DESC:FIELD OF THE INVENTION
The present invention relates to novel salts of Blarcamesine, their solid-state forms, their
preparative methods, and pharmaceutical compositions thereof.
BACKGROUND OF THE INVENTION
The drug compound, having the International Non-Proprietary Name Blarcamesine has a
chemical name tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine, and has the
structure of Formula I:
Blarcamesine hydrochloride (Anavex2-73) is a Sigma-1 receptor agonist developed by Anavex
Life Sciences and is undergoing clinical studies in Rett Syndrome, Alzheimer’s disease and
Parkinson’s disease dementia.
PCT publication WO1997/30983A1 describes Blarcamesine, its enantiomers and its
hydrochloride salt. Preparation of racemic Blarcamesine is exemplified as compound-7 and its
melting point described is 87-90°C.
PCT publication WO2017/013498A1 describes crystalline polymorphic forms of Blarcamesine
HCl namely Form I, Form II and Form III, their preparative methods and pharmaceutical
compositions thereof.
PCT publication WO2019/200345A1 describes crystalline polymorphic forms of Blarcamesine
HCl, process for their preparation and their use in pharmaceutical compositions. WO ‘345 also
describes crystalline polymorphic form of Blarcamesine fumarate, Blarcamesine benzoate,
Blarcamesine sulfate, Blarcamesine phosphate, Blarcamesine edisylate Blarcamesine
mesylate, Blarcamesine oxalate and Blarcamesine free base.
PCT publication WO2021/158586A1 describes crystalline polymorphic forms of Blarcamesine
HCl, Blarcamesine HBr, Blarcamesine besylate, Blarcamesine tosylate, Blarcamesine maleate
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and Blarcamesine camphorsulfonate, their preparative methods and pharmaceutical compositions.
PCT publication WO2023/208133A1 describes co-crystals of Blarcamesine HCl with tartaric acid, citric acid and malic acid, process for their preparation and their use in pharmaceutical compositions.
Different salts and solid-state forms of an active pharmaceutical ingredient (API) may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulations, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving chemical and physical stability and shelf-life. These variations in the properties of different salts and solid-state forms may also offer improvements to the final dosage forms, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient (API) may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid an active pharmaceutical ingredient (API).
New salts and solid-state forms of an active pharmaceutical ingredient (API) can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. They can enlarge the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional salts and solid-state forms Blarcamesine.
SUMMARY OF THE INVENTION
The present invention generally relates to novel salts of Blarcamesine, their preparative methods and pharmaceutical compositions thereof.
In one aspect, the present invention provides Blarcamesine hemi-succinate salt.
In another aspect, the present invention provides crystalline Blarcamesine hemi-succinate salt.
In another aspect, the present invention provides Blarcamesine hemi-citrate salt.
In another aspect, the present invention provides crystalline Blarcamesine hemi-citrate salt. Docusign Envelope ID: BBE6DF5E-F2D8-4BF9-B3A6-2D07288BC2D0
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In another aspect the present application provides Blarcamesine maleate salt.
In another aspect, the present invention provides crystalline Blarcamesine maleate salt.
In another aspect the present application provides Blarcamesine formate salt.
In another aspect, the present invention provides crystalline Blarcamesine formate salt.
In another aspect the present application provides processes for preparation of Blarcamesine salts of the present invention.
In another aspect the present application provides use of the Blarcamesine salts of the present invention to prepare other solid-state forms of Blarcamesine or its salts and solid-state forms thereof, particularly Blarcamesine HCl and solid-state forms thereof.
In another aspect the present application provides pharmaceutical compositions useful for oral administration comprising Blarcamesine salts of the present invention and one or more pharmaceutically acceptable polymer.
In another aspect the present application provides use of pharmaceutical compositions or formulations of any one of Blarcamesine salts of the present invention for the treatment of Neurodegenerative and Neurodevelopmental diseases such as Alzheimer’s disease, Parkinson’s disease dementia and/or Rett syndrome.
BRIEF DESCRIPTION OF DRAWINGS
Figure-1 is powder X-ray diffraction (PXRD) pattern of crystalline Blarcamesine hemi-succinate salt prepared according to example 1.
Figure-2 is powder X-ray diffraction (PXRD) pattern of crystalline Blarcamesine hemi-citrate salt prepared according to example 2.
Figure-3 is powder X-ray diffraction (PXRD) pattern of crystalline Blarcamesine maleate salt prepared according to example 3.
Figure-4 is powder X-ray diffraction (PXRD) pattern of crystalline Blarcamesine formate salt prepared according to example 4.
Figure-5 is powder X-ray diffraction (PXRD) pattern of crystalline Blarcamesine formate salt prepared according to example 6. Docusign Envelope ID: BBE6DF5E-F2D8-4BF9-B3A6-2D07288BC2D0
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DETAILED DESCRITPION OF THE INVENTION
The present invention provides new salts of Blarcamesine, particularly Blarcamesine hemi-succinate, Blarcamesine hemi-citrate, Blarcamesine maleate and Blarcamesine formate, their preparative methods and pharmaceutical compositions thereof.
In one aspect, the present invention provides Blarcamesine hemi-succinate salt.
In another aspect, the present invention provides crystalline Blarcamesine hemi-succinate salt. The crystalline Blarcamesine hemi-succinate salt may be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 1. The crystalline Blarcamesine hemi-succinate salt may be characterized by an X-ray powder diffraction pattern having peaks at 10.5, 12.9, 13.3, 14.9 and 17.2 degrees 2-theta ± 0.2 degrees 2-theta.
The crystalline Blarcamesine hemi-succinate salt may be further characterized by an X-ray powder diffraction pattern having peaks at 10.5, 12.9, 13.3, 14.9 and 17.2 degrees 2-theta ± 0.2 degrees 2-theta, and also having anyone, two, three, four or five additional peaks selected from 5.2, 8.0, 15.3, 15.9, 18.4, 18.8, 21.1 and 22.2 degrees 2-theta ± 0.2 degrees 2-theta.
The crystalline Blarcamesine hemi-succinate salt may be anhydrous form, as can be determined by TGA. In one aspect, the present invention provides crystalline Blarcamesine hemi-succinate salt having up to 0.5% w/w residual solvent content.
The crystalline Blarcamesine hemi-succinate salt may be prepared by crystallization from a mixture comprising Blarcamesine free base, succinic acid and isopropanol. In one aspect, the process comprises:
(a) providing a mixture of Blarcamesine and succinic acid in a suitable solvent;
(b) optionally stirring the mixture; and
(c) isolating crystalline Blarcamesine hemi-succinate salt.
The mixture in step (a) may be prepared by:
(i) providing a mixture of Blarcamesine free base in a solvent comprising isopropanol;
(ii) combining the mixture with succinic acid; or by
(iii) providing a mixture of succinic acid in a solvent comprising isopropanol, and adding Blarcamesine free base into the succinic acid mixture.
In step (a), the solvent may be present in an amount of about 5 to about 20 ml per gram of Blarcamesine free base, and preferably about 10 ml per gram of Blarcamesine free base. The Docusign Envelope ID: BBE6DF5E-F2D8-4BF9-B3A6-2D07288BC2D0
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mixture may be a solution or a slurry. The succinic acid may be present in an amount of about 0.5 to about 1 molar equivalent with respect to the Blarcamesine free base.
The step (b) is carried out, preferably by stirring at a temperature of about 5 °C to about 60 °C, preferably about 25 °C to about 35 °C. The stirring may be carried out for any suitable time, preferably for about 30 minutes to about 30 hours, more preferably for about 16 hour to about 18 hours.
The step (c) may comprise isolating crystalline Blarcamesine hemi-succinate salt from the mixture. The isolation can be carried out by any suitable method, for example by filtration, centrifugation, or decantation. Preferably the isolation can be carried out by filtration. The crystals of Blarcamesine hemi-succinate salt may be washed with the reaction solvent, and optionally dried. The drying may be conducted in a vacuum oven at a temperature of about 20°C to about 80°C, preferably about 40 °C to about 45°C. The drying may be carried out over a period of about 1 hour to about 24 hours, about 2 hours to about 10 hours.
In another aspect, the present invention provides Blarcamesine hemi-citrate salt.
In another aspect, the present invention provides crystalline Blarcamesine hemi-citrate salt. The crystalline Blarcamesine hemi-citrate salt may be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 2. The crystalline Blarcamesine hemi-citrate salt may be characterized by an X-ray powder diffraction pattern having peaks at 11.3, 13.6, 15.1, 18.2 and 22.7 degrees 2-theta ± 0.2 degrees 2-theta.
The crystalline Blarcamesine hemi-citrate salt may be further characterized by an X-ray powder diffraction pattern having peaks at 11.3, 13.6, 15.1, 18.2 and 22.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 11.1, 17.6, 19.9, 20.9, 22.0 and 24.8 degrees 2-theta ± 0.2 degrees 2-theta.
In one aspect, the present invention provides crystalline Blarcamesine hemi-citrate salt that is an isopropanol solvate.
The crystalline Blarcamesine hemi-citrate salt may be prepared by crystallization from a mixture comprising Blarcamesine free base, citric acid and isopropanol. In one aspect, the process comprises:
(a) providing a mixture of Blarcamesine and citric acid in a suitable solvent; Docusign Envelope ID: BBE6DF5E-F2D8-4BF9-B3A6-2D07288BC2D0
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(b) optionally stirring the mixture; and
(c) isolating crystalline Blarcamesine hemi-citrate salt.
The mixture in step (a) may be prepared by:
(i) providing a mixture of Blarcamesine free base in a solvent comprising isopropanol;
(ii) combining the mixture with citric acid; or by
(iii) providing a mixture of citric acid in a solvent comprising isopropanol, and adding Blarcamesine free base into the citric acid mixture.
In step (a), the solvent may be present in an amount of about 5 to about 20 ml per gram of Blarcamesine free base, and preferably about 10 ml per gram of Blarcamesine free base. The mixture may be a solution or a slurry. The citric acid may be present in an amount of about 0.5 to about 1 molar equivalent with respect to the Blarcamesine free base.
The step (b) is carried out, preferably by stirring at a temperature of about 5°C to about 60°C, preferably about 25°C to about 35°C. The stirring may be carried out for any suitable time, preferably for about 30 minutes to about 36 hours, more preferably for about 20 hours to about 24 hours.
The step (c) may comprise isolating crystalline Blarcamesine hemi-citrate salt from the mixture. The isolation can be carried out by any suitable method, for example by filtration, centrifugation, or decantation. Preferably the isolation can be carried out by filtration. The crystals of Blarcamesine hemi-citrate salt may be washed with the reaction solvent, and optionally dried. The drying may be conducted in a vacuum oven at a temperature of about 20°C to about 80°C, preferably about 40°C to about 45°C. The drying may be carried out over a period of about 1 hour to about 24 hours, about 2 hours to about 10 hours.
In another aspect, the present invention provides Blarcamesine maleate salt.
In another aspect, the present invention provides crystalline Blarcamesine maleate salt. The crystalline Blarcamesine maleate salt may be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 3. The crystalline Blarcamesine maleate salt may be characterized by an X-ray powder diffraction pattern having peaks at 9.5, 15.7, 19.1, 25.4 and 23.9 degrees 2-theta ± 0.2 degrees 2-theta.
The crystalline Blarcamesine maleate salt may be further characterized by an X-ray powder diffraction pattern having peaks at 9.5, 15.7, 19.1, 25.4 and 23.9 degrees 2-theta ± 0.2 degrees Docusign Envelope ID: BBE6DF5E-F2D8-4BF9-B3A6-2D07288BC2D0
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2-theta, and also having any one, two, three, four or five additional peaks selected from 10.4, 11.6, 13.2, 17.2, 18.6 and 25.4 degrees 2-theta ± 0.2 degrees 2-theta.
The crystalline Blarcamesine maleate salt may be anhydrous form, as can be determined by TGA. In one aspect, the present invention provides crystalline Blarcamesine maleate salt having up to 0.5% w/w residual solvent content.
The crystalline Blarcamesine maleate may be prepared by crystallization from a mixture comprising Blarcamesine free base, maleic acid and tetrahydrofuran. In one aspect, the process comprises:
(a) providing a mixture of Blarcamesine and maleic acid in a suitable solvent;
(b) optionally stirring the mixture; and
(c) isolating crystalline Blarcamesine maleate salt.
The mixture in step (a) may be prepared by:
(i) providing a mixture of Blarcamesine free base in a solvent comprising tetrahydrofuran;
(ii) combining the mixture with maleic acid; or by
(iii) providing a mixture of maleic acid in a solvent comprising tetrahydrofuran, and adding Blarcamesine free base into the maleic acid mixture.
In step (a), the solvent may be present in an amount of about 5 to about 20 ml per gram of Blarcamesine free base, and preferably about 10 ml per gram of Blarcamesine free base. The mixture may be a solution or a slurry. The maleic acid may be present in an amount of about 0.5 to about 2 molar equivalents with respect to the Blarcamesine free base.
The step (b) is carried out, preferably by stirring at a temperature of about 5°C to about 60°C, preferably about 25°C to about 35°C. The stirring may be carried out for any suitable time, preferably for about 30 minutes to about 30 hours, more preferably for about 16 hours to about 18 hours.
The step (c) may comprise isolating crystalline Blarcamesine maleate salt from the mixture. The isolation can be carried out by any suitable method, for example by filtration, centrifugation, or decantation. Preferably the isolation can be carried out by filtration. The crystals of Blarcamesine maleate salt may be washed with the reaction solvent, and optionally dried. The drying may be conducted in a vacuum oven at a temperature of about 20°C to about
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80°C, preferably about 40°C to about 45°C. The drying may be carried out over a period of about 1 hour to about 24 hours, about 2 hours to about 10 hours.
In one aspect, the present invention provides Blarcamesine formate salt.
In another aspect, the present invention provides crystalline Blarcamesine formate salt. The crystalline Blarcamesine formate salt may be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 4. The crystalline Blarcamesine formate salt may be characterized by an X-ray powder diffraction pattern having peaks at 8.9, 13.3, 15.8, 17.9 and 23.6 degrees 2-theta ± 0.2 degrees 2-theta.
The crystalline Blarcamesine formate salt may be further characterized by an X-ray powder diffraction pattern having peaks at 8.9, 13.3, 15.8, 17.9 and 23.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 9.7, 17.0, 19.4, 20.2, 21.0 and 22.2 degrees 2-theta ± 0.2 degrees 2-theta.
The crystalline Blarcamesine formate salt may be anhydrous form, as can be determined by TGA. In one aspect, the present invention provides crystalline Blarcamesine formate salt having up to 0.5% w/w residual solvent content.
The crystalline Blarcamesine formate salt may be prepared by crystallization from a mixture comprising Blarcamesine free base, formic acid, and isopropanol or tetrahydrofuran or a mixture thereof. In one aspect, the process comprises:
(a) providing a mixture of Blarcamesine and formic acid in a suitable solvent;
(b) optionally stirring the mixture; and
(c) isolating crystalline Blarcamesine formate salt.
The mixture in step (a) may be prepared by:
(i) providing a mixture of Blarcamesine free base in a solvent comprising isopropanol or tetrahydrofuran or a mixture thereof;
(ii) combining the mixture with formic acid; or by
(iii) providing a mixture of formic acid in a solvent comprising isopropanol or tetrahydrofuran or a mixture thereof, and adding Blarcamesine free base into the formic acid mixture.
In step (a), the solvent may be present in an amount of about 5 to about 20 ml per gram of Blarcamesine free base, and preferably about 10 ml per gram of Blarcamesine free base. The Docusign Envelope ID: BBE6DF5E-F2D8-4BF9-B3A6-2D07288BC2D0
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mixture may be a solution or a slurry. The formic acid may be present in an amount of about 0.5 to about 2 molar equivalents with respect to the Blarcamesine free base.
The step (b) is carried out, preferably by stirring at a temperature of about 5°C to about 60°C, preferably about 25°C to about 35°C. The stirring may be carried out for any suitable time, preferably for about 30 minutes to about 30 hours, more preferably for about 16 hour to about 18 hours.
The step (c) may comprise isolating crystalline Blarcamesine formate salt from the mixture. The isolation can be carried out by any suitable method, for example by filtration, centrifugation, or decantation. Preferably the isolation can be carried out by filtration. The crystals of Blarcamesine formate salt may be washed with the reaction solvent, and optionally dried. The drying may be conducted in a vacuum oven at a temperature of about 20°C to about 80°C, preferably about 40°C to about 45°C. The drying may be carried out over a period of about 1 hour to about 24 hours, about 2 hours to about 10 hours.
In another aspect, the present application provides use of Blarcamesine hemi-succinate salt, Blarcamesine hemi-citrate salt, Blarcamesine maleate salt and Blarcamesine formate salt and their crystalline forms in the preparation of other salts of Blarcamesine and their solid-state forms thereof.
In another aspect the present application provides process for preparation of pure Blarcamesine free base, comprising converting crude Blarcamesine free base into a pharmaceutically acceptable salt and treating the Blarcamesine acid addition salt with a suitable base to obtain pure Blarcamesine free base.
In another aspect, the present application provides use of Blarcamesine hemi-succinate salt, Blarcamesine hemi-citrate salt, Blarcamesine maleate salt and Blarcamesine formate salt and their crystalline forms in the preparation of Blarcamesine HCl salt and their solid-state forms thereof.
In another aspect, the present application provides pharmaceutical compositions comprising any one of Blarcamesine hemi-succinate salt, Blarcamesine hemi-citrate salt, Blarcamesine maleate salt and Blarcamesine formate salt or their crystalline forms, and one or more pharmaceutically acceptable polymer.
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The Blarcamesine salts of the present application or their crystalline polymorphs and the pharmaceutical compositions or formulations may be used as medicaments, particularly for the treatment of Neurodegenerative and Neurodevelopmental diseases such as Alzheimer’s diseases, Parkinson’s disease dementia and/or Rett syndrome.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms “amorphous” and “amorphous form” are used herein to describe a substance, component, or product that is not substantially crystalline as determined by X-ray diffraction. In certain embodiments, an amorphous form of a substance may be substantially free of crystal forms. In other embodiments, an amorphous form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more crystal forms on a weight basis. In other embodiments, an amorphous form of a substance may comprise additional components or ingredients (for example, an additive, a polymer, or an excipient that may serve to further stabilize the amorphous form).
Unless otherwise specified, the term “solid dispersion” refers to a solid state which comprises at least two constituents, wherein one constituent is homogenously dispersed significantly evenly throughout the other constituent or constituents. It includes solid or glassy solutions, i.e., the dispersion of the constituents is in such a way that the composition is chemically and physically homogenous in nature.
The term “polymer” refers to a compound comprising repeating structural units (monomers) connected by covalent chemical bonds. Polymers may be further derivatized, crosslinked, grafted or end- capped. Non-limiting examples of polymers include copolymers, terpolymers, quaternary polymers, and homologues. The term “copolymer” refers to a polymer consisting essentially of two or more different types of repeating structural units (monomers).
The term “pharmaceutically acceptable excipient” includes, without limitation, any adjuvant, carrier, excipient, binder, filler, disintegrant, lubricant, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by Docusign Envelope ID: BBE6DF5E-F2D8-4BF9-B3A6-2D07288BC2D0
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the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example, "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
EXAMPLES
Example-1: Preparation of Blarcamesine hemi-succinate salt
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A mixture of Blarcamesine free base (1.0 g, purity by HPLC: 99.09%) in IPA (10 mL) was gently warmed at 40°C for 6 minutes to obtain a clear solution, which was then cooled to 30°C before being treated with succinic acid (419 mg) at the same temperature. The obtained mixture was stirred at 30°C for 18 h. The resulting suspension was filtered and the wet cake was washed with isopropanol (5 mL). The solid was dried for 1 h at 45°C to yield 400 mg of Blarcamesine hemi-succinate salt. The PXRD is shown in Figure 1. Purity: 99.74%. The 1H NMR indicates hemi-succinate salt.
Example-2: Preparation of Blarcamesine hemi-citrate salt
A mixture of Blarcamesine free base (1.0 g, purity by HPLC: 99.09%) in IPA (10 mL) was gently warmed at 40°C for 6 minutes to obtain a clear solution, which was then stirred for an additional 10 minutes at 30°C before being treated with citric acid monohydrate (746 mg) at the same temperature. The obtained mixture was stirred at 30°C for 22 h. The suspension was filtered and the wet cake washed with isopropanol (5 mL). The solid was dried for 1 h at 45°C to yield 810 mg of Blarcamesine hemi-citrate salt as white solid. The PXRD is shown in Figure 2. Purity: 99.67%. The 1H NMR indicates hemi-citrate salt with 6.34% w/w isopropanol.
Example-3: Preparation of Blarcamesine maleate salt
Maleic acid (1.23 g) was added to a solution of Blarcamesine free base (3.0 g, purity by HPLC: 71.38%) in THF (30 mL) at 30°C. The obtained mixture was stirred at 30°C for 18 h. The resulting suspension was filtered, and the wet material was washed with tetrahydrofuran (15 mL). The solid was dried for 1 h at 45°C to yield 850 mg of Blarcamesine maleate salt. The PXRD is shown in Figure 3. Purity: 96.59%. The 1H NMR indicates mono-maleate salt.
Example-4: Preparation of Blarcamesine formate salt
Formic acid (0.067 mL) was added to a solution of Blarcamesine free base (500 mg, purity by HPLC: 99.09%) in THF (5 mL) at 30°C. The obtained mixture was stirred was stirred at 30°C for 18 h. The resulting suspension was filtered, and the wet solid was washed with tetrahydrofuran (2.5 mL). The solid was dried for 1 h at 45°C to yield 370 mg of Blarcamesine formate salt. The PXRD is shown in Figure 4. Purity: 99.46%. The 1H NMR indicates mono-formate salt.
Example-5: Preparation of Blarcamesine HCl
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Step-1: Preparation of N,N-dimethyl-5-oxo-2,2-diphenyltetrahydrofuran-3-carboxamide
5-oxo-2,2-diphenyltetrahydrofuran-3-carboxylic acid (20 g) and thionyl chloride (68.0 mL)
were charged into round-bottom flask, the resulting reaction mixture was heated to 60-65°C.
After stirring at 60-65°C for 1 h, the reaction mixture was concentrated to afford the crude acid
chloride as a pale brown solid which was directly dissolved in 100 mL of THF. The obtained
solution was cooled to 5°C and stirred at the same temperature for 10 min. Thereafter a solution
of dimethylamine (40% aqueous, 48.0 mL, 2.4 V) in THF (40.0 mL) was slowly added to the
acid chloride solution maintained at 5?C. After the addition was complete, the reaction mixture
was brought to room temperature and stirred at the same temperature for 3h. Upon completion
of the reaction, the reaction mixture was quenched with saturated aqueous NaHCO3 solution
(100.0 mL). The mixture thus obtained was extracted with EtOAc (2?100 mL). The EtOAc
extracts were combined, washed successively with saturated aqueous NaHCO3 solution (50.0
mL) and brine (100.0 mL), dried over anhydrous Na2SO4 and finally concentrated under
reduced pressure to obtain the amide as a light brown solid. Yield: 18.62 g. Purity by HPLC:
96.57%.
Step-2: Preparation of Blarcamesine HCl.
N,N-dimethyl-5-oxo-2,2-diphenyltetrahydrofuran-3-carboxamide (21.0 g) and THF (420 mL)
were charged into round-bottomed flask and stirred for 10 minutes at room temperature. The
solution was then cooled to 5°C, and DIBAL-H (452.5 mL, 1.5M in toluene) was added slowly
with cannula while maintaining an internal temperature below 5°C. After completion of
DIBAL-H addition, the reaction mixture was brought to room temperature, and stirred at the
same temperature for 5 hours. Thereafter the reaction mixture was cooled to 5°C and quenched
with saturated aqueous Rochelle salt (25-30 mL) while maintaining an internal temperature
below 5°C. The resulting mixture was diluted with DCM (500 mL), vigorously stirred for 10
minutes and filtered through a Celite bed which was then washed with DCM (3?500 mL). The
filtrate and washings were combined, dried over anhydrous Na2SO4 and concentrated under
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reduced pressure at <40°C to obtain the crude 2-((dimethylamino)methyl)-1,1-diphenylbutane-1,4-diol [18.0 g, Purity by HPLC: 64.46%] as a light greenish colored syrup which was taken forward to the next step without any further purification.
The obtained crude diol compound was taken in to a round-bottom flask. 450 mL of toluene and PTSA (22.87 g) were added to the flask. The mixture was heated to 120°C and stirred at the same temperature for 5 hours. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature and quenched with saturated aqueous NaHCO3 solution (100 mL). The organic layer was separated from the aqueous layer, which was then extracted with EtOAc (2?200 mL). The separated organic layer and EtOAc extracts were combined, washed successively with saturated NaHCO3 solution (100 mL), water (200 mL) and brine (200 mL), dried over anhydrous Na2SO4, and finally concentrated under reduced pressure at < 40 oC to obtain crude Blarcamesine base [13.12 g, purity by HPLC: 50.53%] as a brown colored syrup which was taken forward to the next step without any further purification. The obtained crude Blarcamesine base was directly treated with 4.0 M HCl in dioxane (26.24 mL) at 0°C. After allowing to stir at room temperature for 30 minutes, the reaction mixture was evaporated to dryness. 15 mL of diisopropyl ether was added to the obtained gummy mass which was then gently scratched using a spatula for 5 minutes. The supernatant diisopropyl ether layer was decanted off; the residue, thus obtained, was subjected to two more repetitions of scratching in diisopropyl ether (15 mL each) followed by decantation of the supernatant diisopropyl ether layer. The obtained light brown colored solid (12.53 g) was taken in EtOAc (65.6 mL) and heated at 70?C for 1 hour. The solution was then cooled to room temperature. The obtained suspension was filtered to collect the solids (8.3 g, off-white colored) which were then stirred in isopropanol (41.65 mL) at 70°C for 30 minutes. The resulting suspension was cooled and filtered. The obtained wet cake was dried under reduced pressure at 45°C to obtain Blarcamesine HCl as an off-white crystalline solid [yield: 5.21 g (lot-1) + 1.53 g (lot-2) = 6.74 g, purity by HPLC: 99.05% (lot-1) and 97.64% (lot-2)].
Example-6: Preparation of pure Blarcamesine base
Crude Blarcamesine base (89.79 g) and 4.0 M HCl in dioxane (179.58 mL) were charged into a round bottom flask at 5°C. The obtained reaction mixture was stirred at 0-5°C for 30 minutes and subsequently concentrated under reduced pressure below 45°C to obtain a viscous liquid, which was mixed with EtOAc (448.95 mL). and heated at 70-75°C for 1 hour. After cooling to Docusign Envelope ID: BBE6DF5E-F2D8-4BF9-B3A6-2D07288BC2D0
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25-35°C, the obtained suspension was filtered. The collected solids were dried under reduced pressure below 45°C for 1 hour and then stirred in 1:4 IPA-EtOAc (290.85 mL) at 70-75°C for 1 hour. The resulting suspension was cooled to 25-35°C and filtered. The obtained wet cake was dried under reduced pressure below 45°C for 1 h to obtain Blarcamesine HCl as a white solid (37.16 g, purity ,CLAIMS:1. Crystalline salts of Blarcamesine, selected from the group comprising:
a) Blarcamesine hemi-succinate salt;
b) Blarcamesine hemi-citrate salt;
c) Blarcamesine maleate salt; and
d) Blarcamesine formate salt.
2. The crystalline salts of Blarcamesine according to claim 1, which are characterized by:
a) powder X-ray diffraction (PXRD) pattern of crystalline Blarcamesine hemi-succinate salt as depicted in Figure 1,
b) powder X-ray diffraction (PXRD) pattern of crystalline Blarcamesine hemi-citrate salt as depicted in Figure 2,
c) powder X-ray diffraction (PXRD) pattern of crystalline Blarcamesine maleate salt as depicted in Figure 3,
d) powder X-ray diffraction (PXRD) pattern of crystalline Blarcamesine formate salt as depicted in Figure 4, and
e) powder X-ray diffraction (PXRD) pattern of crystalline Blarcamesine formate salt as depicted in Figure 5.
3. A process for preparation of crystalline Blarcamesine hemi-succinate salt, comprises:
(a) providing a mixture of Blarcamesine and succinic acid in isopropanol;
(b) optionally stirring the mixture; and
(c) isolating crystalline Blarcamesine hemi-succinate salt.
4. The process of claim 3, wherein the step a) is carried out at a temperature of 25°C to about 35°C.
5. A process for preparation of crystalline Blarcamesine hemi-citrate salt, comprises:
a) providing a mixture of Blarcamesine and citric acid in isopropanol;
b) optionally stirring the mixture; and
c) isolating crystalline Blarcamesine hemi-citrate salt.
6. The process of claim 5, wherein the step a) is carried out at a temperature of 25°C to about 35°C.
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7. A process for preparation of crystalline Blarcamesine maleate salt, comprises:
a) providing a mixture of Blarcamesine and maleic acid in tetrahydrofuran;
b) optionally stirring the mixture; and
c) isolating crystalline Blarcamesine maleate salt.
8. A process for preparation of crystalline Blarcamesine formate salt, comprises:
a) providing a mixture of Blarcamesine and formic acid in isopropanol or tetrahydrofuran or a mixture thereof;
b) optionally stirring the mixture; and
c) isolating crystalline Blarcamesine formate salt.
9. Use of a crystalline Blarcamesine salts as defined in any of Claims 1 to 8, for the preparation of other solid-state forms of Blarcamesine, Blarcamesine co-crystals, Blarcamesine salts and their solid-state forms.
10. A pharmaceutical composition comprising crystalline Blarcamesine salts as defined in any of Claims 1 to 9 and at least one pharmaceutically acceptable excipient, preferably wherein the pharmaceutical composition is for oral administration.