Preparation of crystalline form of Anti-parkinsonian drug

Abstract

To provide a novel and safe method for preparing crystalline form I of benserazide hydrochloride, which allows high yield and reduced presence of impurities, particularly non-toxic solvents, making the method highly suitable for industrial production.SOLUTION: A method for preparing crystalline form I of benserazide hydrochloride of formula (I) comprises: forming a dispersion of crystalline form VI of benserazide hydrochloride of formula (I) in ethanol or a mixture of ethanol and isopropanol; holding the dispersion in ethanol or the mixture of ethanol and isopropanol for two hours or longer; and recovering benserazide hydrochloride of formula (I) in crystalline form I.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to the preparation of crystalline forms of DOPA decarboxylase inhibitors. [Background technology]

[0002] Technical level: 2-Amino-3-hydroxy-N'-(2,3,4-trihydroxybenzyl)propanehydrazide hydrochloride is a compound represented by the formula (I) [ka] It is also known as benserazide hydrochloride of formula (I) and is used in combination with L-DOPA to treat Parkinson's disease. Benserazide hydrochloride of formula (I) inhibits the conversion of L-DOPA to dopamine in extracerebral tissues, and thus can suppress the occurrence of extracerebral side effects.

[0003] Benserazide hydrochloride of formula (I) can be prepared starting from DL-serine as described in WO 02 / 04391 (Scheme 1). Reaction of 2,3,4-trihydroxybenzaldehyde with DL-serinoidazide monohydrochloride in water, methanol, ethanol or mixtures thereof gives the dihydrate form of (DL)-2-amino-3-hydroxy-N-[(E)-(2,3,4-trihydroxyphenyl)methyleneamino]propanamide. If the reaction is carried out in an anhydrous solvent such as absolute ethanol, the anhydrous form of the hydrazone is obtained. Subsequent hydrogenation over Pd / C in methanol gives benserazide hydrochloride of formula (I). [ka]

[0004] Commercially available tablet formulations of benserazide hydrochloride of formula (I) contain the compound in crystalline form I. The XRPD of crystalline form I is reported in US Pat. No. 5,399,633. Patent document 2 describes additional crystalline forms of benserazide hydrochloride of formula (I), such as crystalline form VI or a DMF solvate named crystalline form IX, obtained by recrystallization from an aqueous solution of ethanol (90%) and 1-propanol. The DMF solvate crystalline form IX is not a suitable crystalline form for preparing pharmaceutical preparations. According to the ICH guidelines on residual solvents present in active pharmaceutical ingredients, DMF is a class 2 solvent. US Patent No. 5,999,633 also describes the preparation of crystalline Form I by treating the DMF solvate with a mixture of aqueous ethanol (90%) and 1-propanol. The resulting product is washed with 1-propanol until no DMF is detected by HPLC analysis. However, HPLC analysis is not suitable for finding traces of DMF.

[0005] For example, Non-Patent Document 1 developed an HPLC method for measuring DMF and reported a detection limit of 0.019% (Non-Patent Document 1).

[0006] Furthermore, in light of the recently published EU regulation, EU2021 / 2030, legislators are seeking to minimize the use of DMF and there is a need to identify DMF-free methods. As a result, due to the toxicity of DMF, there is a need for alternative methods for the preparation of crystalline form I of benserazide hydrochloride that are efficient, cost-effective, and suitable for industrial-scale production and purification. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] U.S. Patent No. 3,178,476 [Patent Document 2] International Publication No. 2015 / 197909 [Non-patent literature]

[0008] [Non-Patent Document 1] Gan et al.Se Pu.2011,Feb;29(2):184-6.doi:10.3724 / sp.j.1123.2011.00184. Summary of the Invention [Problem to be solved by the invention]

[0009] The authors of the present invention have found a novel and safe method for preparing crystalline form I of benserazide hydrochloride of formula (I). This method is particularly suitable for industrial production due to the high yield and the low presence of impurities, especially non-toxic solvents. This new method provides a pure product suitable for meeting the regulatory requirements mandated for active pharmaceutical ingredients (API). The procedure disclosed herein for preparing benserazide hydrochloride of formula (I) in crystalline form I does not use methanol and / or DMF as crystallization solvents, and even if a solvent is used during the synthesis of benserazide hydrochloride of formula (I), methanol can be removed from the finished product. [Means for solving the problem]

[0010] overview: In a first aspect, the present invention provides a compound of formula (I) [ka] The present invention relates to a novel process for the preparation of crystalline form I of benserazide hydrochloride of formula (I) (characteristic XRPD peaks, measured using CuKα radiation, are found at 7.6°, 11.0°, 12.2°, 18.5°, 18.9°, 21.8°, 23.1°, 24.6° and 25.4°±0.2° in terms of 2θ) starting from crystalline form VI of benserazide hydrochloride of formula (I) (characteristic XRPD peaks, measured using CuKα radiation, are found at 18.6, 22.7, 23.0, 25.5, 27.2, 27.9, 33.1 and 34.6°±0.2° in terms of 2θ). Effect of the Invention

[0011] This procedure is particularly suitable for obtaining crystalline form I of benserazide hydrochloride of formula (I) which is methanol-free or has a methanol content below 500 ppm (parts per million), the limit permitted by the ICH guidelines for residual solvents. [Brief description of the drawings]

[0012] Brief description of the drawings and analytical methods: The crystalline forms I, VI and α of benserazide hydrochloride of formula (I) were characterized by X-ray powder diffraction (XRPD). The water content was determined by titration according to the Karl Fischer method. X-ray diffraction spectra (XRPD) were performed using a Bruker D8 Advance diffractometer with a goniometer radius of 280 mm under the following conditions: CuKα radiation was filtered with a nickel filter (λ = 1.54 Å) and scanned in Bragg-Brentano geometry over the angular range 3–40° in 2θ with an angular pitch of 0.02°. The obtained diffractograms were evaluated using Diffrac.Eva version 4.3.0.1 (Bruker AXS).

[0013] [Figure 1] XRPD spectrum of crystalline form I of benserazide hydrochloride of formula (I). [Diagram 2] XRPD spectrum of crystalline form VI of benserazide hydrochloride of formula (I). [Diagram 3] 1 is an XRPD spectrum of crystalline form α of benserazide hydrochloride of formula (I). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Detailed Description: In a first aspect, the present invention provides a compound of formula (I) [ka] The present invention relates to a novel process for the preparation of crystalline form I of benserazide hydrochloride of formula (I) (characteristic XRPD peaks, measured using CuKα radiation, are found at 7.6°, 11.0°, 12.2°, 18.5°, 18.9°, 21.8°, 23.1°, 24.6° and 25.4°±0.2° in terms of 2θ) starting from crystalline form VI of benserazide hydrochloride of formula (I) (characteristic XRPD peaks, measured using CuKα radiation, are found at 18.6, 22.7, 23.0, 25.5, 27.2, 27.9, 33.1 and 34.6°±0.2° in terms of 2θ).

[0015] This procedure is particularly suitable for obtaining crystalline form I of benserazide hydrochloride of formula (I) which is methanol-free or has a methanol content below 500 ppm (parts per million), the limit permitted by the ICH guidelines for residual solvents.

[0016] Crystalline Form I of benserazide hydrochloride of formula (I) has been characterized by X-ray diffraction and characteristic XRPD peaks measured using CuKα radiation substantially as shown in FIG. 1, and is characterized by the following characteristic peaks:

[0017] [Table 1]

[0018] The crystalline form VI of benserazide hydrochloride of formula (I) is characterized by XRPD substantially as shown in FIG.

[0019] According to one embodiment, the compound of formula (I) [ka] The crystalline form I of benserazide hydrochloride (having characteristic XRPD peaks measured using CuKα radiation at 7.6°, 11.0°, 12.2°, 18.5°, 18.9°, 21.8°, 23.1°, 24.6° and 25.4°±0.2° in 2θ) is prepared by a method comprising: - forming a dispersion of crystalline form VI of benserazide hydrochloride of formula (I) (characteristic XRPD peaks measured using CuKα radiation are found at 18.6, 22.7, 23.0, 25.5, 27.2, 27.9, 33.1 and 34.6°±0.2° in 2θ) in ethanol or a mixture of ethanol and isopropanol, - maintaining the dispersion in ethanol or a mixture of ethanol and isopropanol for 2 hours or for more than 2 hours; and - recovering benserazide hydrochloride of formula (I) in crystalline form I.

[0020] According to the present invention, the term "comprising" means that additional reaction steps may be present, but do not substantially modify the product resulting from the process. The term "comprising" also includes the terms "consisting of" and "essentially consisting of."

[0021] According to the present invention, the term "forming a dispersion of benserazide hydrochloride of formula (I) in crystalline form VI" as used herein means a partial dissolution of crystalline form VI of benserazide hydrochloride of formula (I), and thus the dispersion of crystalline form VI of benserazide hydrochloride of formula (I) does not lead to a complete dissolution of crystalline form VI of benserazide hydrochloride of formula (I).

[0022] According to the Japanese Pharmacopoeia, benserazide hydrochloride of formula (I) is soluble in water and formic acid, soluble in methanol, but only very slightly soluble in ethanol.

[0023] The residual methanol content of benserazide hydrochloride of formula (I) in crystalline form VI used to prepare crystalline form I, as measured by GC-HS, may be about 50,000 ppm or less, such as 20,000 ppm or less, 10,000 ppm or less, 5,000 ppm or less, or 1,000 ppm or less.

[0024] In one embodiment, the residual methanol content of benserazide hydrochloride of formula (I) in crystalline form VI used in preparing crystalline form I, as measured by GC-HS, may be about 1 to about 20,000 ppm, for example, about 10 to about 10,000 ppm or 50 to 5,000 ppm.

[0025] The ratio of crystalline form VI of benserazide hydrochloride of formula (I) to ethanol or a mixture of ethanol and isopropanol may be from 0.1% to 70% (w:w, weight:weight), preferably from 1% to 50%, for example 5%, 10%, 15%, 20%, 25%, 30%, 35% or 40% (w:w).

[0026] Dispersion of crystalline form VI of benserazide hydrochloride of formula (I) in ethanol or in a mixture of ethanol and isopropanol can be advantageously carried out at a temperature of about 15°C to about 30°C, preferably about 15°C to about 25°C, for example about 20°C or about 25°C.

[0027] The dispersion of crystalline form VI of benserazide hydrochloride of formula (I) in ethanol or in a mixture of ethanol and isopropanol may be maintained for 2 hours or for more than 2 hours, for example, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 14 hours, 16 hours, 18 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 96 hours or 144 hours.

[0028] In one embodiment, a dispersion of crystalline Form VI of benserazide hydrochloride of formula (I) in ethanol or a mixture of ethanol and isopropanol may be stirred for 8 hours, 16 hours or 24 hours.

[0029] In one embodiment, the dispersion of crystalline Form VI of benserazide hydrochloride of formula (I) can be carried out in ethanol.

[0030] In one embodiment, the formation of a dispersion of crystalline Form VI of benserazide hydrochloride of formula (I) can be carried out in a mixture of ethanol and isopropanol.

[0031] In one embodiment, the formation of a dispersion of crystalline Form VI of benserazide hydrochloride of formula (I) can be carried out in a mixture consisting of ethanol and isopropanol.

[0032] The ratio of ethanol to isopropanol can be about 1:1000 to 1000:1 (v:v, volume:volume).

[0033] The ratio of ethanol to isopropanol is between about 1:1000 to 1000:1 (v:v), for example, about 1:100 to 100:1 (v:v) or 10:1 to 1:10 (v:v), for example, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8 or 1:9 (v:v).

[0034] The ratio of ethanol to isopropanol can be, for example, about 1:100 to 100:1 (v:v).

[0035] The ratio of ethanol to isopropanol can be, for example, about 10:1 to 1:10 (v:v).

[0036] The ratio of ethanol to isopropanol can be, for example, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1 or 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10 (v:v).

[0037] In a preferred embodiment, the ratio between ethanol and isopropanol can be, for example, about 1:100 to 100:1 (v:v), more preferably about 10:1 to 1:10 (v:v), such as 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8 or 1:9 (v:v).

[0038] The suspension of benserazide hydrochloride of formula (I) in ethanol or in a mixture of ethanol and isopropanol can be optionally cooled, for example, to about 5°C to about 25°C, preferably about 7°C to about 25°C, for example, to about 10°C, about 15°C, about 20°C or about 25°C.

[0039] Optionally, previously obtained seeds of crystalline form I of benserazide hydrochloride of formula (I) can be added to the suspension of benserazide hydrochloride of formula (I) in ethanol or in a mixture of ethanol and isopropanol.

[0040] Recovery of the solid consisting of crystalline form I of benserazide hydrochloride of formula (I) can be carried out according to known techniques, for example by filtration or centrifugation, preferably by filtration.

[0041] The crystalline form I of benserazide hydrochloride of formula (I) can be dried according to known methods, for example, drying can be carried out under reduced pressure in air or a nitrogen stream.

[0042] In a preferred embodiment, the drying is carried out at a pressure of less than 0.5 bar. The drying temperature can be from room temperature to 70°C, preferably from 25°C to 60°C, for example, 40°C, 45°C or 50°C.

[0043] The crystal size of the crystalline form I of benserazide hydrochloride of formula (I) obtained according to the described procedure is characterized by a D50 value between 5 μm and 250 μm. If necessary, the size can be reduced by a micronization step or by milling / grinding.

[0044] The crystalline form I of benserazide hydrochloride of formula (I) obtainable according to the present invention has a high purity, typically ≧99% (area) as measured by HPLC at 210 nm, and impurities are present in an amount of ≦0.1%, preferably ≦0.05%, as measured by HPLC at 210 nm.

[0045] The resulting crystalline form I of benserazide hydrochloride of formula (I) has a water content of about 0 to about 1% (w:w), preferably about 0.05 to 0.9% (w:w), and can be defined as substantially anhydrous.

[0046] Furthermore, by virtue of the fact that no methanol or DMF is used for the crystallization procedure of benserazide hydrochloride, the obtained crystalline form I of benserazide hydrochloride of formula (I) is free of methanol or has a methanol content of less than 500 ppm, preferably less than 300 ppm, more preferably less than 100 ppm, e.g., 0 ppm, 4.5 ppm, 10 ppm or 50 ppm.

[0047] A further aspect of the present invention relates to a crystallization process for the preparation of benserazide hydrochloride of formula (I) without the use of methanol or DMF as solvent.

[0048] A further aspect of the present invention relates to a crystallization process for the preparation of benserazide hydrochloride of formula (I) without the use of methanol and DMF as solvents.

[0049] Crystalline form VI of benserazide hydrochloride of formula (I) is described in WO 2005 / 023991 and its preparation from a DMF solvate, also referred to as crystalline form IX, is described.

[0050] Although according to ICH guidelines DMF is included in the group of solvents to be avoided (DMF is a member of class 2 solvents), the inventors have surprisingly found a method for preparing crystalline Form VI and Form I of benserazide hydrochloride of formula (I) using only water, ethanol and isopropanol.

[0051] In one embodiment, the crystalline form VI of benserazide hydrochloride of formula (I) can be prepared by a process comprising: - forming a solution of benserazide hydrochloride of formula (I) in water, - adding isopropanol to the resulting aqueous solution; - recovering benserazide hydrochloride of formula (I) in crystalline form VI.

[0052] The benserazide hydrochloride of formula (I) used as the starting material for the crystalline form VI of benserazide hydrochloride of formula (I) can be in any known form.For example, it can be amorphous or crystalline benserazide hydrochloride.For example, the benserazide hydrochloride of formula (I) can be in crystalline form I.

[0053] The dissolution of benserazide hydrochloride of formula (I) in water can be carried out advantageously at a temperature of about 15°C to about 30°C, preferably about 15°C to about 25°C, for example, about 20°C or about 25°C.

[0054] Dissolution of benserazide hydrochloride of formula (I) in water can advantageously be carried out within 15 minutes or more than 15 minutes, for example within 30 minutes, within 45 minutes, within 1 hour, within 2 hours, within 3 hours, within 4 hours or within 5 hours.

[0055] In one embodiment, the dissolution time of benserazide hydrochloride of formula (I) in water before the addition of isopropanol is 15 minutes or more than 15 minutes, for example 30 minutes, 45 minutes, 1 hour or 2 hours. In one embodiment, the dissolution time of benserazide hydrochloride of formula (I) in water before the addition of isopropanol is less than 2 hours. In a preferred embodiment, the dissolution time of benserazide hydrochloride of formula (I) in water before the addition of isopropanol is less than 1 hour.

[0056] In one embodiment, the ratio between water and isopropanol can be, for example, between about 1000:1 and 1:2 (v:v), such as 100:1, 10:1 or 1:1 (v:v).

[0057] The suspension of benserazide hydrochloride of formula (I) in water and isopropanol can optionally be cooled, for example, to about 5°C to 25°C, preferably about 7°C to about 25°C, for example, to about 10°C, about 15°C, about 20°C or about 25°C.

[0058] The suspension of benserazide hydrochloride of formula (I) in water and isopropanol can be stirred for 1 hour or for more than 1 hour, for example, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18 hours, 24 hours, 48 ​​hours, 72 hours or 96 hours.

[0059] Before separating the solid, the solution can be cooled to increase the yield. The solution can be cooled to a temperature of about 20° C. or less, preferably about 0° C. to about 20° C., more preferably about 5° C. to about 10° C. The cooling can be performed slowly, for example, at a rate of about 0.1° C. to 0.4° C. per minute.

[0060] If necessary, seeds of previously obtained desired crystal form can be added.

[0061] Isolation of the solid consisting of crystalline form VI of benserazide hydrochloride of formula (I) can be carried out by known techniques, such as filtration or centrifugation, preferably filtration.

[0062] The crystalline form VI of benserazide hydrochloride of formula (I) can be dried according to known methods, for example, drying can be carried out under reduced pressure in air or a nitrogen stream.

[0063] Preferably, the drying is carried out at a pressure of less than or equal to 0.5 bar. The drying temperature can be from room temperature to 70°C, preferably from 25°C to 55°C, for example, 45°C.

[0064] In another aspect, the present disclosure provides crystalline form α of formula (I), [ka] Regarding the crystalline form of benserazide hydrochloride,

[0065] According to a further embodiment, the characteristic XRPD peaks for crystalline form α of Benserazide hydrochloride of formula (I), obtained using CuKα radiation, are found at 8.6, 9.2, 13.9, 17.2 and 18.4°±0.2° in 2θ.

[0066] In a preferred embodiment, the crystalline form α of benserazide hydrochloride of formula (I) is characterized by XRPD substantially as shown in Figure 3 and comprises peaks at substantially the following positions in degrees 2θ: 7.1, 12.8, 16.3, 20.1, 20.7, 21.3, 21.6, 22.6, 23.4, 24.0, 24.5, 25.1, 25.5, 25.8, 26.1, 26.8, 27.7, 28.0, 28.3, 29.0, 29.2, 29.9, 31.7, 32.5 and 33.1°±0.2° in terms of 2θ obtained using CuKα radiation.

[0067] According to a further embodiment, the crystalline form α of benserazide hydrochloride of formula (I) is characterized by X-ray diffraction, wherein the characteristic XRPD peaks measured using CuKα radiation are substantially as shown in FIG. 3 and are characterized by the following characteristic peaks:

[0068] [Table 2]

[0069] According to a further embodiment, the compound of formula (I) [ka] The crystalline form α of benserazide hydrochloride can be prepared by a process comprising: - forming a solution of benserazide hydrochloride of formula (I) in water, - adding isopropanol to the resulting aqueous solution (the ratio of water to isopropanol may be, for example, between about 1:3 and 1:100 (v:v)); and - recovering benserazide hydrochloride of formula (I) in crystalline form α.

[0070] The benserazide hydrochloride of formula (I) used as starting material can be one of the known forms, it can be amorphous or crystalline benserazide hydrochloride.For example, the benserazide hydrochloride of formula (I) can be crystalline form I.

[0071] The ratio of benserazide hydrochloride of formula (I) to water can be 0.1% to 70% (w:w), preferably 10% to 50% (w:w), for example, 15%, 20%, 25%, 30%, 35% or 40% (w:w).

[0072] The dissolution of benserazide hydrochloride of formula (I) in water can be advantageously carried out at, for example, about 15°C to about 30°C, preferably about 15°C to about 25°C, for example, about 20°C or about 25°C.

[0073] Dissolution of benserazide hydrochloride of formula (I) in water can advantageously be carried out within 15 minutes or more than 15 minutes, for example within 30 minutes, within 45 minutes, within 1 hour, within 2 hours, within 3 hours, within 4 hours or within 5 hours.

[0074] In one embodiment, the dissolution time of benserazide hydrochloride of formula (I) in water before the addition of isopropanol is 15 minutes or more than 15 minutes, for example 30 minutes, 45 minutes, 1 hour or 2 hours. In one embodiment, the dissolution time of benserazide hydrochloride of formula (I) in water before the addition of isopropanol is less than 2 hours. In a preferred embodiment, the dissolution time of benserazide hydrochloride of formula (I) in water before the addition of isopropanol is less than 1 hour.

[0075] The ratio of benserazide hydrochloride of formula (I) to isopropanol can be from 0.1 g to 50 g of benserazide hydrochloride of formula (I) per 100 mL of isopropanol, preferably from 2 g to 30 g, for example, 5 g, 10 g, 15 g or 20 g of benserazide hydrochloride of formula (I) per 100 mL of isopropanol.

[0076] The ratio of water to isopropanol can be, for example, about 1:3 to 1:100 (v:v), preferably about 1:3 to 1:50 (v:v), for example, 1:4 (v:v) or 1:5 (v:v).

[0077] The solution containing benserazide hydrochloride of formula (I) in water and isopropanol can be optionally cooled, for example, to about 5°C to about 25°C, preferably about 7°C to about 25°C, for example, to about 10°C, about 15°C, about 20°C or about 25°C.

[0078] The suspension of benserazide hydrochloride of formula (I) in water and isopropanol can be maintained for 1 hour or for more than 1 hour, for example, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18 hours, 24 hours, 48 ​​hours, 72 hours or 96 hours.

[0079] Before separation, the dispersion can be cooled to increase the yield. The dispersion can be cooled to a temperature of about 20° C. or less, preferably about 0° C. to about 20° C., more preferably about 5° C. to about 10° C. Cooling can be performed slowly, for example, at a rate of about 0.1° C. to 0.4° C. per minute.

[0080] If necessary, previously obtained seeds can be added.

[0081] Isolation of the solid consisting of crystalline form α of benserazide hydrochloride of formula (I) can be carried out by known techniques, such as filtration or centrifugation, preferably filtration.

[0082] The crystalline form α of benserazide hydrochloride of formula (I) can be dried according to known methods, for example, the drying step can be carried out under reduced pressure or under a stream of air or nitrogen.

[0083] Preferably, the drying is carried out at a pressure of less than or equal to 0.5 bar. The drying temperature can be from room temperature to 70°C, preferably from 25 to 55°C, for example, 45°C.

[0084] Crystalline form α of benserazide hydrochloride of formula (I) prepared according to the present disclosure has a high purity, typically ≧99%, as measured by HPLC at 210 nm.

[0085] The obtained crystalline form α of benserazide hydrochloride of formula (I) has a water content of about 0 to about 1% (w:w), preferably about 0.05 to 0.9% (w:w), and can be defined as substantially anhydrous.

[0086] A further aspect of the present disclosure relates to a pharmaceutical composition comprising, as an active ingredient, crystalline form α of benserazide hydrochloride of formula (I), one or more pharma- ceutically acceptable excipients and / or vehicles. EXAMPLES

[0087] The following examples further illustrate the invention.

[0088] Example 1. Preparation of crystalline form I of benserazide hydrochloride of formula (I): 20 g (61 mmol) of 2-amino-3-hydroxy-N-[(E)-(2,3,4-trihydroxyphenyl)methyleneamino]propenamide, which can be prepared by treating 2,3,4-trihydroxybenzaldehyde with DL-serinoidazide monohydrochloride as described in US Pat. No. 5,999,363, and 1.3 g of Pd / C in 460 mL of methanol are placed in a 500 mL four-neck flask equipped with a magnetic stirrer at 25° C. The mixture is then vigorously stirred under a hydrogen atmosphere at ambient conditions for 6 hours. The suspension is then cooled to 5° C. and filtered through Celite. The panel is washed with 20 mL of methanol and the combined solution is concentrated by vacuum distillation until a pale orange oily residue is obtained. 100 mL of ethanol is added to the oily residue at 25 °C and the pale orange mixture is stirred at an internal temperature of 25 °C. After about 30-60 min, an off-white solid is formed. The mixture is stirred protected from light for 6 h and then the solid is filtered. The panel is washed twice with 20 mL of ethanol and the collected white / off-white solid is dried in an oven at 45 °C for 8 h to give 13.4 g (75% yield) of benserazide hydrochloride of formula (I) in crystalline form I. The residual methanol amount measured by GC-HS was 2500 ppm.

[0089] Example 2. Preparation of crystalline form VI of benserazide hydrochloride of formula (I): 20 g (61 mmol) of 2-amino-3-hydroxy-N-[(E)-(2,3,4-trihydroxyphenyl)methyleneamino]propenamide, which can be prepared by treating 2,3,4-trihydroxybenzaldehyde with DL-serinoidazide monohydrochloride as described in US Pat. No. 5,999,363, and 3 g of Pd / C in 460 mL of methanol are charged at 25° C. in a 1000 mL four-neck flask equipped with a magnetic stirrer. The mixture is then vigorously stirred under a hydrogen atmosphere at ambient conditions for 6 hours. The suspension is then cooled to 5° C. and filtered through Celite. The panel is washed with 20 mL of methanol and the combined solution is concentrated by vacuum distillation until a pale orange oily residue is obtained. 40 mL of water is added to the residue at 25 °C and 40 mL of isopropanol is added within 30 min. The clear pale yellow solution is stirred at 25 °C for 16 h. Optionally, 0.02 g of seeds of crystalline form VI of benserazide hydrochloride of formula (I) may be added to the solution. The suspension is cooled to 3 °C at a rate of 10 °C per hour and kept at 3 °C for 2 h. The solid is then filtered off and the panel is washed with 20 mL of an isopropanol / water mixture (5:1, v:v) and 20 mL of isopropanol and dried in an oven at 45 °C for 16 h to obtain crystalline form VI of benserazide hydrochloride of formula (I) having a white / off-white color (70% yield). The product is a monohydrate with a water content of 5-6% and a purity of 99.40% by Karl Fischer analysis (HPLC detector at 210 nm). The residual methanol amount measured by GC-HS was 900 ppm.

[0090] Example 3. Preparation of crystalline form I of benserazide hydrochloride of formula (I): 20 g (0.064 mol) of crystalline form VI of benserazide hydrochloride of formula (I), obtained as described in Example 2, and 200 ml of a mixture of ethanol and isopropanol (1:1, v:v) are charged at 25° C. into a 500 mL four-necked reactor equipped with a mechanical stirrer, reflux condenser, thermometer and under nitrogen atmosphere. The suspension is stirred at 25° C. for 16 hours and then filtered. The panel is washed twice with 20 mL of an isopropanol / ethanol mixture (1:1, v:v) and the resulting white / off-white solid is dried in vacuum at 50° C. for 8 hours to give 17.9-18.6 g of crystalline form I of benserazide hydrochloride of formula (I) (yield 95-99%) with a water content of <1% and a purity of 99.51% (HPLC detector at 210 nm) as determined by Karl Fischer analysis. The residual methanol content measured by GC-HS is 0-5 ppm.

[0091] Example 4. Preparation of crystalline form α of benserazide hydrochloride of formula (I): 30 g (0.10 mol) of crystalline form I of benserazide hydrochloride of formula (I), obtained as described in Example 1, and 60 mL of water are placed in a 500 mL four-necked reactor equipped with a mechanical stirrer, reflux condenser, thermometer and under nitrogen atmosphere at 25 °C. 300 mL of isopropanol are added to the pale yellow solution at 20-25 °C and the mixture is stirred at 20-25 °C until a precipitate forms. After stirring for another 4 hours at 20-25 °C, the resulting precipitate is filtered. The panel is washed twice with 30 mL of isopropanol and the recovered white / off-white solid is dried in vacuum at 45 °C for 16 hours to give 24.9 g (83% yield) of crystalline form α of benserazide hydrochloride of formula (I) with a water content of 0.68% and a purity of 99.22% (HPLC detector at 210 nm) as determined by Karl Fischer analysis.

[0092] Example 5. Preparation of crystalline form α of benserazide hydrochloride of formula (I): 30 g (0.10 mol) of crystalline form I of benserazide hydrochloride of formula (I), obtained as described in Example 1, and 75 mL of water are placed in a 100 mL four-necked reactor equipped with a mechanical stirrer, reflux condenser, thermometer and under nitrogen atmosphere at 25 °C. 300 mL of isopropanol are added to the pale yellow solution at 20-25 °C and the mixture is stirred at 20-25 °C until a precipitate forms. After stirring at 20-25 °C for another 4 hours, the product obtained is filtered. The panel is washed twice with 30 mL of isopropanol and the white / off-white solid recovered is dried under vacuum at 45 °C for 16 hours to obtain 24 g (80% yield) of crystalline form α of benserazide hydrochloride of formula (I) with a water content of 0.89% and a purity of 99.24% (HPLC detector at 210 nm) as determined by Karl Fischer analysis. Residual methanol content measured by GC-HS is 4.5 ppm.

[0093] Example 6. Crystalline form α of benserazide hydrochloride of formula (I): Crystalline form α of benserazide hydrochloride of formula (I), prepared as described in Example 4 or 5, does not convert to another polymorph when suspended in a mixture of ethanol and isopropanol (1:1, v:v) or in isopropanol according to the conditions described in Example 3. Crystalline form α of benserazide hydrochloride of formula (I) is also stable in a water / ethanol / isopropanol mixture (0.02:1:1, v:v:v) or in a water / isopropanol mixture (0.01:1, v:v). Thus, contrary to crystalline form VI of benserazide hydrochloride of formula (I), crystalline form I of benserazide hydrochloride of formula (I) cannot be prepared by suspending crystalline form α in ethanol / isopropanol or in isopropanol, both in the presence or absence of water.

Claims

1. Formula (I) 【Chemistry 1】 1. A process for preparing crystalline form I of benserazide hydrochloride of formula (having characteristic XRPD peaks at 7.6°, 11.0°, 12.2°, 18.5°, 18.9°, 21.8°, 23.1°, 24.6° and 25.4°±0.2° in degrees 2θ, as measured using CuKα radiation), comprising: - forming a dispersion of crystalline form VI of benserazide hydrochloride of formula (I) (characteristic XRPD peaks, measured using CuKα radiation, are found at 18.6, 22.7, 23.0, 25.5, 27.2, 27.9, 33.1 and 34.6°±0.2° in 2θ) in ethanol or a mixture of ethanol and isopropanol; - keeping said dispersion in ethanol or a mixture of ethanol and isopropanol for 2 hours or for more than 2 hours; and - recovering benserazide hydrochloride of formula (I) in crystalline form I.

2. The process according to claim 1, wherein the dispersion of benserazide hydrochloride of formula (I) in ethanol or in a mixture of ethanol and isopropanol is carried out at temperatures between 15°C and 30°C.

3. 2. The method according to claim 1, wherein the dispersion of crystalline form VI of benserazide hydrochloride of formula (I) is carried out in a mixture consisting of ethanol and isopropanol.

4. 4. The method of claim 3, wherein the ratio of ethanol to isopropanol is from 1:1000 to 1000:1 (v:v).

5. 4. The method of claim 3, wherein the ratio of ethanol to isopropanol is from 1:10 to 10:

1.

6. 10. The method of claim 1, wherein no methanol is used.

7. 10. The method of claim 1 further comprising: - forming a solution of benserazide hydrochloride of formula (I) in water, - adding isopropanol to the aqueous solution obtained; - recovering benserazide hydrochloride of formula (I) in crystalline form VI.

8. 8. The method of claim 7, wherein the ratio of water to isopropanol is from 1000:1 to 1:2 (v:v).

9. 2. The crystalline form I of benserazide hydrochloride of formula (I) according to claim 1, wherein the content of methanol is less than or equal to 500 ppm relative to the content of benserazide hydrochloride.

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