Example of patent protection information for A2-73.
Here is Jimmy's excellent post from 8/16/17.
jimmy667 Wednesday, 08/16/17 12:07:02 PM
Re: Amatuer17 post# 115707 0
Post #
115752
of 157953
A2-73 IP is 100% locked down until the 2030s.
Again for those that would ignore facts:
Anavex has a complete portfolio of patent and patents pending 100% protecting A2-73 from generics until the 2030s here is just one example:
ABSTRACT
Polymorphic forms of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride (ANAVEX2-73) and a metabolite of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73) are disclosed and characterized. Compositions and method for treatment of Alzheimer's disease that includes the polymorphic forms and metabolite of tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73).
CLAIMS (OCR text may contain errors)
CLAIMS What is claimed is:
1. A crystalline form of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride characterized by the PXRD pattern shown in FIG. 1, FIG. 4, or FIG. 8.
2. The crystalline form of claim 1, further characterized by the FTIR spectrum shown in FIG. 5 or FIG. 9.
3. The crystalline form of claim 1, further characterized by the ^-NMR spectrum shown in FIG. 6 or FIG. 10.
4. The crystalline form of claim 1, further characterized by the particle shapes depicted in FIG. 2, FIG. 3, FIG. 7 or FIG. 11.
5. The crystalline form of claim 1, further characterized by the particle sizes depicted in FIG. 2, FIG. 3, FIG. 7 or FIG. 11.
6. The crystalline form of claim 1, wherein the habit is plate-like.
7. The crystalline form of claim 1, wherein the habit is needle-like.
The crystalline form of claim 1, wherein the habit is lath
9. A method of making the crystalline form of claim 1, wherein the method uses a supercritical fluid (SCF) technique.
10. A dosage form comprising a therapeutically neuroprotective amount of the crystalline form of claim 1.
11. A pharmaceutical composition for the treatment of Alzheimer's disease comprising a therapeutically effective amount of the crystalline form of any of claims 1-8.
12. A method of treating Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of the crystalline form of any of claims 1-8.
13. Crystalline Form I of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride characterized by the PXRD pattern shown in FIG. 1.
14. The crystalline Form I according to claim 13, characterized by the particle shapes as depicted in FIG. 2.
15. The crystalline Form I according to claim 13, characterized by the particle shapes as depicted in FIG. 3.
16. The crystalline Form I according to claim 13, characterized by the particle sizes as depicted in FIG. 2.
17. The crystalline Form I according to claim 13, characterized by the particle sizes as depicted in FIG. 3.
18. The crystalline form of claim 13, wherein the habit is plate-like.
19. A method of making the crystalline form of any of claims 13-18, wherein the method uses a supercritical fluid (SCF) technique.
20. A dosage form comprising a therapeutically neuroprotective amount of the crystalline form of any of claims 13-18.
21. A pharmaceutical composition for the treatment of Alzheimer's disease comprising a therapeutically effective amount of the crystalline form of any of claims 13-18.
22. A method of treating Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of the crystalline form of any of claims 13-18.
23. Crystalline Form II of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride characterized by the PXRD pattern shown in FIG. 4.
24. Crystalline Form II of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride characterized by the FTIR spectrum shown in FIG. 5.
25. Crystalline Form II of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride characterized by the ^-NMR spectrum shown in FIG. 6.
26. The crystalline Form II according to any of claims 23-25, characterized by particle shapes as depicted in FIG. 7.
27. The crystalline Form II according to any of claims 23-25, characterized by particle sizes as depicted in FIG. 7.
28. The crystalline Form II of any of claims 23-25, wherein the habit is plate-like.
29. A method of making the crystalline Form II of any of claims 23-28, wherein the method uses a supercritical fluid (SCF) technique.
30. A dosage form comprising a therapeutically neuroprotective amount of the crystalline Form II of any of claims 23-28.
31. A pharmaceutical composition for the treatment of Alzheimer's disease comprising a therapeutically effective amount of the crystalline Form II of any of claims 23-28.
32. A method of treating Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of the crystalline Form II of any of claims 23-28.
33. Crystalline Form III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride characterized by the PXRD pattern shown in FIG. 8.
34. Crystalline Form III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride characterized by the FTIR spectrum shown in FIG. 9.
35. Crystalline Form III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride characterized by the ^-NMR spectrum shown in FIG. 10.
36. The crystalline Form III according to any of claims 33-35, characterized by particle shapes as depicted in FIG. 11.
37. The crystalline Form III according to any of claims 33-35, characterized by particle sizes as depicted in FIG. 11.
38. The crystalline Form III of any of claims 33-35, wherein the habit is lath-like.
39. A method of making the crystalline Form III of any of claims 33-38, wherein the method uses a supercritical fluid (SCF) technique.
40. A dosage form comprising a therapeutically neuroprotective amount of the crystalline Form III of any of claims 33-38.
41. A pharmaceutical composition for the treatment of Alzheimer's disease comprising a therapeutically effective amount of the crystalline Form III of any of claims 33-38.
42. A method of treating Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of the crystalline Form III of any of claims 33-38.
43. The metabolite ANAVEX19-144 characterized by the PXRD pattern shown in FIG. 12.
44. The metabolite ANAVEX19-144 characterized by the DSC-TGA data shown in FIG. 13.
45. The metabolite ANAVEX19-144 characterized by the FTIR spectrum shown in FIG. 14.
46. The metabolite ANAVEX19-144 of any of claims 43-45 characterized by particle shapes as depicted in FIG. 15.
47. The metabolite ANAVEX19-144 of any of claims 43-45 characterized by particle sizes as depicted in FIG. 15.
48. The metabolite ANAVEX19-144 of any of claims 43-45, wherein the habit is needle-like.
49. A method of making the metabolite ANAVEX19-144 of any of claims 43-48, wherein the method uses a supercritical fluid (SCF) technique.
50. A dosage form comprising a therapeutically neuroprotective amount of the metabolite ANAVEX19-144 of any of claims 43-48.
51. A pharmaceutical composition for the treatment of Alzheimer's disease comprising a therapeutically effective amount of the metabolite ANAVEX19-144 of any of claims 43-48.
52. A method of treating Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of the metabolite ANAVEX19-144 of any of claims 43-48.
53. The metabolite ANAVEX19-144 characterized by the PXRD pattern shown in FIG. 17.
54. The metabolite ANAVEX19-144 characterized by the DSC-TGA data shown in FIG. 18.
55. The metabolite ANAVEX19-144 of any of claims 53-54 characterized by particle shapes as depicted in FIG. 16.
56. The metabolite ANAVEX19-144 of any of claims 53-54 characterized by particle sizes as depicted in FIG. 16.
57. A method of making the metabolite ANAVEX19-144 of any of claims 53-56, wherein the method uses a supercritical fluid (SCF) technique.
58. A dosage form comprising a therapeutically neuroprotective amount of the metabolite ANAVEX19-144 of any of claims 53-56.
59. A pharmaceutical composition for the treatment of Alzheimer's disease comprising a therapeutically effective amount of the metabolite ANAVEX19-144 of any of claims 53-56.
60. A method of treating Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of the metabolite ANAVEX19-144 of any of claims 53-56.
DESCRIPTION (OCR text may contain errors)
CRYSTAL FORMS OF TETRAHYDRO-N,N-DIMETHYL-2,2-DIPHENYL-3- FURANM ETHAN AMINE HYDROCHLORIDE, PROCESSES OF MAKING SUCH
FORMS, AND THEIR PHARMACEUTICAL COMPOSITIONS
FIELD
[0001] The present disclosure is directed to crystalline forms of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine
hydrochloride, as well as compositions, processes of preparation, and uses thereof.
BACKGROUND
[0002] Because improved drug formulations showing, for example, better bioavailability or better stability are consistently sought, there is an ongoing need for more fully characterized, new, polymorphic and derivative forms of drug molecules. Characterization of tetra hydro -N,N - dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride, and crystalline polymorphs and a metabolite of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride are described herein toward this end.
SUMMARY OF THE PRESENT DISCLOSURE
[0003] The present disclosure comprises crystalline forms of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride characterized by the PXRD pattern shown in FIG. 1, FIG. 4, or FIG. 8. The crystalline forms are further characterized by the FTIR spectrum shown in FIG. 5 or FIG. 9. The crystalline forms are further characterized by the H-NMR spectrum shown in FIG. 6 or FIG. 10. The crystalline forms are further characterized by the particle shapes depicted in FIG. 2, FIG. 3, FIG. 7 or FIG. 11. The crystalline forms are further characterized by the particle sizes depicted in FIG. 2, FIG. 3, FIG. 7 or FIG. 11. The crystalline forms can have a plate-like habit. The crystalline forms can also have a needle-like habit. The crystalline forms can have a lath-like habit. Further included, is a method of making the crystalline forms using a supercritical fluid (SCF) technique. Further included is a dosage form comprising a therapeutically neuroprotective amount of the crystalline forms. Further included is a pharmaceutical composition for the treatment of Alzheimer's disease comprising a therapeutically effective amount of the crystalline forms. Further included is a method of treating Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of the crystalline forms.
[0004] The present disclosure also comprises crystalline Form I of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride characterized by the PXRD pattern shown in FIG. 1. The crystalline Form I according is also characterized by the particle shapes as depicted in FIG. 2. The crystalline Form I is also characterized by the particle shapes as depicted in FIG. 3. The crystalline Form I is also characterized by the particle sizes as depicted in FIG. 2. The crystalline Form I is also characterized by the particle sizes as depicted in FIG. 3. Crystalline Form I is also characterized by a plate-like habit. Further included is a method of making crystalline Form I using a supercritical fluid (SCF) technique. Further included is a dosage form comprising a therapeutically neuroprotective amount of crystalline Form I. Further included is a pharmaceutical composition for the treatment of Alzheimer's disease comprising a therapeutically effective amount of crystalline Form I. Further included is a method of treating Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of the crystalline Form I.
[0005] The present disclosure also comprises crystalline Form II of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride characterized by the PXRD pattern shown in FIG. 4. Crystalline Form II is also characterized by the FTIR spectrum shown in FIG. 5. Crystalline Form II is also characterized by the ^-NMR spectrum shown in FIG. 6. Crystalline Form II is also characterized by particle shapes as depicted in FIG. 7. Crystalline Form II is also characterized by particle sizes as depicted in FIG. 7. Crystalline Form II can also have a plate-like habit. Further included is a method of making crystalline Form II using a supercritical fluid (SCF) technique. Further included is a dosage form comprising a therapeutically neuroprotective amount of crystalline Form
II. Further included is a pharmaceutical composition for the treatment of Alzheimer's disease comprising a therapeutically effective amount of crystalline Form II. Further included is a method of treating Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of crystalline Form II.
[0006] The present disclosure also comprises crystalline Form III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride characterized by the PXRD pattern shown in FIG. 8. Crystalline Form III is also characterized by the FTIR spectrum shown in FIG. 9. Crystalline Form III is also characterized by the ^-NMR spectrum shown in FIG. 10. Crystalline Form III is also characterized by particle shapes as depicted in FIG. 11. Crystalline Form III is also characterized by particle sizes as depicted in FIG. 11. Crystalline Form III can also have a lath-like habit. Further included is a method of making crystalline Form III using a supercritical fluid (SCF) technique. Further included is a dosage form comprising a therapeutically neuroprotective amount of crystalline Form
III. Further included is a pharmaceutical composition for the treatment of Alzheimer's disease comprising a therapeutically effective amount of crystalline Form III. Further included is a method of treating Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of crystalline Form III.
[0007] The present disclosure also comprises metabolite ANAVEX19- 144 characterized by the PXRD pattern shown in FIG. 12. Metabolite ANAVEX19-144 is also characterized by the DSC-TGA data shown in FIG. 13. Metabolite ANAVEX19-144 is also characterized by the FTIR spectrum shown in FIG. 14. Metabolite ANAVEX19-144 can also be characterized by particle shapes as depicted in FIG. 15. Metabolite ANAVEX19-144 can also be characterized by particle sizes as depicted in FIG. 15. Metabolite ANAVEX19-144 can also have a needle-like habit. Further included is a method of making the metabolite ANAVEX19-144 using a supercritical fluid (SCF) technique. Further included is a dosage form comprising a therapeutically neuroprotective amount of the metabolite ANAVEX19-144. Further included is a pharmaceutical composition for the treatment of Alzheimer's disease comprising a therapeutically effective amount of the metabolite ANAVEX19-144. Further included is a method of treating Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of the metabolite ANAVEX19-144.
[0008] The present disclosure also comprises metabolite ANAVEX19- 144 characterized by the PXRD pattern shown in FIG. 17. Metabolite ANAVEX19-144 is also characterized by the DSC-TGA data shown in FIG. 18. Metabolite ANAVEX19-144 can also be characterized by particle shapes as depicted in FIG. 16. Metabolite ANAVEX19-144 can also be characterized by particle sizes as depicted in FIG. 16. Further included is a method of making the metabolite ANAVEX19-144 using a supercritical fluid (SCF) technique. Further included is a dosage form comprising a therapeutically neuroprotective amount of metabolite ANAVEX19-144. Further included is a pharmaceutical composition for the treatment of Alzheimer's disease comprising a therapeutically effective amount of metabolite ANAVEX19-144. Further included is a method of treating Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of metabolite ANAVEX19-144.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] In order to describe the manner in which the advantages and features of the disclosure can be obtained, reference is made to embodiments thereof which are illustrated in the appended drawings. Understanding that these drawings depict only exemplary embodiments of the disclosure and are not therefore to be considered to be limiting of its scope, the principles herein are described and explained with additional specificity and detail through the use of the accompanying drawings in which :
[0010] FIG. 1 depicts a powder X-ray diffraction (PXRD) pattern characteristic of polymorph Form I of tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73);
[0011] FIG. 2 depicts scanning electron microscope (SEM) micrographs demonstrating the size and morphology of particles of polymorph Form 1 of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride (ANAVEX2-73) produced using acetonitrile as the solvent in the supercritical fluid process;
[0012] FIG. 3 depicts SEM micrographs demonstrating the size and morphology of particles of polymorph Form 1 of tetrahydro-N,N-dimethyl-
2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73) produced using ethanol as the solvent in the supercritical fluid process;
[0013] FIG. 4 depicts a PXRD pattern characteristic of polymorph
Form II of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73); [0014] FIG. 5 depicts a fourier transform infrared (FTIR) spectrum characteristic of polymorph Form II of tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73);
[0015] FIG. 6 depicts a proton nuclear magnetic resonance ^H-NMR) spectrum characteristic of polymorph Form II of tetrahydro-N,N-dimethyl-
2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73);
[0016] FIG. 7 depicts SEM micrographs demonstrating the size and morphology of particles of polymorph Form II of tetra hydro -N,N - dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-
73);
[0017] FIG. 8 depicts a PXRD pattern characteristic of polymorph Form III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73);
[0018] FIG. 9 depicts an FTIR spectrum characteristic of polymorph Form III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73);
[0019] FIG. 10 depicts a ^-NMR spectrum characteristic of polymorph Form III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73);
[0020] FIG. 11 depicts SEM micrographs demonstrating the size and morphology of particles of polymorph Form III of tetra hydro- N,N - dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2- 73);
[0021] FIG. 12 depicts a PXRD pattern characteristic of metabolite ANAVEX19-144 produced using ethanol as the solvent in the supercritical fluid process;
[0022] FIG. 13 depicts DSC-TGA data characteristic of metabolite ANAVEX19-144 produced using ethanol as the solvent in the supercritical fluid process; [0023] FIG. 14 depicts a FTIR spectrum characteristic of metabolite ANAVEX19-144 produced using ethanol as the solvent in the supercritical fluid process;
[0024] FIG. 15 depicts SEM micrographs demonstrating the size and morphology of particles of metabolite ANAVEX19-144 produced using ethanol as the solvent in the supercritical fluid process;
[0025] FIG. 16 depicts SEM micrographs demonstrating the size and morphology of particles of metabolite ANAVEX19-144 produced using dichloromethane as the solvent in the supercritical fluid process;
[0026] FIG. 17 depicts a PXRD pattern characteristic of metabolite ANAVEX19-144 produced using dichloromethane as the solvent in the supercritical fluid process; and
[0027] FIG. 18 depicts DSC-TGA data characteristic of metabolite ANAVEX19-144 produced using dichloromethane as the solvent in the supercritical fluid process.
DETAILED DESCRIPTION
[0028] Various embodiments of the disclosure are discussed in detail below. While specific implementations are discussed, it should be understood that this is done for illustration purposes only. A person skilled in the relevant art will recognize that other components and configurations may be used without parting from the spirit and scope of the disclosure.
[0029] It should be understood at the outset that although illustrative implementations of one or more embodiments are illustrated below, the disclosed method may be implemented using any number of techniques. The disclosure should in no way be limited to the illustrative implementations, drawings, and techniques illustrated herein, but may be modified within the scope of the appended claims along with their full scope of equivalents.
[0030] In the following discussion and in the claims, the terms "including" and "comprising" are used in an open-ended fashion, and thus should be interpreted to mean "including, but not limited to The various characteristics described in more detail below, will be readily apparent to those skilled in the art with the aid of this disclosure upon reading the following detailed description, and by referring to the accompanying drawings.
[0031] The present disclosure relates to tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride, also referred to as ANAVEX2-73 :
Figure imgf000009_0001
[0032] It has been reported that ANAVEX2-73 shows neuroprotective potential against amyloid toxicity in mice. In particular, ANAVEX2-73 has been reported as attenuating oxidative stress, caspases induction, cellular loss and learning and memory deficits observed in mice one week after the i.c.v. injection of an oligomeric preparation of amyloid 625-35 peptide (?ß25-35) . See J. Psvchopharmacol. 25(8), 1101-1117 (2011). More recently, it has been reported that ANAVEX2-73 blocked the ?ß25-35- induced P-Akt decrease and P-GSK-3 increase, indicating activation at the PI3K neuroprotective pathway. See Neuropsvchopharmacoloav 38, 1706-1723 (2013). In the dose-range tested, ANAVEX2-73 attenuated the hyperphosphorylation of Tau on physiological epitopes (AT-8 antibody clone) and on pathological epitopes (AT-100 clone). ANAVEX2-73 also has been reported to decrease the A 25-35-induced endogenous ?ß?-42 seeding.
[0033] Reference is made to U.S. Patent Publication No. 2014/0296211 entitled "ANAVEX2-73 AND CERTAIN
ANTICHOLINESTERASE INHIBITORS COMPOSITION AND METHOD FOR NEUROPROTECTION," to Vamvakides et al., filed July 12, 2013; USSN 62/065,833 entitled "A19-144, A2-73 AND CERTAIN ANTICHOLINESTERASE INHIBITOR COMPOSITIONS AND METHOD FOR ANTI-SEIZURE THERAPY," filed October 20, 2014; U.S. Patent application entitled "ANAVEX2-73 FOR THE TREATMENT OF ALZHEIMER'S DISEASE" and filed on date even herewith; U.S. Patent application entitled "ENANTIOMERS OF A2-73, ANALOGUES, AND SIGMA AGONIST ACTIVITY" and filed on date even herewith. The teaching of these applications and publications and all references cited herein are incorporated by reference in their entirety.
[0034] The present disclosure, provides a crystalline polymorph (Form I) of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride , characterized by PXRD and other data provided herein.
[0035] The present disclosure provides another crystalline polymorph (Form II) of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride characterized by the PXRD and other data provided herein.
[0036] The present disclosure further provides another crystalline polymorph (Form III) of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride characterized by the PXRD and other data provided herein.
[0037] The present disclosure also provides a metabolite of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine
hydrochloride, referred to as ANAVEX19-144, characterized by the PXRD and other data provided herein and having the structure:
Figure imgf000011_0001
[0038] The present disclosure further provides use of the polymorphs and metabolite material in the treatment of Alzheimer's disease.
[0039] Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73) was characterized by powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), fourier transform infrared (FTIR) spectroscopy, proton nuclear magnetic resonance ^H-NMR) and scanning electron microscopy (SEM), as detailed in FIGS. 1-15.
[0040] The present disclosure further provides processes of preparing the polymorphic forms of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride (ANAVEX2-73). In one embodiment, the polymorphic forms, disclosed herein, can be prepared by a supercritical fluid (SCF) anti-solvent process. In an embodiment, the anti-solvent is a supercritical fluid, although in some embodiments near- critical fluids may also be suitable. A "supercritical fluid" is a fluid at or above its critical pressure (Pc) and critical temperature (Tc) simultaneously. In practice, the pressure of the fluid is likely to be in the range between 1.01 and 7.0 of its critical pressure, and its temperature in the range between 1.01 and 4.0 of its critical temperature (in Kelvin). However, some fluids (e.g., helium and neon) have particularly low critical pressures and temperatures, 10 and may need to be used under operating conditions well in excess of those critical values, such as up to 200 times the relevant critical value. The term "near-critical fluid" encompasses both high pressure liquids, which are fluids at or above their critical pressure but below (although preferably close to) their critical temperature, and dense vapors, which are fluids at or above their critical 15 temperature but below (although preferably close to) their critical pressure. By way of example, a high pressure liquid might have a pressure between about 1.01 and 7 times its Pc, and a temperature between about 0.5 and 0.99 times its Tc. A dense vapor might, correspondingly, have a pressure between about 0.5 and 0.99 times its Pc, and a temperature between about 1.01 and 4 times its Tc.
[0041] Suitably, the anti-solvent and solution may be introduced into a precipitation chamber via respective passages with respective outlets, the outlets being arranged relative to one another such that anti-solvent introduced through a first passage and solution introduced through a second passage both enter the precipitation chamber at substantially the same point, which is substantially the point at which the anti-solvent and solution meet. To provide for good levels of mixing and dispersion, the anti-solvent and the solution may, for example, be co-fed into a precipitation chamber via a nozzle having co-axial passages which terminate adjacent to one another. Alternatively, one or more streams of the antisolvent may be arranged to impinge on a stream of the solution to provide good levels of mixing and dispersion. However, other mixing architectures are also possible. Examples of suitable apparatus are known, inter alia, from WO-30 95/01221, WO-96/00610, WO-98/36825, WO-99/44733, WO-99/59710, WO-01/03821, and WO-03/008082, which are incorporated herein by reference.
[0042] According to the present disclosure, new crystalline forms of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73) were prepared by a supercritical fluid (SCF) process. The basic process involved preparing a solution of tetrahydro-N,N-dimethyl- 2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73) in a suitable solvent, such as acetonitrile or ethanol, and introducing the solution to an SCF environment, typically supercritical CO2, in a pressure vessel. The supercritical CO2 acted as a powerful antisolvent allowing particles to be rapidly precipitated. Different polymorphic forms of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73) were produced by manipulating SCF process parameters, including the solvent used, flow rate, pressure, and temperature. Additionally, manipulation of SCF process parameters determined the size, morphology, and habit of crystalline particles produced by the SCF process.
[0043] The SCF process parameters used to produce the three polymorphic forms of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride (ANAVEX2-73), Forms I-III, are provided in Tables 1-3. As shown in Table 1, crystalline Form I was produced by placing the ANAVEX2-73 starting material in a solvent of acetonitrile or ethanol and processed by the supercritical fluid technique. The resulting particle shape differed depending upon the solvent. The particle shape for the crystalline Form I produced using acetonitrile solvent was plate-like. As used herein, the term "plate-like" refers to a flat particle of similar length and width. The particle shape for the crystalline Form I produced using ethanol solvent was a conglomerate. As used herein, the term "conglomerate" refers to a mixture of two or more types of particle shapes. The resulting material was characterized by PXRD and SEM. The PXRD for crystalline Form I of ANAVEX2-73 is shown in FIG. 1. SEM micrographs showing the particle size and morphology of crystalline Form I are shown in FIGs. 2-3. FIG. 2 shows the particle size and morphology of crystalline Form I produced using acetonitrile solvent (plate-like morphology). FIG. 3 shows the particle size and morphology of crystalline Form I produced using ethanol as the solvent (conglomerate morphology).
[0044] As shown in Table 2, crystalline Form II was produced by placing the ANAVEX2-73 starting material in a solvent of acetonitrile, 1 : 9 v/v trifluoroethanol + ethanol, 1 : 1 v/v acetone + ethanol, or 3-methyl-l- butanol, and processed by the supercritical fluid technique. In all cases, crystalline Form II was characterized by a plate-like habit. The resulting material was characterized by PXRD and SEM . The PXRD for crystalline Form II of ANAVEX2-73 is shown in FIG. 4. Crystalline Form II is further characterized by the FTIR spectrum shown in FIG. 5 and the ^-NMR shown in FIG. 6. SEM micrographs showing the particle size and morphology of crystalline Form II are shown in FIG. 7.
[0045] As shown in Table 3, crystalline Form III was produced by placing the ANAVEX2-73 starting material in a solvent of ethanol or 1 : 9 v/v trifluoroethanol + ethanol and processed by the supercritical fluid technique. In all cases, crystalline Form III was characterized by a lathlike habit. As used herein, "lath-like" refers to a long, thin blade-like particle. The resulting material was characterized by PXRD and SEM . The PXRD for crystalline Form III of ANAVEX2-73 is shown in FIG. 8. Crystalline Form III is further characterized by the FTIR spectrum shown in FIG. 9 and the ^-NMR shown in FIG. 10. SEM micrographs showing the particle size and morphology of crystalline Form III are shown in FIG. 11.
