NZ620948B2 - Noribogaine salt ansolvates - Google Patents

Abstract

Disclosed are noribogaine salt ansolvates and phosphate salt polymorphs prepared by slurrying methanol solvated forms of the salt in ethanol/water. The disclosed noribogaine salt ansolvates are more stable and less dense providing the advantage of more compact and smaller tablets than solvated polymorphs for tableting while using the same amount of a noribogaine salt. The noribogaine salt ansolvates are useful for preparing pharmaceutical compositions for alleviating nociceptive pain in a patent. orphs for tableting while using the same amount of a noribogaine salt. The noribogaine salt ansolvates are useful for preparing pharmaceutical compositions for alleviating nociceptive pain in a patent.

Description

[Annotation] hjg NORIBOGAINE SALT ANSOLVATES CROSS REFERENCE TO D APPLICATION This application claims the benefit under 35 U.S.C. l 19(e) of U.S. Provisional Application Serial No. 61/535,300 filed September 15, 2011, which is hereby incorporated by reference into this ation in its entirety.

FIELD OF THE INVENTION This invention relates to stable solid forms of noribogaine salts and pharmaceutical uses thereof. In one embodiment, the stable salts are crystalline ansolvates. In another embodiment, the stable salts are amorphous ansolvates.

STATE OF THE ART Noribogaine is a compound of formula: Noribogaine and its pharmaceutically acceptable salts, such as for example the hydrochloride salt, have recently received significant attention as a non—addictive alkaloid useful in treating drug dependency (US. Patent No. 6,348,456) and as a potent sic (U.S. Patent Nos. 7,220,737 and 7,754,710). Each of these s are incorporated herein by reference in their entirety.

When used for treating , an orally delivered, solid formulations of therapeutic agent preferably need to meet certain criteria. For a tablet ition of the therapeutic agent, the tablet must be ssible and shear»stable, where the agent should be compatible with one or more excipients and not o morphological change during storage or manufacture. Likewise, the therapeutic agent in a tablet or capsule must be dense enough to pack enough of the agent with the understanding that smaller tablets or capsules are deemed to be more easily ingested than larger ones.

One of the critical factors for processing such a therapeutic agent is the packing of the agent in its crystal lattice. Accordingly, the selection of a polymorph from a manufacturing perspective is very critical, The eutic agent must also be sufficiently 4834-761 8-1 2651 stable, must retain its polymorphic form during manufacture of a tablet or a e dosage form, and must not e during a normal shelf-life storage. Each of these criteria is critical to ensure that unacceptable by-products are not formed. Very few polymorphic forms of an active agent satisfy all of these criteria so as to be suitable for use as the active ient in a orally delivered, solid formulation of the therapeutic agent.

As to noribogaine hydrochloride a number of crystal polymorphs in the form of a solvate have been identified. These solvated crystalline polymorphs unfortunately lack one or more of the characteristics defined above to be suitable as an active in a pharmaceutical composition.

Accordingly, there is a need to define one or more forms of noribogaine hydrochloride which meet each of the above ia.

SUMMARY It has now been unexpectedly discovered that certain ansolvates of noribogaine salts are substantially more stable and can maintain their polymorphic forms during manufacture and storage and have a suitable density to allow for facile manufacture of capsules and/or tablets. These certain ansolvates are characterized by either a crystalline or amorphous structure.

In one embodiment is presented a stable pharmaceutically acceptable salt of noribogaine selected from: a noribogaine ansolvate, which is amorphous or is a crystalline hydrochloride salt having an X-ray powder diffraction pattern comprising peaks at 11.6±0.2° 2θ, 12.1±0.2° 2θ, 13.5±0.2° 2θ, 14.0±0.2° 2θ, .2° 2θ, 15.8±0.2° 2θ, 17.2±0.2° 2θ, 18.0±0.2° 2θ, 18.4±0.2° 2θ, 20.0±0.2° 2θ, 20.9±0.2° 2θ, 21.1±0.2° 2θ, 22.0±0.2° 2θ, 22.8±0.2° 2θ, 23.0±0.2° 2θ, .2° 2θ, 25.9±0.2°2θ, 26.5±0.2° 2θ, 29.5±0.2° 2θ and .2° 2θ; or is a crystalline sulfate salt having an X-ray powder diffraction n comprising peaks at 2° 2θ, 11.4±0.2° 2θ, 12.0±0.2° 2θ, 13.3±0.2° 2θ, .4±0.2° 2θ, 16.6±0.2° 2θ, 17.2±0.2° 2θ, 18.3±0.2° 2θ, .2° 2θ, 21.0±0.2° 2θ and 21.5±0.2° 2θ; when analyzed using CuKα X-ray radiation; and a crystalline gaine hydrochloride solvate rph having an X-ray powder diffraction pattern comprising peaks at 9.7±0.2° 2θ, 10.5±0.2° 2θ, 12.2±0.2° 2θ, 13.2±0.2° 2θ, 13.8±0.2° 2θ, 16.1±0.2° 2θ, 16.5±0.2° 2θ, 17.5±0.2° 2θ, 18.0±0.2° 2θ, 11420382 -2a- 19.5±0.2° 2θ, 21.5±0.2° 2θ, 22.2±0.2° 2θ, 23.0±0.2° 2θ, 24.5±0.2° 2θ and 25.2±0.2° 2θ, when analyzed using CuKα X-ray radiation; and a crystalline rph of a phosphate salt of noribogaine, having an X-ray powder diffraction pattern comprising peaks at 8.5±0.2° 2θ, 9±0.2° 2θ, 11±0.2° 2θ, 12.6±0.2° 2θ, 14.7±0.2° 2θ, 20±0.2° 2θ, 21±0.2° 2θ, 24.2±0.2° 2θ, and 25.5±0.2° 2θ when analyzed using CuKα X-ray ion.

In another embodiment, the ansolvates of this invention preferably have a density that is at least 3% and up to 20%, or more preferably at least 5% and up to 15%, r than the density of a ed crystalline hydrochloride salt of noribogaine.

In another embodiment, ansolvates are crystalline ansolvates of noribogaine hloride having a by a unit cell volume of less than about 1850 cubic angstrom, ably less than about 1800 cubic angstrom, more preferably, less than about 1750 cubic angstrom, or most preferably less than 1700±2% cubic angstrom. For a crystalline ansolvate polymorph, it is contemplated that a smaller unit cell volume correlates with a higher density of that polymorph.

Such stable crystalline ansolvate salts include the hloride salt, the sulfate salt, and the tosylate salt, each of which demonstrate superior ity and other superior physicochemical properties compared to solvated crystalline forms, which include methanol or water as the solvent. Preferably, the salt is a hydrochloride salt.

The crystalline ansolvate polymorphs of this invention provide several advantages including enhanced heat stability as compared to solvated forms. Also, its density is increased compared to ansolvates d by desolvation of solvated polymorphs of noribogaine hydrochloride. In the latter case, the loss of solvent in the ed polymorph 11420382 [Annotation] hjg leads to l gaps (holes) in the crystal structure which render it less dense and potentially capable of undergoing an undesirable form conversion during high-pressure lations of tableting and formulating. The denser ansolyate polymorphs of this ion provide more compact and smaller tablets than solyated polymorphs for tableting while using the same amount of a noribogaine salt.

As used herein, the term “stable” or “stability” of a polymorph refers to polymorphic and/or chemical stability at about 25°C, and preferably at about 400C for at least 1 day, preferably for at least a week, and more ably for several months. More preferably, the ansolvate polymorphs of this invention are stable under the aforementioned conditions and at about 75% relative humidity (RH), yet more preferably at about 97% RH.

Still more preferably, stability refers to stability for at least 1 day, preferably for at least a week, at about 25°C and about 75% RH, more preferably at about 400C and 75% relative ty (RH), and still more preferably at about 40°C and about 97% RH. A “stable” polymorph does not undergo polymorphic transformation when exposed to moisture and or g, for example, up to about 40°C. In addition, chemical/polymorphic stability can be further measured by no observable change in one or more of, preferably, two of, more preferably three of, and most preferably all of, XRPD, TGA, DVS, IR, and 1H-NMR of the solid form. However, the ity of compounds somewhat less stable under humidity or moisture exposure can be ed by adding desiccants well known to the skilled artisan.

Surprisingly, the corresponding crystalline solvated salts of noribogaine are not stable and/or are not polymorphically pure, nor are these crystalline noribogaine forms obtained by desolvating these es. Such unstable desolyated forms are referred to herein as “unstable porous crystalline noribogaine ansolvate salts” as removal of the solvate results in the formation of pores within the crystalline ure. As used herein, stable crystalline ansolvate gaine salts do not include “unstable porous crystalline noribogaine ansolyate salts.” Accordingly, in one aspect, this ion provides for stable ansolvate noribogaine salts and, in particular, stable crystalline ansolvate salt; In one embodiment, the salt is a pharmaceutically acceptable salt, In one embodiment, the salt is an ansolvate of the hydrochloride salt of gaine (NIHCl, Form A or Form I). in another embodiment, the salt is an ansolvate of the te salt of noribogaine (NI.TsOH, Form B). In another embodiment, the salt is an ansolvate sulfate salt {NI.HZSO4, Form D).

In one embodiment, the crystalline stable ansolvate noribogaine hydrochloride shows substantially no weight loss at temperatures under 3006C in its thermograyimetric 4834-7618—1265.1 analysis (TGA) thermogram evidencing the lack of solvent in the crystal structure. In another embodiment, the crystalline stable ansolvate noribogaine hydrochloride has a y that is at least 3% and up to 20%, or preferably at least 5% and up to 15% greater than the density of a solvated crystalline hydrochloride salt of gaine. In another embodiment, the crystalline stable ansolvate gaine hloride has a unit cell volume of less than about 1850 cubic om, preferably less than about 1800 cubic angstrom, more preferably, less than about 1750 cubic om, or most preferably less than 1700±2% cubic angstrom.

In another embodiment, this invention provides a solvated crystalline noribogaine hydrochloride polymorph characterized by about 4% weight loss at temperatures under 125oC, ably at temperatures ranging from 27oC to 125oC in its TGA thermogram. In another ment, the solvated crystalline noribogaine hydrochloride polymorph is characterized by at least one X-ray powder diffraction peak (Cu Kα radiation) selected from 9.7, 10.5, 12.2, 13.2, 13.8, 16.1, 16.5, 17.5, 18.0, 19.5, 21.5, 22.2, 23.0, 24.5, and 25.2° 2θ (each ±0.2 °2θ). In another embodiment, such a solvated polymorph is characterized by the X-ray diffraction pattern as substantially shown in the two top panels of It has also been discovered that a solvated hydrochloride polymorph of noribogaine obtained from MeOH is surprisingly converted to a pure, ansolvate polymorph of noribogaine hydrochloride upon stirring in EtOH/water, e.g., 9:1 EtOH/water. Accordingly, also provided herein is a process of ing a noribogaine hydrochloride ansolvate comprising slurrying a noribogaine solvate, preferably, one obtained from MeOH, in EtOH/water. It is noted that solvated hydrochloride polymorph of noribogaine obtained from methanol is an intermediate for the preparation of a polymorph of this invention and, accordingly, is part of the invention as claimed.

The table below demonstrates the or re stability of the ansolvate, hydrochloride Form A polymorph.

Table 1 Salt/Form Stoichiometry Approx. Aqueous RH Stability Solubility HCl, Form A 1:1 salt 1-4 mg/mL About 97% RH/RT: no form change after 7 days.

Tosylate, Form B Likely 1:1 salt 3 mg/mL About 75% RH/ RT: no deliquescence after 1 day.

About 97% RH/RT: esced after 1 day.

Phosphate, Form C 1:1 salt 23 mg/mL About 75% RH/ RT: no deliquescence after 1 day.

About 97% RH/RT and about AH26(11061205_1):RTK [Annotation] hjg 75% RH/ about 41°C: no deliquescence and no form change after 7 days. I Sulfate, Form D 121 salt > 80 mg/mL About 75% RH/ RT: no deliquescence.

About 97% Riel/RT: deliquesced after 1 day.

About 75% RH/ about 410C: no deliqueseence and no form after 7 days. . change The superior polymorphic and thermal stability of Form A and the other polymorphic forms are also evidenced by comparing the XRPD patterns of FIGS. 3 and 5, and the thermograms of Fle. l and 2 and those of Fle. 6 and lO~l2.

To determine the effect of relative humidity, weighed s of nt noribogaine starting materials were transferred to vials, which were then uncapped and placed inside a jar containing a saturated aqueous salt solution: sodium chloride was used for ~75% RH and potassium sulfate for ~97% RH. Relative humidity stressing experiments were conducted at ambient and elevated temperatures for given durations.

Two other moisture absorbing, unstable, polymorphs of noribogaine hydrochloride, Forms F and G, which had mutually similar XRPD patterns were also identified. Form G was isolated from a slurry of Form A in MeOH at ambient temperature. Material G likely contains MeOH and water, and Form F (or Form 11) is likely hydrated. After drying, material G exhibited 7.95% gravimetric weight loss and ted to Form A, as characterized by XRPD. Form F showed 4.1% gravimetric weight lossindicating the presence of t in the polymorph and is converted to Form A as characterized by XRPD. A sharp weight loss at ~312°C indicated likely decomposition. Both Forms G and F are contemplated to readily pick up moisture from the atmosphere.

In r embodiment, the crystalline noribogaine hydrochloride ansolvate is characterized by the onset of an endothermic peak at imately 3080C with a peak as measured by differential scanning calorimetry at imately 3 15 OC, In another ment, the lline noribogaine hydrochloride ate is characterized by the substantial absence of thermal events at temperatures below the endothermic peak at about 308i°C as measured by differential scanning calorimetry. In another embodiment, the crystalline noribogaine hydrochloride ansolvate is characterized by a DSC or a TGA thermogram substantially similar to that of FlG. 1. In another embodiment, the crystalline noribogaine hydrochloride ansolvate is characterized by a DVS pattern substantially similar 4834—7618-1255.1 to that of In another embodiment, the crystalline noribogaine hydrochloride ate is terized by at least one, at least two, or at least three X-ray powder ction peaks (Cu Kα radiation) selected from 11.6°, 12.1°, 13.5°, 14.0°, 15.0°, 15.8°, 17.2°, 18.0°, 18.4°, .0°, 20.9°, 21.1°, 22.0°, 22.8°, 23.0°, 24.9°, 25.9°, 26.5°, 29.5° and 31.5°2θ (each ±0.2 °2θ).

In another embodiment, the crystalline noribogaine hydrochloride ansolvate is characterized by an X-ray powder diffraction pattern (Cu Kα radiation) ntially similar to that of In another embodiment, the crystalline NI.H3PO4 is characterized by an XRPD n substantially similar to that of any one of patterns in In another embodiment, the crystalline NI.H3PO4 is characterized by a DSC or a TGA thermogram substantially similar to that of In another embodiment, the crystalline noribogaine sulfate ansolvate (NI.H2SO4) is characterized by at least one, at least two, or at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 8.5°, 11.4°, 12.0°, 15.4°, 16.6°, 17.2°, and 18.3°2θ (each ±0.2 °2θ). In another ment, the crystalline noribogaine sulfate ansolvate (NI.H2SO4) is characterized by an X-ray powder diffraction pattern (Cu Kα radiation) substantially similar to that of In another embodiment, the lline O4 is characterized by a DSC or a TGA thermogram similar to that of In another embodiment, the crystalline NI.H2SO4 is characterized by a DVS pattern similar to that of .

In one of its composition embodiments, this invention provides a composition comprising the stable, crystalline noribogaine salt ansolvates provided herein, and preferably the Form A ansolvate. In another of its ition embodiments, this invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and the stable crystalline noribogaine salt ansolvates provided herein, preferably the Form A ansolvate.

In another of its composition embodiments, this invention provides a kit comprising: the ansolvates provided herein, ably the sulfate and the tosylate Forms B and D; or a composition comprising the ate provided herein, preferably the sulfate and the te Forms B and D; or a pharmaceutical composition comprising the ate provided herein, preferably the e and the tosylate Forms B and D; and a pharmaceutically acceptable excipient, and a ant. Various suitable desiccants appropriate for use in this kit is well known to the skilled artisan.

AH26(11061205_1):RTK [Annotation] hjg In one of its method embodiments, this invention provides a method of storing the ansolvtes provided herein, preferably the tosylate and sulfate Forms B and D, comprising storing the ansolvate crystals or a composition or a pharmaceutical composition comprising the ansolvate crystals, in an anhydrous environment, preferably in the presence of en or argon, and more preferably in the ce of a desiccant.

In one of its method embodiments, this invention provides a method of treating a patient to alleviate nociceptive pain in the absence of the treatment of drug ence or drug abuse and in the absence of any concombinant opioid analgesic therapy, comprising: administering systemically to said patient a pharmaceutical composition comprising an effective amount of the lline noribogaine salt, ably an ansolvate salt as provided here, or the compositions, including the pharmaceutically acceptable compositions, provided here, to said patient effective to reduce or eliminate said nociceptive pain in said patient. As used herein, opioids refer to compounds that show its pharmacological effect by binding to opioid receptors, and include natural (such as the opiates) and synthetic compounds well lmown to the skilled artisan. In all of such treatments, the dosing of crystalline noribogaine salt to the treated t is already disclosed in the art. See, for example, US. Patent Nos. 6,348,456, 7,220,737, and 7,754,710, each of these s are incorporated herein by reference in their entirety.

BRIEF DESCRIPTION OF THE DRAWINGS is an overlay of a differential scanning calorimetry (DSC) and a thermogravimetric analysis (TGA) patterns of gaine hydrochloride ansolvate Form A. shows dynamic vapor on (DVS) curves for noribogaine hydrochloride ansolvate Form A. shows X-ray powder diffraction (XRPD) patterns of two samples of gaine hydrochloride ansolvate Form A. shows, in the top panel, an XRPD pattern of the noribogaine hydrochloride Form G obtained when a methanol slurry of noribogaine hydrochloride Form A was kept at room temperature for 7 days, in the middle panei, an XRPD pattern of Form F3 and in the bottom pane}, an XRPD pattern of noribogaine hydrochloride ansoivate Form A. shows XRPD y ofNIH3P04 Form C with minor peak shifting. shows DSC and TGA overlay of 04 Form C. shows DVS curves for 04 Form Ct shows the XRPD n ofNLH3804 Form D l(3038l FIG; 9 shows DSC and TGA overlay ofNngSCL; Form D. 4834—7618-1265.1 [Annotation] hjg shows DVS curves for NIHZSOi; Form D.

FIG. ll shows a DSC pattern of noribogaine hydrochloride Form F. . shows a TGA pattern of gaine hydrochloride Form F.

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 As used herein, the ing terms have the following gs.

The singular forms “a,” “an,” and “the” and the like include plural referents unless the context y es otherwise. Thus, for example, reference to “a compound” includes both a single nd and a plurality of different compounds.

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 £210 %, i5 % or i1%.

“Administration” refers to introducing an agent into a patient. A therapeutic amount can be administered, which can be ined 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 tical 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 t of the drug.

The “crystalline ansolvate” of noribogaine hloride is a lline 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. Howeverg any solvent present is not included in the crystai lattice and is randomly distributed e the crystal lattice. Therefore, ansolvate crystals in bulk may n, 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. 4834461 8~1 265.1 [Annotation] hjg “Comprising” or “comprises” is intended to mean that the compositions and s 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 ts as defined herein would not exclude, respectively, other als or steps that do not materially affect the basic and novel characteristic(s) of the claimed composition or method. “Consisting of” shall mean ing 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. aceutically acceptable” refers to non-toxic material suitable for in vivo and preferably human stration.

“Therapeutically effective ” 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, cg, 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 ent chosen, the dosing regimen to be ed, 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.

“Treatment”, “treating”, and “treat” are defined as acting upon a e, disorder, or condition with an agent to reduce or ameliorate the harmful or any other undesired effects of the e, disorder, or condition andr’or its symptoms and produce beneficial or desired eiinicai results. Treatment, as used herein, covers the treatment of a human patient, and es: (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) ing the condition, 316., causing regression of the condition andfor relieving one or more ms of the condition. For purposes of this 4834-761842651 [Annotation] hjg invention} ial or desired clinical results include, but are not limited to, reducing or eliminating nociceptive pain.

Preparing and characterizing the noribogaineyolymomhs [0052} The noribogaine hydrochloride ansolvate Form A is prepared by reacting gaine free base with hydrochloric acid in a variety of solvents, or by llizing the hydrochloride from a variety of solvents as tabulated in the Examples section below. Upon stow evaporation of ncribogaine hydrochloride from a methanol slurry over 7 days, a Form G crystal different from Form A is ed. See top panel, Form G or F crystals are converted to form A ansolvates upon stirring in EtOH-water, as described herein below.

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 Bravais type Primitive orthorhombic a [A] 8,943 b {A} 13.019 c [A] 14.534 11 [deg] 90 Bldegl 90 r ideal 90 Volume {New} 1,698.1 Chiral ts? Chiral tion Symbol : P 21 21 21 Space Group(s) P 21 21 21 {19) Thermogravimetric data for Form A crystals show negligible weight loss prior to ~3160C at which point a sharp weight loss is observed, indicating probable decomposition (. The DSC thermcgram shows likely simultaneous melting and decomposition above approximately 300°C, consistent with the TGA data. Form A crystals, when characterized by DSCg did not Show cne er mere bread endetherms related t0 deselvaticm as abserveds for Farm F solids {see} FIG it}. The compound exhibited virtually no ccpicity by dynamic vaper serption (DVSL showing weight gainfloss of oniy approximately 0.03% between S and 95% relative humidity (. [0055} The imate ambient-temperature lities of noribogaine hydrochloride Form A were measured in a variety of solvents and t mixtures using the solvent additien method (Table 2). The material exhibited low snlubility in most of the solvents 48341265.1 [Annotation] hjg tested. and was more soluble in a number of cequeons mixtures; HFIPA, MeOH, and TFE. s from the slurry and accelerated ity 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.

Bravais type nic 21111) 9.190 b {A} £0,234 0 {A} i 1.009 0: {deg} 75.45 [3 {deg} 73.16 7' {deg} f 78.38 Volume l} _' 949.9 Chiral Contents? ‘ Chiral Extinction Symbol P ~ Space Group(s) P l (l) For another slightly peak shifted form of Form C, the following indexing was obtained.

Bravais type Triclinic a {A} 9.226 b [A] 10.212 0 {A} 1 1.022 or [deg] 75.48 [3 {deg} 72.65 7 {deg} 78.02 Volume [Nikon] 949.6 Chiral Contents? Chiral tion Symbol P - Space Group(s) P 1 (l) An overlay of the DSC and TGA thermograms for Form C is presented in A broad endotherm at approximately 75°C in the DSC thermogram corresponds with approximately 1.6% weight loss from 30 to 140°C by TGA, indicating volatilization of solvent, likely water. A sharp decline in the TGA thermogram, with an onset marked at 2415C. indicates probable decomposition. No melting was observed by DSC as decomposition of the salt likely oeeure prior to or concurrent with the melting.

The DVS enrvee fer norihogaine phosphate (Form C) are shown in Weight loss of approximately 1 wt% occurred upon equilibration to 5% RH, indicating loss of water that was present in the sample prior to the start of the experiment. Steady weight gain of approximately 3.3 wt% between 5 and 95% RE is observed; all of this weight was lost on 4834*751 8-1 265.1 [Annotation] hjg desorption from 95 to 5% RH. XRPD of the poszVS solids showed that the sample remained Form C after sorption/desorption.

Form D crystals were indexed as shown below.

Bravais type Primitive orthorhombic 3 {Al 81328 1A1 14.122 c {A} 15.455 a {deal 90 [deal 90 7 ides} 90 Volume {Ab’colll 1,883.1 Chiral ts? Chiral Extinction Symbol l) 21 21 21 Space Group(s) P 21 21 21 (19) [0061 ] Form F crystals were indexed as shown below. It is plated 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. s type Primitive orthorhombic a [A] 10.043 b {A} 10.842 C [A] 16.903 a [dog] 90 B ideal 9O if [deal 90 Volume [Al/cell} 1,840.55 Chiral Contents? Chiral tion Symbol P Zl 21 21 Space Grooms) P 21 21 Zl (19) An overlay of the DSC and TGA thermograms for sulfate Form D is presented in Weight loss of 4.9 wt% from approximately 160 to 245°C by TGA corresponds with a small shoulder erm at approximately 1920C overlapping a sharp endotherm at 214°C by DSC, likely corresponding with simultaneous melting and dissociation of the salt (.

The onset of likely decomposition is marked at approximately 274°C in the TGA thermogram. [0063} The DVS curves for the sulfate salt are shown in . Relatively insignificant weight gain {about (is? Witt/é) was ed up to 25% RH? followed by approximately 26 wt% gain between 75 and 95% RH? indicating the material is very hygroscopic above 75% RH. The water gained was not completely lost on desorption from 95 to 5% RH. Alter analysis, the sample was ed to have deliquescedg consistent with the RH stressing experiments conducted previously.

Characterizing the solids 4834-76184 265.1 [Annotation] hjg Selected XRPD patterns were collected with an lnel XRG-3000 diffractometer. An incident beam of Cu Kn radiation was produced using a fine-focus tube and a parabolically graded multilayer mirror. Prior to the analysis, a n standard (NIST SRM 640C) was ed to verify the Si 111 peak position. A en of the sample was packed into a thin-walled glass capillary, and a beam-stop was used to minimize the background from air. ction patterns were collected in transmission geometry using Windif v. 6.6 software and a curved position sensitive Equinox detector with a 20 range of 1200.

Selected XRPD patterns were also collected with a PANalytical X’Pert PRO MPD diffractometer using an nt beam ofCu radiation produced using an Optix long, fine- focus source. An elliptically graded multilayer mirror was used to focus Cu Koc 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 pm 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 ng position-sensitive detector (X’Celerator) located 240 mm from the specimen and Data Collector software V. 22b.

DSC was performed using a TA Instruments Q2000 ential 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 um pan red as the sample pan was placed on the reference side ofthe cell. {0067} Thermogravimetric analyses were performed using a TA Instruments Q5000 lR thermogravimetric analyzer. Temperature calibration was performed using nickel and AlumelTM.

Each sample was placed in an aluminum pan. The sample was hermetically sealed, the lid pierced, then ed into the TO furnace. The furnace was heated under nitrogen. {0068} Dynamic vapor sorption (DVS) data were collected on a VTI SOAanG Vapor Sorption Analyzer. NaCi and PVP were used as calibration standards. Samples were not dried prior to is. on and tion data were collected over a range from 5 to 05% 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 re content of the samples.

Examples 4834461842651 [Annotation] hjg The following abbreviations are used in the es and in this disclosure: ACN acetonitrile EtOH l 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 cone. concentrated endo erm PO. preferred orientation ppt. precipitation/ precipitate RH ve humidity RT room (ambient) temperature TGA Thermogravimetric analysis Example 1. Solubility of Form Ahpolymorph The solubility of noribogaine hydrochloride ansolvate were determined as tabulated below Table 2 WWWESclventSyetem ESelubility (mgmela l acetone <1 e: water 50:50 11 i 4834-7618~1265.1 [Annotation] hjg Solvent System Solubility (mg/mL)a ACN: water 80:20 9 chloroform <l form: EtOH 50:50 <1 ane <l EtOAc <1 EtOH <1 HFIPA l«10 MeOH 2 MeOH: THF 50:50 1 TFE 4 TFE: water 50:50 10 THF <1 water <4 a. Solubilities were calculated based on the total solvent used to give a solution. 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 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 d to a L flange flask fitted with a en 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. panol/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 d to 0»5"C. After 30 minutes the solid was collected by fiitratiori and washed with DCM {2 X 0.49 L) and sucked dry to constant weight under nitrogen purge. The solid was further dried under vacuum at 605C for four days to . 150 g of Noribogaine hydrochloride which was shown to be Form A by XRPD.

Various solid forms of noribogaine obtained from various solvents are tabulated below Table 3 4834461842651 [Annotation] hjg [Annotation] hjg fish/Em? Sfih’éfii’ Ceaéiiiem , Eafiififlesm’égfisa Sigma: sag-aim 391%: : 35’ aka: black saiazim} Sefiimiim 313$ mm. , 13;}; GE @3ng 92%thV_ , , . 2.18%th 34:12:? WE 2311:1313 mspmswn SEW at RT? €333an hmwm‘sh-gmy < k SKSERQSIOE}, 12:23! pameiagV ’ \ 1 :33? 32:43 aggregates: BEEx , éfigsfii‘w fag bage WE aim biaak seiuiieg fléfi ! aéé com. I 933:. farmed: epaqae fiat}: gait? WK EPA - . ‘ bmWfi Saspmgmfi 9%gaging 033mm: ish-gray Stir 3i RT} impemign; war}? 1:221}; yazficiag and aggregages} gaffiai BEE {Eiswive fret bags WE aim: black mimic}: mnfiwtfim afié cam. . . deaf h—biack amé WE 3911111133y_ MESH A gammy 210mg émwa, gufigemisn {Saiiéi prasem}; afier stir at RT: $033:ng - afi-Whiie, £1213; 1 {ia’g pafiicks and aggragamg? 4834—7518—1285“! [Annotation] hjg Table 4 Solvent/ lMébnditions Habit/Description System i TFE stir at ~689C for clear solution ~15 hrs, SC, ~68°C to RT, stir at RT 1 day erator, 1 day clear solution mill, 30 Hz, White, tiny particles and min. f aggregates, partial B/E water VS, ~410C, 7 days dry off-white , 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; gular plates, B/E IPA slurry, ~39°C, 3 days clear liquid phase, off white solids; rectangular L 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; gular plates, B/E VS, , 7 days damp off—white solids; gular 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 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 l: l 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 dryng on the filter. The resulting solids were designated as a mixture of Form C (phosphate) and r Form, B, by XRPD. A portion of the solids 4834-761 8~1 265,1 (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. e 4. Preparation of crystal Form D, the e salt Noribogaine free base (0.7730 g) was dissolved in IPA (25 mL) with sonication, resulting in a clear green on. 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 ions 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 Form F was prepared by precipitation of the HCl salt from a MeOH solution of the free base by adding olic HCl and subsequently purifying by slurrying in MeOH.

Form F was characterized by XRPD as shown in the middle panel of e 6. Conversion of form F to pure form A ansolvate Surprisingly, it was ed 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 r 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 When a methanol slurry of noribogaine hydrochloride was kept at room temperature for 7 days, off white, rectangular aggregates and irregular plates were ed (Form G), which showed XRPD as shown in the top panel of 11420524 WE

Claims (6)

CLAIM :

1. A noribogaine salt ansolvate, which is a crystalline hydrochloride salt having an X-ray powder diffraction pattern comprising peaks at 11.6±0.2° 2θ, 12.1±0.2° 2θ, 13.5±0.2° 2θ, 14.0±0.2° 2θ, 15.0±0.2° 2θ, 15.8±0.2° 2θ, 17.2±0.2° 2θ, 18.0±0.2° 2θ, 18.4±0.2° 2θ, 20.0±0.2° 2θ, 20.9±0.2° 2θ, 21.1±0.2° 2θ, 22.0±0.2° 2θ, 22.8±0.2° 2θ, 23.0±0.2° 2θ, 24.9±0.2° 2θ, 25.9±0.2°2θ, 26.5±0.2° 2θ, 29.5±0.2° 2θ and 31.5±0.2° 2θ; or is a crystalline sulfate salt having an X-ray powder diffraction pattern comprising peaks at 8.5±0.2° 2θ, 11.4±0.2° 2θ, 12.0±0.2° 2θ, 13.3±0.2° 2θ, .2° 2θ, .2° 2θ, 17.2±0.2° 2θ, 18.3±0.2° 2θ, 20.6±0.2° 2θ, 21.0±0.2° 2θ and 21.5±0.2° 2θ; when analyzed using CuKα X-ray ion.

2. The gaine salt ansolvate of claim 1, which is a crystalline hydrochloride salt having an X-ray powder diffraction pattern comprising peaks at 11.6±0.2° 2θ, 12.1±0.2° 2θ, 13.5±0.2° 2θ, 14.0±0.2° 2θ, 15.0±0.2° 2θ, 15.8±0.2° 2θ, 17.2±0.2° 2θ, 18.0±0.2° 2θ, 18.4±0.2° 2θ, 20.0±0.2° 2θ, 20.9±0.2° 2θ, 2θ, 21.1±0.2° 2θ, 22.0±0.2° 2θ, 22.8±0.2° 2θ, 23.0±0.2° 2θ, 24.9±0.2° 2θ, 25.9±0.2° 2θ, 26.5±0.2° 2θ, 29.5±0.2° 2θ and 31.5±0.2° 2θ, when ed using CuKα X-ray radiation.

3. The noribogaine salt ansolvate of claim 1, which is a crystalline sulfate salt having an X- ray powder diffraction pattern comprising peaks at 8.5±0.2° 2θ, 11.4±0.2° 2θ, .2° 2θ, 13.3±0.2° 2θ, 15.4±0.2° 2θ, .2° 2θ, 17.2±0.2° 2θ, .2° 2θ, .2° 2θ, 21.0±0.2° 2θ and 21.5±0.2° 2θ, when analyzed using CuKα X-ray radiation.

4. A composition comprising the noribogaine salt ansolvate of claim 1.

5. Use of a noribogaine salt ansolvate according to any one of claims 1-3 for the manufacture of a ment to alleviate nociceptive pain in the e of the treatment of drug dependence or drug abuse and in the absence of any itant opioid analgesic therapy.

6. A noribogaine ansolvate according to any one of claims 1-3, substantially as hereinbefore described with reference to any one of