.1, 17.9, 18.3, 19.8, 20.8, 21.0, 21.9, 22.8, 23.3, 24.9, 25.9, 26.4, 29.3, and 29.8 2 (each 0.2 2).
5. The crystalline salt of claim 3, which shows substantially no thermal transitions under 300 C. in its differential scanning calorimetry thermogram.
6. The crystalline salt of claim 3, which shows substantially no weight loss at a temperature under 300 C. in its thermogravimetric analysis thermogram.
7. The crystalline ansolvate salt of claim 3, which has a density that is at least 3% and up to 20% greater than the density of a solvated crystalline hydrochloride salt of noribogaine.
8. The crystalline ansolvate salt of claim 3, which has a unit cell volume of less than about 1800 cubic angstrom, or less than about 1750 cubic angstrom, or less than 17002% cubic angstrom.
9. A crystalline noribogaine hydrochloride solvate polymorph characterized by about 4% weight loss at temperatures under 125 C. in its differential scanning calorimetry thermogram.
10. The crystalline solvate polymorph of claim 9 characterized by at least one X-ray powder diffraction peak (Cu K radiation) selected from 9.7, 10.2, 12.0, 13.3, 13.7, 16.0, 16.3, 17.7, 18.0, 19.4, 21.4, 22.1, 22.8, 24.4, 25.1 2 (each 0.2 2).
11. The stable ansolvate salt of noribogaine of claim 1, wherein the salt is a sulfate salt.
12. The salt of claim 11, which is crystalline.
13. The crystalline salt of claim 12 characterized by at least one X-ray powder diffraction peak (Cu K radiation) selected from 8.5, 11.4, 12.0, 13.3, 15.4, 16.6, 17.2, 18.3 2, 20.6, 21.0, and 21.5 (each 0.2 2).
14. A composition comprising the stable noribogaine ansolvate salt of any one of claims 1-8 and 11-14.
15. The composition of claim 14, further comprising a pharmaceutically acceptable excipient.
16. A crystalline polymorph of a phosphate salt of noribogaine.
17. A method of treating a patient to alleviate nociceptive pain in the absence of the treatment of drug dependence or drug abuse and in the absence of any concomitant opioid analgesic therapy, comprising: administering systemically to said patient a pharmaceutical composition comprising effective amount of the stable noribogaine salt ansolvate of any one of claims 1-8 and 11-14, or the composition of claim 14 or 15, to said patient effective to reduce or eliminate said nociceptive pain in said patient.
18. A method of treating a patient to alleviate nociceptive pain in the absence of the treatment of drug dependence or drug abuse and in the absence of any concomitant opioid analgesic therapy, comprising: administering systemically to said patient a pharmaceutical composition comprising effective amount of the stable noribogaine salt ansolvate of claim 1, or the phosphate salt of claim 16, or the composition of claim 14 or 15, to said patient effective to reduce or eliminate said nociceptive pain in said patient.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION OF THE INVENTION
[0042] As noted above, this invention is directed, in part, to a stable crystalline ansolvates of noribogaine salts and, in particular, to the hydrochloride salt. However, prior to discussing this invention in further detail, the following terms will be defined.
DEFINITIONS
[0043] As used herein, the following terms have the following meanings.
[0044] The singular forms a, an, and the and the like include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a compound includes both a single compound and a plurality of different compounds.
[0045] The term about when used before a numerical designation, e.g., temperature, time, amount, and concentration, including a range, indicates approximations which may vary by 10%, 5% or 1%.
[0046] Administration refers to introducing an agent into a patient. A therapeutic amount can be administered, which can be determined by the treating physician or the like. An oral route of administration is preferred. The related terms and phrases administering and administration of, when used in connection with a compound or pharmaceutical composition (and grammatical equivalents) refer both to direct administration, which may be administration to a patient by a medical professional or by self-administration by the patient, and/or to indirect administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient. In any event, administration entails delivery to the patient of the drug.
[0047] The crystalline ansolvate of noribogaine hydrochloride is a crystalline solid form of a noribogaine salt, such as, e.g., the crystalline Form A or D. Such a crystal lattice is substantially free of solvents of crystallization. However, any solvent present is not included in the crystal lattice and is randomly distributed outside the crystal lattice. Therefore, ansolvate crystals in bulk may contain, outside the crystal lattice, small amounts of one or more solvents, such as the solvents used in its synthesis or crystallization. As used above, substantially free of and small amounts, refers to the presence of solvents preferably less that 10,000 parts per million (ppm), or more preferably, less than 5000 ppm.
[0048] Comprising or comprises is intended to mean that the compositions and methods include the recited elements, but not exclude others. Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition or a method consisting essentially of the elements as defined herein would not exclude, respectively, other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed composition or method. Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
[0049] Pharmaceutically acceptable refers to non-toxic material suitable for in vivo and preferably human administration.
[0050] Therapeutically effective amount or therapeutic amount refers to an amount of a drug or an agent that when administered to a patient suffering from a condition, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of the condition in the patient. The therapeutically effective amount will vary depending upon the subject and the condition being treated, the weight and age of the subject, the severity of the condition, the particular composition or excipient chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can be determined readily by one of ordinary skill in the art. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. For example, and without limitation, a therapeutically effective amount of an agent, in the context of alleviating nociceptive pain, refers to an amount of the agent that reduce or eliminate one or more manifestations of the nociceptive pain in the patient.
[0051] Treatment, treating, and treat are defined as acting upon a disease, disorder, or condition with an agent to reduce or ameliorate the harmful or any other undesired effects of the disease, disorder, or condition and/or its symptoms and produce beneficial or desired clinical results. Treatment, as used herein, covers the treatment of a human patient, and includes: (a) reducing the risk of occurrence of the condition in a patient determined to be predisposed to the disease but not yet diagnosed as having the condition, (b) impeding the development of the condition, and/or (c) relieving the condition, i.e., causing regression of the condition and/or relieving one or more symptoms of the condition. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, reducing or eliminating nociceptive pain.
Preparing and Characterizing the Noribogaine Polymorphs
[0052] The noribogaine hydrochloride ansolvate Form A is prepared by reacting noribogaine free base with hydrochloric acid in a variety of solvents, or by crystallizing the hydrochloride from a variety of solvents as tabulated in the Examples section below. Upon slow evaporation of noribogaine hydrochloride from a methanol slurry over 7 days, a Form G crystal different from Form A is obtained. See top panel,
[0053] The Form A crystals were indexed as shown below. Successful indexing of the XRPD patterns indicates that sample is composed primarily of a single crystalline phase.
Noribogaine Hydrochloride Form A
[0054]
TABLE-US-00002 Bravais type Primitive orthorhombic a [] 8.943 b [] 13.019 c [] 14.584 [deg] 90 [deg] 90 [deg] 90 Volume [.sup.3/cell] 1,698.1 Chiral Contents? Chiral Extinction Symbol P 21 21 21 Space Group(s) P 21 21 21 (19)
[0055] Thermogravimetric data for Form A crystals show negligible weight loss prior to 316 C. at which point a sharp weight loss is observed, indicating probable decomposition (
[0056] The approximate ambient-temperature solubilities of noribogaine hydrochloride Form A were measured in a variety of solvents and solvent mixtures using the solvent addition method (Table 2). The material exhibited low solubility in most of the solvents tested, and was more soluble in a number of organic-aqueous mixtures, HFIPA, MeOH, and TFE.
[0057] Samples from the slurry and accelerated stability experiments of Form C exhibited a minor amount of peak shifting by XRPD, indicating a family of XRPD patterns. The XRPD patterns were successfully indexed as shown below.
TABLE-US-00003 Bravais type Triclinic a [] 9.190 b [] 10.234 c [] 11.009 [deg] 75.45 [deg] 73.16 [deg] 78.38 Volume [.sup.3/cell] 949.9 Chiral Contents? Chiral Extinction Symbol P - Space Group(s) P 1 (1)
[0058] For another slightly peak shifted form of Form C, the following indexing was obtained.
TABLE-US-00004 Bravais type Triclinic a [] 9.226 b [] 10.212 c [] 11.022 [deg] 75.48 [deg] 72.65 [deg] 78.02 Volume [.sup.3/cell] 949.6 Chiral Contents? Chiral Extinction Symbol P - Space Group(s) P 1 (1)
[0059] An overlay of the DSC and TGA thermograms for Form C is presented in
[0060] The DVS curves for noribogaine phosphate (Form C) are shown in
[0061] Form D crystals were indexed as shown below.
TABLE-US-00005 Bravais type Primitive orthorhombic a [] 8.628 b [] 14.122 c [] 15.455 [deg] 90 [deg] 90 [deg] 90 Volume [.sup.3/cell] 1,883.1 Chiral Contents? Chiral Extinction Symbol P 21 21 21 Space Group(s) P 21 21 21 (19)
[0062] Form F crystals were indexed as shown below. It is contemplated that the larger cell volume of Form F compared with Form A could possibly accommodate one or two molecules of water or an additional hydrochloride molecule.
TABLE-US-00006 Bravais type Primitive orthorhombic a [] 10.043 b [] 10.842 c [] 16.903 [deg] 90 [deg] 90 [deg] 90 Volume [.sup.3/cell] 1,840.5 Chiral Contents? Chiral Extinction Symbol P 21 21 21 Space Group(s) P 21 21 21 (19)
[0063] An overlay of the DSC and TGA thermograms for sulfate Form D is presented in
[0064] The DVS curves for the sulfate salt are shown in
Characterizing the Solids
[0065] Selected XRPD patterns were collected with an Inel XRG-3000 diffractometer. An incident beam of Cu K radiation was produced using a fine-focus tube and a parabolically graded multilayer mirror. Prior to the analysis, a silicon standard (NIST SRM 640c) was analyzed to verify the Si 111 peak position. A specimen of the sample was packed into a thin-walled glass capillary, and a beam-stop was used to minimize the background from air. Diffraction patterns were collected in transmission geometry using Windif v. 6.6 software and a curved position sensitive Equinox detector with a 20 range of 120.
[0066] Selected XRPD patterns were also collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror was used to focus Cu K X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640d) was analyzed to verify the Si 111 peak position. A specimen of the sample was sandwiched between 3 m thick films and analyzed in transmission geometry. A beam-stop, short antiscatter extension, and antiscatter knife edge (select samples only) were used to minimize the background generated by air. Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 2.2b.
[0067] DSC was performed using a TA Instruments Q2000 differential scanning calorimeter. Temperature calibration was performed using NIST traceable indium metal. The sample was placed into an aluminum DSC pan, covered with a lid, and the weight was accurately recorded. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell.
[0068] Thermogravimetric analyses were performed using a TA Instruments Q5000 IR thermogravimetric analyzer. Temperature calibration was performed using nickel and Alumel Each sample was placed in an aluminum pan. The sample was hermetically sealed, the lid pierced, then inserted into the TO furnace. The furnace was heated under nitrogen.
[0069] Dynamic vapor sorption (DVS) data were collected on a VTI SOA-100 Vapor Sorption Analyzer. NaCl and PVP were used as calibration standards. Samples were not dried prior to analysis. Sorption and desorption data were collected over a range from 5 to 95% RH at 10% RH increments under a nitrogen purge. The equilibrium criterion used for analysis was less than 0.0100% weight change in 5 minutes with a maximum equilibration time of 3 hours. Data were not corrected for the initial moisture content of the samples.
Examples
[0070] The following abbreviations are used in the examples and in this disclosure:
ACN acetonitrile
EtOH ethanol
EtOAc ethyl acetate
HFIPA hexafluoroisopropanol
MeOH methanol
MTBE tert-butyl methyl ether
TFE 2,2,2-trifluoroethanol
THF tetrahydrofuran
SC slow cool
SE slow evaporation
VD vapor diffusion
VS vapor stress
DSC differential scanning calorimetry
DVS Dynamic vapor sorption
XRPD x-ray powder diffraction
B/E birefringence with extinction
conc. concentrated
endo endotherm
P.O. preferred orientation
ppt. precipitation/precipitate
RH Relative humidity
RT room (ambient) temperature
TGA Thermogravimetric analysis
Example 1
Solubility of Form A Polymorph
[0071] The solubility of noribogaine hydrochloride ansolvate were determined as tabulated below.
TABLE-US-00007 TABLE 2 Solvent System Solubility (mg/mL).sup.a Acetone <1 Acetone:water 50:50 11 CAN <1 ACN:water 80:20 9 chloroform <1 chloroform:EtOH 50:50 <1 p-dioxane <1 EtOAc <1 EtOH <1 HFIPA 10 MeOH 2 MeOH:THF 50:50 1 TFE 4 TFE:water 50:50 10 THF <1 Water .sup.<4 .sup.b .sup.aSolubilities were calculated based on the total solvent used to give a solution. .sup.b Solubility measurement made by adding water all at once and allowing mixture to stir for ~24 hours, resulting in a clear solution with a very small amount of find solids in suspension.
Example 2
Preparation of Crystal Form A
[0072] Noribogaine hydrochloride ansolvate Form A was prepared by formation of the hydrochloride salt from the free base in IPA. Noribogaine free base (136 g) was charged to a 5 L flange flask fitted with a nitrogen inlet, gas bubbler, overhead stirrer, dropping funnel and thermometer. Isopropanol (3.27 L) was added and the mixture was heated under stirring and nitrogen atmosphere to 45-55 C. over one hour to afford a clear solution. Isopropanol/HCl (5 M, 128.6 ml, 1.4 eq). was added over one hour. Precipitation of an off-white solid was observed and the suspension was allowed to cool under stirring to room temperature overnight. The mixture was further chilled to 0-5 C. After 30 minutes the solid was collected by filtration and washed with DCM (20.49 L) and sucked dry to constant weight under nitrogen purge. The solid was further dried under vacuum at 60 C. for four days to afford. 150 g of Noribogaine hydrochloride which was shown to be Form A by XRPD.
[0073] Various solid forms of noribogaine obtained from various solvents are tabulated below
TABLE-US-00008 TABLE 3 Solvent/Solvent System Conditions Habit/Description acetone dissolve free clear black solution base w/ sonication add conc. ppt. on contact, opaque acid w/ purple suspension stirring stir at RT, opaque brownish-gray 1 day suspension; tiny particles and aggregates, B/E IPA dissolve free clear black solution base w/ sonication add conc. ppt. formed, opaque dark acid w/ brown suspension stirring stir at RT, opaque purplish-gray 1 day suspension; very tiny particles and aggregates, partial B/E MeOH dissolve free clear black solution base w/ sonication add conc. clear reddish-black acid w/ solution stirring stir at RT, cloudy brown suspension 1 day (solids present); after isolating - off-white, tiny particles, and aggregates, B/E
TABLE-US-00009 TABLE 4 Solvent/Solvent System Conditions Habit/Description TFE stir at ~68 C. for clear solution ~1.5 hrs., SC, ~68 C. to RT, stir at RT 1 day refrigerator, 1 day clear solution mill, 30 Hz, white, tiny particles and 30 min. aggregates, partial B/E water VS, ~41 C., 7 days dry off-white solids, droplets of solvent on walls; rectangular plates, B/E mill, 30 Hz, 30 min. white, tiny particles and aggregates, partial B/E slurry, ~38 C., 3 days cloudy brown solution, off white solids; rectangular plates, B/E IPA slurry, ~39 C., 3 days clear liquid phase, off white solids; rectangular plates, B/E HFIPA VD w/MTBE, 8 days clear liquid phase, small amount white solids on bottom; aggregates and unknown morphology, partial B/E EtOH slurry, ~39 C., 3 days clear liquid phase, off white solids; rectangular plates, B/E VS, ~41 C., 7 days damp off-white solids; rectangular plates, B/E ACN:water slurry, RT, 7 days clear liquid phase, off white 90:10 solids; rectangular plates, B/E
Example 3
Preparation of Crystal Form C, the Phosphate Salt
[0074] Noribogaine free base (0.9055 g) was dissolved in IPA (20 mL) with sonication, yielding a clear, very dark green solution. Phosphoric acid (0.209 mL, concentrated) was added in a 1:1 stoichiometric ratio with stirring, causing precipitation on contact and resulting in an opaque gray suspension. The mixture was allowed to stir at ambient conditions for 3 days, at which time an opaque dark purple suspension was observed. Solids were collected by vacuum filtration, causing a color change from dark purple to light purplish-gray while the solids were air drying on the filter. The resulting solids were designated as a mixture of Form C (phosphate) and another Form, E, by XRPD. A portion of the solids (0.6009 g) was added to an 80:20 mixture of EtOH and water (total of 2 mL), and undissolved solids remained. The slurry was loaded onto an orbital shaker and was agitated at ambient temperature and 150 rpm for 3 days, affording an opaque purplish-gray suspension. The solids were collected by vacuum filtration and vacuum dried at ambient temperature for 1 day, resulting in pure Form C (phosphate) by XRPD.
Example 4
Preparation of Crystal Form D, the Sulfate Salt
[0075] Noribogaine free base (0.7730 g) was dissolved in IPA (25 mL) with sonication, resulting in a clear green solution. Concentrated sulfuric acid (0.1463 mL) was added in a 1:1 molar ratio with stirring, causing precipitation on contact, giving an opaque very light gray suspension. The mixture was allowed to stir at ambient conditions for 3 days, and the solids were collected by vacuum filtration and washed with IPA (89% yield).
Example 5
Preparation of Crystal Form F of the Hydrochloride Salt
[0076] Form F was prepared by precipitation of the HCl salt from a MeOH solution of the free base by adding methanolic HCl and subsequently purifying by slurrying in MeOH. Form F was characterized by XRPD as shown in the middle panel of
Example 5
Conversion of Form F to Pure Form A Ansolvate
[0077] Surprisingly, it was observed that the solvated polymorph F, converted to the ansolvate form A, upon stirring in 9:1 ethyl alcohol and water. Such a desolvation is surprising, given that it occurs upon stirring in another solvent, which comprises hydroxy groups and alkyl moieties as in MeOH. As described above, form F is a solvated polymorph that is obtained from MeOH. The form F polymorph also converts to the ansolvate form A upon heating.
Example 7
Preparation of Crystal Form G of the Hydrochloride Salt
[0078] When a methanol slurry of noribogaine hydrochloride was kept at room temperature for 7 days, off white, rectangular aggregates and irregular plates were obtained (Form G), which showed XRPD as shown in the top panel of