Crystalline forms of tetrahydro-n, n-dimethyl-2, 2-diphenyl-3-furanmethylamine hydrochloride, methods of preparing such crystalline forms, and pharmaceutical compositions thereof

Abstract

The invention discloses a polymorphic form of tetrahydro-N, N-dimethyl-2, 2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX2-73) and a metabolite of the tetrahydro-N, N-dimethyl-2, 2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX2-73), and relates to the technical field of chemical engineering, and discloses and characterizes the polymorphic form of the tetrahydro-N, N-dimethyl-2, 2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX2-73). Comprising polymorphic forms and metabolites of tetrahydro-N, N-dimethyl-2, 2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX2-73), and methods of use in the treatment of Alzheimer's disease.

Description

[0001] The present application is a divisional application of a Chinese patent application filed on July 19, 2016, with application number 201680033152.9 and invention name “Crystalline forms of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride, methods for preparing such crystal forms, and pharmaceutical compositions thereof”. Technical Field

[0002] The present invention relates to a crystalline form of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride, as well as a composition, a preparation method and a use thereof. Background Art

[0003] As there is a continuous search for improved pharmaceutical formulations that exhibit, for example, better bioavailability or better stability, there is a continuous need for more fully characterized, new polymorphs and derived forms of drug molecules. In the present invention, the characterization of polymorphs and metabolites of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride and tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride is described for this purpose. SUMMARY OF THE INVENTION

[0005] The present disclosure includes a crystalline form of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride, characterized in that Figure 1 , Figure 4 ,or Figure 8 The PXRD spectrum shown in . The crystal form is also characterized by Figure 5 or Fig. 9 The FTIR spectrum shown in . The crystal form is also characterized by Figure 6 or Fig.10 As shown in 1 H-NMR spectrum. The crystal form is also characterized by Figure 2 , Figure 3 , Figure 7 ,or Fig.11 The particle shape shown. The crystal form is also characterized by Figure 2 , Figure 3 , Figure 7 ,or Fig.11 The particle size shown. The crystalline form may have a plate-like habit. The crystalline form may also have a needle-like habit. The crystalline form may have a lath-like habit. Also included is a method for preparing the crystalline form using supercritical fluid (SCF) technology. Also included is a dosage form comprising a therapeutic neuroprotective amount of the crystalline form. Also included is a pharmaceutical composition for treating Alzheimer's disease, comprising a therapeutically effective amount of the crystalline form. Also included is a method for treating Alzheimer's disease in a subject, comprising administering a therapeutically effective amount of the crystalline form to the subject.

[0006] The present disclosure also includes a crystalline form I of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride, characterized in that Figure 1 The PXRD spectrum shown in . According to this, the crystal form I is also characterized by Figure 2 The particle shape shown in FIG. Form I is also characterized by Figure 3 The particle shape shown in FIG. Form I is also characterized by Figure 2 The particle size shown in . Form I is also characterized by Figure 3 The invention also includes a particle size as shown in . Form I is also characterized by a plate-like crystal habit. Also included is a method of preparing Form I using supercritical fluid (SCF) technology. Also included is a dosage form comprising a therapeutic neuroprotective amount of Form I. Also included is a pharmaceutical composition for treating Alzheimer's disease comprising a therapeutically effective amount of Form I. Also included is a method of treating Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of Form I.

[0007] The present disclosure also includes a crystalline form II of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride, characterized in that Figure 4 The PXRD spectrum shown in . Form II is also characterized by Figure 5 The FTIR spectrum shown in . Form II is also characterized by Figure 6 As shown in 1 H-NMR spectrum. Form II is also characterized by Figure 7 The particle shape shown in FIG. Form II is also characterized by Figure 7 The particle size shown in . Form II may also have a plate-like habit. Also included is a method for preparing Form II using supercritical fluid (SCF) technology. Also included is a dosage form, which contains a therapeutic neuroprotective amount of Form II. Also included is a pharmaceutical composition for treating Alzheimer's disease, which contains a therapeutically effective amount of Form II. Also included is a method for treating Alzheimer's disease in a subject, which comprises administering a therapeutically effective amount of Form II to the subject.

[0008] The present disclosure also includes a crystalline form III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride, characterized in that Figure 8 The PXRD spectrum shown in . Form III is also characterized by Fig. 9 The FTIR spectrum shown in . Form III is also characterized by Fig.10 As shown in 1 H-NMR spectrum. Form III is also characterized by Fig.11 The particle shape shown in FIG. Form III is also characterized by Fig.11The particle size shown in . Crystal III may also have a lath-like crystal habit. Also included is a method for preparing Crystal III using supercritical fluid (SCF) technology. Also included is a dosage form, which contains a therapeutic neuroprotective amount of Crystal III. Also included is a pharmaceutical composition for treating Alzheimer's disease, which contains a therapeutically effective amount of Crystal III. Also included is a method for treating Alzheimer's disease in a subject, which comprises administering a therapeutically effective amount of Crystal III to the subject.

[0009] The present disclosure also includes metabolite ANAVEX19-144, characterized in that Fig.12 The PXRD spectrum shown in . Metabolite ANAVEX19-144 is also characterized by Fig.13 The DSC-TGA data are shown in . The metabolite ANAVEX19-144 is also characterized in Fig.14 The FTIR spectrum shown in . Metabolite ANAVEX19-144 is also characterized by Fig.15 The metabolite ANAVEX19-144 is also characterized by Fig.15 The particle size shown. The metabolite ANAVEX19-144 may also have a needle-shaped crystal habit. Also included is a method for preparing the metabolite ANAVEX19-144 using supercritical fluid (SCF) technology. Also included is a dosage form, which contains a therapeutic neuroprotective amount of the metabolite ANAVEX19-144. Also included is a pharmaceutical composition for treating Alzheimer's disease, which contains a therapeutically effective amount of the metabolite ANAVEX19-144. Also included is a method of treating Alzheimer's disease in a subject, comprising administering a therapeutically effective amount of the metabolite ANAVEX19-144 to the subject.

[0010] The present disclosure also includes metabolite ANAVEX19-144, characterized in that Fig.17 The PXRD spectrum shown in . Metabolite ANAVEX19-144 is also characterized by Fig.18 The DSC-TGA data are shown in . Metabolite ANAVEX19-144 is also characterized by Fig.16 The metabolite ANAVEX19-144 is also characterized by Fig.16 The invention also includes a method for preparing the metabolite ANAVEX19-144 using supercritical fluid (SCF) technology. Also included is a dosage form comprising a therapeutic neuroprotective amount of the metabolite ANAVEX19-144. Also included is a pharmaceutical composition for treating Alzheimer's disease, comprising a therapeutically effective amount of the metabolite ANAVEX19-144. Also included is a method for treating Alzheimer's disease in a subject, comprising administering a therapeutically effective amount of the metabolite ANAVEX19-144 to the subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] In order to describe the manner in which the advantages and features of the present disclosure can be obtained, reference is made to the embodiments thereof shown in the accompanying drawings. Understanding that these drawings depict only exemplary embodiments of the present disclosure and are not therefore to be considered 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:

[0013] Figure 1 The powder X-ray diffraction (PXRD) spectrum characteristics of the polymorph I of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX2-73) are described;

[0014] Figure 2 Described are scanning electron microscope (SEM) micrographs showing particle size and morphology of polymorph I of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX 2-73) produced in a supercritical fluid process using acetonitrile as solvent;

[0015] Figure 3 Described are SEM micrographs showing particle size and morphology of polymorph I of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX 2-73) produced in a supercritical fluid process using ethanol as solvent;

[0016] Figure 4 The PXRD spectrum characteristics of polymorph II of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX2-73) are described;

[0017] Figure 5 The Fourier transform infrared (FTIR) spectral characteristics of the polymorph II of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX2-73) are described;

[0018] Figure 6 The proton NMR ( 1 H-NMR) spectral characteristics;

[0019] Figure 7 Described are SEM micrographs showing particle size and morphology of Form II polymorph of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX 2-73);

[0020] Figure 8The PXRD pattern characteristics of polymorph III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX2-73) are described;

[0021] Fig. 9 The FTIR spectral characteristics of the polymorph III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX2-73) are described;

[0022] Fig.10 The polymorph III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX 2-73) is described 1 H-NMR spectrum characteristics.

[0023] Fig.11 Described are SEM micrographs showing particle size and morphology of polymorph III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX 2-73);

[0024] Fig.12 The PXRD pattern characteristics of the metabolite ANAVEX19-144 produced in a supercritical fluid method using ethanol as solvent are described;

[0025] Fig.13 The DSC-TGA data characterization of the metabolite ANAVEX19-144 produced in a supercritical fluid process using ethanol as solvent is described;

[0026] Fig.14 The FTIR spectral characteristics of the metabolite ANAVEX19-144 produced in a supercritical fluid method using ethanol as solvent are described;

[0027] Fig.15 describes SEM micrographs showing particle size and morphology of metabolite ANAVEX 19-144 produced in a supercritical fluid process using ethanol as solvent;

[0028] Fig.16 describes SEM micrographs showing particle size and morphology of metabolite ANAVEX 19-144 produced in a supercritical fluid process using dichloromethane as solvent;

[0029] Fig.17 describes the PXRD spectral characteristics of the metabolite ANAVEX 19-144 produced in a supercritical fluid process using dichloromethane as a solvent; and

[0030] Fig.18DSC-TGA data characterization of the metabolite ANAVEX 19-144 produced in a supercritical fluid process using dichloromethane as solvent is described. DETAILED DESCRIPTION OF THE INVENTION

[0032] The various embodiments of the present disclosure are discussed in detail below. Although specific implementations are discussed, it should be understood that this is done only for illustrative purposes. Those skilled in the relevant art will recognize that other components and configurations can be used without departing from the spirit and scope of the present disclosure.

[0033] First, it should be understood that although the following shows an illustrative implementation of one or more embodiments, the disclosed method can be implemented using any number of techniques. The present disclosure should not be limited to the illustrative embodiments, drawings, and techniques shown herein, but can be modified within the scope of the appended claims and the full scope of their equivalents.

[0034] In the following discussion and 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 features described in more detail below will become apparent to those skilled in the art in light of this disclosure by reading the following detailed description and referring to the accompanying drawings.

[0035] The present disclosure relates to tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride, also known as ANAVEX 2-73:

[0036]

[0037] ANAVEX2-73 has been reported to show neuroprotective potential against amyloid toxicity in mice. In particular, ANAVEX2-73 has been reported to mitigate the effects of intracerebroventricular (icv) injection of amyloid β 25-35 Peptide (Aβ 25-35 ) was used for one week to treat mice with oligomeric preparations of ANAVEX2-73, which inhibited Aβ. 25-35 The induced P-Akt decreased and P-GSK-3β increased, indicating activation of the PI3K neuroprotective pathway. See Neuropsychopharmacology 38, 1706-1723 (2013). Within the dose range tested, ANAVEX2-73 reduced Tau hyperphosphorylation on physiological epitopes (AT-8 antibody clone) and pathological epitopes (AT-100 clone). ANAVEX2-73 has also been reported to reduce Aβ 25-35 Induced endogenous Aβ 1-42Seeding.

[0038] Reference is made to U.S. Patent Publication No. 2014 / 0296211, filed on July 12, 2013, by Vamvakides et al., entitled “ANAVEX2-73AND CERAINANTICHOLINESTERASE INHIBITORS COMPOSITION AND METHOD FOR NEUROPROTECTION”; USSN 62 / 065,833, filed on October 20, 2014, entitled “A19-144, A2-73 AND CERTAINANTICHOLINESTERASE INHIBITOR COMPOSITIONS AND METHOD FOR ANTI-SEIZURETHERAPY”; U.S. Patent Application entitled “ANAVEX2-73 FOR THE TREATMENT OF ALZHEIMER'S DISEASE” and filed on the same date as this document; U.S. Patent Application entitled “ENANTIOMERS OF A2-73, ANALOGUES, AND SIGMA AGONIST ACTIVITY” and filed on the same date as this document. The teachings of these applications and publications and all references cited herein are incorporated by reference in their entirety.

[0039] The present disclosure provides a crystalline polymorph of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (Form I) characterized by the PXRD and other data provided herein.

[0040] The present disclosure provides another crystalline polymorph (Form II) of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride, characterized by the PXRD and other data provided herein.

[0041] The present disclosure also provides another crystalline polymorph (Form III) of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride, characterized by the PXRD and other data provided herein.

[0042] The present disclosure also provides a tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride metabolite (referred to as ANAVEX 19-144) characterized by the PXRD and other data provided herein and having the structure:

[0043]

[0044] The present disclosure also provides for the use of polymorphic forms and metabolite materials in treating Alzheimer's disease.

[0045] like Figure 1-15 The products were characterized by powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, proton nuclear magnetic resonance ( 1 H-NMR) and scanning electron microscopy (SEM) were used to characterize tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX 2-73).

[0046] The present disclosure also provides a method for preparing tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX2-73) polymorphs. In one embodiment, the polymorphs disclosed herein can be produced by a supercritical fluid (SCF) antisolvent method. Although in some embodiments, near-critical fluids may also be suitable, in one embodiment, the antisolvent is a supercritical fluid. A "supercritical fluid" is a fluid that is simultaneously equal to or higher than its critical pressure (Pc) and critical temperature (Tc). In practice, the pressure of the fluid may be in the range of between 1.01 and 7.0 of its critical pressure, and its temperature is in the range of between 1.01 and 4.0 of its critical temperature (in Kelvin). However, certain fluids (such as helium and neon) have particularly low critical pressures and temperatures and may need to be used under operating conditions exceeding these critical values, for example up to 200 times the relevant critical values. The term "near-critical fluid" includes high-pressure liquids, which are fluids at or above their critical pressure but below (although preferably near) their critical temperature, and dense steam, which are fluids at or above their critical temperature but below (although preferably near) their critical pressure. As an example, a high-pressure liquid can 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. Dense steam can 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.

[0047] Suitably, antisolvent and solution can be introduced into the precipitation chamber through the corresponding channels with respective outlets, and the outlets are arranged relative to each other so that the antisolvent introduced by the first channel and the solution introduced by the second channel enter the precipitation chamber at substantially the same point, which is substantially the point where the antisolvent and solution meet. In order to provide good mixing and dispersion level, antisolvent and solution can be fed into the precipitation chamber together, for example, through the nozzle of the coaxial channel with the ends adjacent to each other. Alternatively, one or more antisolvent streams can be arranged to impact solution streams to provide good mixing and dispersion level. However, other mixing architectures are also possible. The example of suitable device is particularly known from WO-3095 / 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.

[0048] According to the present disclosure, new crystalline forms of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX2-73) are prepared by a supercritical fluid (SCF) process. The basic method includes preparing a solution of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX2-73) in a suitable solvent such as acetonitrile or ethanol, and introducing the solution into a SCF environment, typically supercritical CO2 in a pressure vessel. Supercritical CO2 acts as a strong antisolvent, causing the particles to precipitate rapidly. Different polymorphs of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX2-73) are produced by manipulating the SCF process parameters, including the solvent used, flow rate, pressure and temperature. In addition, the manipulation of the SCF process parameters determines the particle size, morphology and crystal habit of the crystals produced by the SCF process.

[0049] The SCF process parameters for producing three polymorphs (Forms I-III) of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX2-73) are provided in Tables 1-3. As shown in Table 1, Form I is produced by placing the ANAVEX2-73 starting material in a solvent of acetonitrile or ethanol and treating it by supercritical fluid technology. The resulting particle shape varies depending on the solvent. The particle shape of Form I produced using acetonitrile solvent is plate-like. As used herein, the term "plate-like" refers to flat particles with similar length and width. The particle shape of Form I produced using ethanol solvent is agglomerates. As used herein, the term "agglomerates" refers to a mixture of two or more types of particle shapes. The resulting material was characterized by PXRD and SEM. The PXRD of Form I of ANAVEX2-73 is Figure 1 The SEM micrographs showing the particle size and morphology of Form I are shown in Figure 2-3 Displayed in. Figure 2 The particle size and morphology (plate-like morphology) of Form I produced using acetonitrile solvent are shown. Figure 3 Shown are the particle size and morphology (agglomerate morphology) of Form I produced using ethanol as solvent.

[0050] As shown in Table 2, 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-1-butanol and processing it by supercritical fluid technology. In all cases, Form II is characterized by a plate-like crystal habit. The resulting material was characterized by PXRD and SEM. The PXRD of Form II of ANAVEX2-73 is Figure 4 The further feature of Form II is Figure 5 The FTIR spectra shown in Figure 6 As shown in 1 H-NMR. SEM micrographs showing the particle size and morphology of Form II Figure 7 Displayed in.

[0051] As shown in Table 3, Form III was prepared by placing the ANAVEX2-73 starting material in a solvent of ethanol or 1:9 V / V trifluoroethanol + ethanol and processing it by supercritical fluid technology. In all cases, Form III is characterized by a lath-like crystal habit. As used herein, "lath-like" refers to long, thin, plate-like particles. The resulting material was characterized by PXRD and SEM. The PXRD of Form III of ANAVEX2-73 is Figure 8 The crystal form III is also characterized by Fig. 9 The FTIR spectra shown in Fig.10 As shown in 1 H-NMR. SEM micrographs showing the particle size and morphology of Form III are shown in Fig.11 Displayed in.

[0052]

[0053]

[0054] The present disclosure also provides a metabolite of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride, ANAVEX19-144. ANAVEX19-144 has been documented to have anti-amnestic and neuroprotective potential similar to ANAVEX2-73. See, e.g., J. of Psychopharmacol. 25 (8), 1101-1117 (2011). The ANAVEX19-144 crystalline form is produced by placing the ANAVEX19-144 starting material in a solvent of ethanol or dichloromethane and treating it by supercritical fluid technology. The ANAVEX19-144 crystalline form produced by supercritical fluid technology was characterized by PXRD, FTIR, DSC and SEM under the process parameters of 40 mg / mL ethanol solution, 200 bar pressure, 80°C temperature, 20 g / min flow rate of supercritical CO2 solution and 0.4 mL / min TS flow, as shown in FIG. Figure 12-15 As shown. Fig.15 As shown in , the crystalline form of ANAVEX 19-144 is characterized by needle-shaped crystals. In contrast, the crystalline form of ANAVEX 19-144 produced by similar process parameters using the solvent dichloromethane shows a mixed crystal habit of needle-shaped and lath-shaped particles, such as Fig.16 The crystalline form of ANAVEX19-144 produced using dichloromethane supercritical fluid technology produced a powder with better flow properties and improved downstream processing fluidity. The crystalline form of ANAVEX19-144 was further characterized by PXRD and DSC, as shown in Figure 17-18 As shown. Two crystalline forms of ANAVEX 19-144 produced in ethanol or dichloromethane according to supercritical fluid technology were stored in an uncovered container at 40°C and 75% relative humidity for 1 week and then characterized by PXRD to determine the stability of the two forms. After one week, the PXRD of the two crystalline forms did not show any difference, thereby indicating that the two crystalline forms are stable under the tested conditions.

Claims

1. Form I of ANAVEX19-144 is basically characterized by The PXRD spectrum shown in Figure 12 shows that ANAVEX 19-144 has the structure:

2. The crystalline form I of ANAVEX19-144 of claim 1, further characterized by DSC-TGA data shown in FIG13 .

3. The crystalline form I of ANAVEX19-144 of claim 1, further characterized by FTIR spectrum shown in Figure 14.

4. The crystalline form I of ANAVEX19-144 of claim 1, further characterized by Particle size and morphology shown in Figure 15.

5. The crystalline form I of ANAVEX19-144 of claim 1, further characterized by It has a needle-like crystal habit as shown in FIG15 .

6. A method for preparing Form I of ANAVEX 19-144 according to any one of claims 1 to 5, wherein the method uses supercritical fluid (SCF) technology and ethanol as a solvent in the SCF method.

7. A dosage form comprising a therapeutic neuroprotective amount of the crystalline Form I of ANAVEX 19-144 according to any one of claims 1 to 5.

8. A pharmaceutical composition for treating Alzheimer's disease, comprising a therapeutically effective amount of the crystalline form I of ANAVEX 19-144 according to any one of claims 1 to 5.

9. A method of treating Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of Form I of ANAVEX 19-144 of any one of claims 1-5.

10. Use of the crystalline Form I of ANAVEX 19-144 according to any one of claims 1 to 5 for the preparation of a medicament for treating Alzheimer's disease in a subject.

11. Form II of ANAVEX19-144, which is essentially characterized by The PXRD spectrum shown in Figure 17, where ANAVEX19-144 has the structure:

12. Form II of ANAVEX19-144 according to claim 11, characterized in that DSC-TGA data shown in FIG. 18 .

13. Form II of ANAVEX19-144 according to claim 11, characterized in that It has a mixed crystal habit of needle-shaped and lath-shaped particles as shown in FIG16 .

14. The crystalline form II of ANAVEX19-144 of claim 11, further characterized by The particle sizes are shown in Figure 16.

15. Form II of ANAVEX19-144 according to claim 11, characterized in that Improved flow characteristics.

16. A process for preparing Form II of ANAVEX 19-144 according to any one of claims 11 to 15, wherein the process uses supercritical fluid (SCF) technology and dichloromethane as a solvent in the SCF process.

17. A dosage form comprising a therapeutic neuroprotective amount of Form II of ANAVEX 19-144 according to any one of claims 11 to 15.

18. A pharmaceutical composition for treating Alzheimer's disease, comprising a therapeutically effective amount of the crystalline form II of ANAVEX 19-144 according to any one of claims 11 to 15.

19. A method of treating Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of Form II of ANAVEX 19-144 of any one of claims 11-15.

20. Use of Form II of ANAVEX 19-144 according to any one of claims 11 to 15 for the preparation of a medicament for treating Alzheimer's disease in a subject.

21. Form I of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX 2-73), characterized essentially in that The PXRD spectrum is shown in Figure 1.

22. The crystalline form I of ANAVEX2-73 of claim 21, further characterized by The particle shape is shown in Figure 2.

23. The crystalline form I of ANAVEX2-73 of claim 21, further characterized by The particle shape is shown in Figure 3.

24. The crystalline form I of ANAVEX2-73 of claim 21, further characterized by The particle sizes are shown in Figure 2.

25. The crystalline form I of ANAVEX2-73 of claim 21, further characterized by The particle sizes are shown in Figure 3.

26. The crystalline form I of ANAVEX2-73 of claim 21, further characterized by It has a plate-like crystal habit.

27. A process for preparing Form I of ANAVEX 2-73 according to claim 21, wherein the process uses supercritical fluid (SCF) technology and acetonitrile or ethanol as a solvent in the SCF process.

28. A dosage form comprising a therapeutic neuroprotective amount of Form I of ANAVEX 2-73 according to any one of claims 21-26.

29. A pharmaceutical composition for treating Alzheimer's disease, comprising a therapeutically effective amount of the crystalline form I of ANAVEX 2-73 according to any one of claims 21 to 26.

30. Use of the crystalline Form I of ANAVEX 2-73 according to any one of claims 21-26 for the preparation of a medicament for treating Alzheimer's disease in a subject.

31. Form III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride (ANAVEX 2-73), characterized substantially by the PXRD spectrum shown in FIG8 .

32. The crystalline form III of ANAVEX2-73 of claim 31, further characterized by FTIR spectrum shown in Figure 9.

33. The crystalline form III of ANAVEX2-73 of claim 31, further characterized by As shown in Figure 10 1 H-NMR spectrum.

34. The crystalline form III of ANAVEX2-73 of claim 31, further characterized by The particle shape is shown in Figure 11.

35. The crystalline form III of ANAVEX2-73 of claim 31, further characterized by The particle sizes are shown in Figure 11.

36. The crystalline form III of ANAVEX2-73 of claim 31, further characterized by It has a lath-like crystal habit.

37. A process for preparing Form III of ANAVEX 2-73 according to any one of claims 31 to 36, wherein the process uses supercritical fluid (SCF) technology and ethanol or 1:9 v / v trifluoroethanol / ethanol as the solvent in the SCF process.

38. A dosage form comprising a therapeutic neuroprotective amount of Form III of ANAVEX 2-73 according to any one of claims 31-36.

39. A pharmaceutical composition for treating Alzheimer's disease, comprising a therapeutically effective amount of the crystalline form III of ANAVEX 2-73 according to any one of claims 31 to 36.

40. Use of Form III of ANAVEX 2-73 according to any one of claims 31 to 36 for the preparation of a medicament for treating Alzheimer's disease in a subject.

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