ITMI20081406A1 - CRYSTAL FORM OF RASAGILINE AND PROCEDURE FOR ITS PREPARATION - Google Patents

Description

Description of the patent for industrial invention entitled:

"CRYSTALLINE FORM OF RASAGILINE AND PROCEDURE FOR ITS PREPARATION"

FIELD OF THE INVENTION

The present invention relates to (R) -N-propargyl-1-aminoindane in crystalline form, a process for its preparation and a pharmaceutical composition thereof.

STATE OF THE TECHNIQUE

(R) -N-Propargil-1-aminoindane, or Rasagiline, having formula

is a compound, marketed as a mesylate salt, having a potent, selective and irreversible MAOI activity (monoamine oxidase inhibition) and also used in the clinic as an anti-Parkinson's and in the treatment of various neurological disorders.

US 5,532,415 describes its preparation and isolation as hydrochloride, tartrate and mesylate salt.

Until now the compound (R) -N-propargyl-1-aminoindane, hereinafter also identified for simplicity as Rasagiline, had never been isolated in solid form. For example, the experimental part of US 5,532,415 describes its isolation dissolved in various solvents or as an oil, and its use as such in the subsequent preparation of its salts.

The present invention is based on the physical properties of free base Rasagiline in crystalline form. As is known, the physical properties of a drug are of fundamental importance in pharmaceutical technique in the preparation of pharmaceutical forms. An important aspect of drugs in solid form, especially in the case of addition salts of acids to amines, is their solubility, a crucial parameter that conditions the speed of dissolution in aqueous fluids and therefore the bioavailability of the drug. As is known, pharmaceutical forms such as medicated (transdermal) patches or creams require highly lipophilic active pharmaceutical ingredients for their preparation, which allow their dissolution in fatty or generally hydrophobic matrices.

Until now Rasagiline has been used in therapy only as a mesylate salt, in solid forms for oral use. On the other hand, its addition salts with organic or mineral acids are poorly lipophilic and therefore do not lend themselves to the preparation of pharmaceutical forms for transdermal use. The present invention, by making Rasagiline base available in solid, more lipophilic form, now provides the pharmaceutical technician with the possibility of preparing pharmaceutical forms, for example as an adhesive or transdermal medicated plaster (patch), in particular with prolonged release, which are better suited for the long-term treatment of patients suffering from disabling diseases, where in particular the oral administration can be difficult and it is necessary to maintain a constant blood level of the drug.

SUMMARY OF THE INVENTION

It has been found here that (R) -N-propargyl-1-aminoindane can exist in crystalline solid form, in particular in anhydrous form, hereinafter defined as Form Α, stable at room temperature.

The invention therefore provides (R) -N-propargyl-1-aminoindane in this solid form, a method for its preparation and a pharmaceutical composition containing this product.

BRIEF DESCRIPTION OF THE FIGURES AND ANALYTICAL METHODS

The crystalline form of (R) -N-propargyl-1-aminoindane was characterized by X-ray powder diffraction (X-ray powder diffraction), by 1H-NMR nuclear magnetic resonance spectrometer and by calorimetry differential scanning (DSC).

The water content in the compound was determined by titration with the Karl Fischer technique.

The X-ray diffraction spectrum (XRPD) was collected with the automatic θ / θ diffractometer for powders and liquids APD-2000 from Ital-Structures in the following operating conditions: CuKα radiation (λ = 1.5418 Å), scanning with angular interval 3-40 ° in 2θ, with an angular step of 0.03 ° for a time of 1 sec.

The DSC trace was acquired with the Mettler-Toledo DSC 822e differential scanning calorimeter, under the following operating conditions: aluminum capsules, range 30-400 ° C with a rate of 10 ° C / min, with nitrogen as purge gas (80 ml / min).

The particle size was determined with the known technique of "laser light scattering" using a Malvern Mastersizer MS1 instrument under the following operating conditions:

• 300RF mm lens with 2.4 mm laser beam length; • 500 mg sample dispersed in 10 ml of hexane (ACS reagent) with 1% of SPAN 85 <®>, without presonication, and with a stirring speed of 2500 rpm.

Figure 1: XRPD spectrum of Form Α of (R) -N-propargyl-1-aminoindane (crystalline Rasagiline);

Figure 2: DSC trace of Form Α of (R) -N-propargyl-1-aminoindane (Rasagiline crystalline).

DETAILED DESCRIPTION OF THE INVENTION

As a first object, the present invention provides (R) -N-propargyl-1-aminoindane in solid form, in particular in crystalline form, substantially anhydrous, hereinafter defined as Form A. Said form has a water content of approximately between 0 and 0.2%, so that it can be defined as substantially anhydrous. This shape has a DSC trace as substantially reported in Figure 2, having a melting point between about 39 and 42 ° C, and an XRPD spectrum as substantially illustrated by Figure 1, where the most intense diffraction peaks are found at 8, 4; 12.3; 12.4; 16.0; 16.8; 20.2; 20.9; 24.9; 25.4 and 26.3 ± 0.2 ° in 2θ.

(R) -N-Propargyl-1-aminoindane in solid form, as defined above, can be prepared for example by a process comprising:

A1) formation of a solution of rasagiline base in an organic solvent;

A2) cooling the solution to obtain a precipitate; and A3) recovery of the solid; or:

B1) formation of a solution of rasagiline base in an organic solvent;

B2) adding anti-solvent to the solution to obtain a precipitate; And

B3) recovery of the solid obtained; or:

C1) forming a mixture of a rasagiline addition salt with water and an organic solvent;

C2) treatment of the mixture with an alkali or alkaline earth metal base;

C3) separation of the phases and concentration of the organic solution down to residue;

C4) crystallization of the residue thus obtained from an aprotic apolar solvent; And

C5) recovery of the solid obtained.

Rasagiline base can be prepared for example according to US 5,532,415.

According to alternative A1) an organic solvent can be, for example, an apolar aprotic solvent, such as a C5-C12 alkane, linear or branched, cyclic or polycyclic, for example hexane, heptane, cyclohexane or decalin, or an aromatic hydrocarbon, for example for example benzene, toluene or xylene. Preferably it is an aprotic apolar solvent, preferably a C5-C12 alkane, in particular cyclohexane.

According to alternative A1) the formation of a solution of rasagiline base in an organic solvent can be obtained, for example, by heating the dispersion of rasagiline base in the solvent to a temperature between approximately 20-100 ° C, preferably approximately 40 ° C and 85 ° C.

The concentration of rasagiline base in the organic solvent, in particular in an aprotic apolar solvent, as defined above, is normally between 0.1M and 10M, preferably between 1M and 2M.

According to alternative A2) the cooling of the solution, to obtain a precipitate of solid rasagiline, can be carried out at a temperature generally comprised between -20 ° C and 40 ° C, more preferably between approximately 0 ° C and 10 ° C.

The crystalline solid product can be recovered according to known techniques, for example by filtration or centrifugation, optionally followed by drying under vacuum. Preferably the product is recovered by filtration, followed by drying under vacuum at room temperature.

According to alternative B1) an organic solvent can be, for example, an aprotic polar solvent, typically dimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide; an ether, for example diethyl ether, methyl-tert-butyl ether, tetrahydrofuran or dioxane; a chlorinated solvent, for example, dichloromethane, dichloroethane, chloroform or chlorobenzene; an aprotic apolar solvent, such as an aromatic hydrocarbon, for example benzene, toluene or xylene; an ester, for example ethyl or methyl acetate; or a C3-C12 ketone, for example acetone, methylethyl ketone, methylisobutyl ketone; or a mixture of two or more, preferably two or three, of said solvents. Preferably it is selected from acetonitrile, ethyl acetate and tetrahydrofuran, in particular ethyl acetate.

According to alternative B1) a solution of rasagiline base in an organic solvent can be obtained for example as reported above for the alternative method A1). Similarly, the concentration of rasagiline base in the organic solvent, in particular in an aprotic polar solvent, is normally between 1M and 10M, preferably between 2M and 5M.

According to alternative B2) an anti-solvent is for example an aprotic apolar solvent, preferably a C5-C12 alkane, linear or branched, cyclic or polycyclic, more preferably hexane, heptane, cyclohexane or decalin.

The recovery of the solid can be obtained for example as reported above for the alternative method A3).

A rasagiline addition salt can be, for example, a pharmaceutically acceptable acid addition salt thereof, for example a salt with a strong inorganic acid or an organic carboxylic or sulphonic acid, typically hydrochloric acid, tartaric acid or methanesulfonic acid. Preferably this salt is rasagiline mesylate.

A rasagiline addition salt can be obtained according to methods known in the art, for example as reported in US 5,532,415.

According to the alternative C1) an organic solvent can be any organic solvent capable of dissolving the rasagiline base formed in the subsequent step C2), for example it can be a polar or apolar, protic or aprotic solvent, as defined above , preferably methylene chloride, toluene, chloroform, acetone, tetrahydrofuran, ethyl acetate and acetonitrile, more preferably ethyl acetate.

A base of an alkaline or alkaline-earth metal can be for example an inorganic base thereof, such as a hydroxide of an alkaline or alkaline earth metal, typically a hydroxide of sodium, potassium or barium; or a carbonate or bicarbonate of an alkali or alkaline earth metal, typically sodium bicarbonate or potassium carbonate, preferably sodium bicarbonate.

The concentration up to residue of the organic solution can be carried out in accordance with methods known in the art.

The crystallization of the residue thus obtained can be carried out by first dissolving the residue in an aprotic apolar solvent, as defined above, preferably a C5-C12 alkane, more preferably cyclohexane and, if necessary, by heating the mixture thus formed, preferably in a temperature range including between 25 ° C and 85 ° C; and then by cooling the solution, to obtain a precipitate of solid rasagiline, preferably at a temperature generally comprised between -20 ° C and 40 ° C, more preferably approximately between 0 ° C and 10 ° C.

The subsequent recovery of rasagiline in crystalline form can be carried out as described above.

The size of rasagiline crystals in crystalline solid form, obtained according to the methods described here, is characterized by a value of D50 between about 25 and 250 µm, where D50 indicates the diameter of the particles such that 50% (by volume) of the sample of particles has a diameter equal to or less than the specified value. This value, if desired, can be reduced by micronization or fine milling. Rasagiline in crystalline solid form has a purity equal to or greater than 99.5%, preferably equal to or greater than 99.9%, as per HPLC determination.

Given the high purity of Rasagiline base, as obtainable with the process of the invention, this can be advantageously used for the preparation of Rasagiline salts having high purity, for example equal to or greater than 99.5%, preferably equal to or greater than 99 , 9%, as per HPLC determination.

A further object of the present invention is a pharmaceutical composition, in particular in the form of medicated plaster, preferably transdermal, comprising as the active ingredient Rasagiline base in solid form, in particular in crystalline form, substantially anhydrous, preferably as Form A, as defined herein, and a suitable carrier and / or excipient. This pharmaceutical form can be prepared according to methods known in the pharmaceutical technique.

The following example illustrates the invention.

Example. Preparation (R) -N-propargyl-aminoindane in crystalline form

(R) -Rasagiline mesylate (10.1 g, 38 mmol) is suspended in a mixture of water (50 ml) and ethyl acetate (200 ml) and treated with a saturated solution of sodium bicarbonate up to a pH range included between about 8 and 9. The phases are separated and the organic one is washed with water (2 x 50 ml) and filtered on paper, then concentrated under reduced pressure to constant weight. The oily residue obtained is treated with cyclohexane (25 ml) and the mixture obtained is heated under stirring until a clear solution is obtained. The solution is then slowly cooled and kept under stirring for 3 hours at 5 ° C. The crystals obtained are filtered, washed with cyclohexane and dried under vacuum. 5.1 g of rasagiline in crystalline solid form are obtained, with a yield of 78%; m.p. 40-41 ° C; and purity of 99.8% HPLC.

The water content in the compound determined by titration according to Karl Fischer is approximately 0.1%. The same product has a DSC trace as substantially reported in Figure 2, and an XRPD spectrum as substantially illustrated by Figure 1, where the most intense diffraction peaks are found at 8.4; 12.3; 12.4; 16.0; 16.8; 20.2; 20.9; 24.9; 25.4 and 26.3 ± 0.2 ° in 2θ.

Claims (9)

CLAIMS 1. (R) -N-Propargyl-1-aminoindane in solid form. 2. (R) -N-Propargyl-1-aminoindane, according to claim 1, in crystalline form. 3. (R) -N-Propargyl-1-aminoindane, according to claims 1 or 2, in substantially anhydrous form. 4. (R) -N-Propargyl-1-aminoindane, according to claim 3, with a water content comprised between about 0 and 0.2%. 5. (R) -N-Propargyl-1-aminoindane, according to claims 1, 2, 3 or 4 with a melting point between about 39 and 42 ° C, and an XRPD spectrum where the most intense diffraction peaks they are found at 8.4; 12.3; 12.4; 16.0; 16.8; 20.2; 20.9; 24.9; 25.4 and 26.3 ± 0.2 ° in 2θ. 6. (R) -N-Propargyl-1-aminoindane, according to claim 1, 2 or 3, having a DSC trace as substantially reported in Figure 2, and an XRPD spectrum as substantially illustrated in Figure 1. 7. Process for the preparation of (R) -N-propargyl-1-aminoindane, as defined in each of claims 1 to 6, comprising: A1) formation of a solution of rasagiline base in an organic solvent; A2) cooling the solution to obtain a precipitate; and A3) recovery of the solid; or: B1) formation of a solution of rasagiline base in an organic solvent; B2) adding an anti-solvent to the solution to obtain a precipitate; And B3) recovery of the solid obtained; or: C1) forming a mixture of a rasagiline addition salt with water and an organic solvent; C2) treatment of the mixture with an alkali or alkaline earth metal base; C3) separation of the phases and concentration of the organic solution up to the residue; C4) crystallization of the residue thus obtained from an aprotic apolar solvent; And C5) recovery of the solid obtained. 8. Pharmaceutical composition, comprising as active ingredient Rasagiline base, as defined in each of claims 1 to 6, and a carrier and / or excipient. 9. Pharmaceutical composition, according to claim 8, in the form of medicated plaster. 10. (R) -N-Propargyl-1-aminoindane, as defined in each of claims 1 to 6, having a purity equal to or greater than 99.5%. Milan, 29 July 2008