Field of the invention

The present invention relates to the process for preparation of prasugrel hydrochloride polymorphic form B of pharmaceutical purity.

Prasugrel, 5-[2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl acetate, is a P2Y12 inhibitor of ADP-induced platelet aggregation. It is indicated for the reduction of thrombotic cardiovascular events in patients with acute coronary syndromes managed with percutaneous coronary intervention (PCI), when managed with primary or delayed PCI. Background of the invention

Hydrochloric acid addition salt of 5-[2-Cyclopropyl-l-(2-fluorophenyl)-2- oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate is the active ingredient of Effient® tablets. Prasugrel hydrochloride has been claimed in EP 1 298 132 Bl as the substance exhibiting excellent oral absorption, activity in inhibition of platelet aggregation after being metabolized into the active substance, low cytotoxicity, and excellent handling and storage stability. In the same EP 1 298 132 Bl patent there has been disclosed the process for preparation of prasugrel hydrochloride in the reaction of prasugrel base and concentrated hydrochloric acid in acetone. Depending on reaction temperature, prasugrel hydrochloride crystallizes in polymorphic forms A, B 1 or B2, which are characterized by different melting points, mass and IR spectra. X-Ray powder diffraction patterns of polymorphic forms A, Bl and B2 obtained according to the procedures disclosed in EP 1 298 132 Bl, have been reprinted in the patent application EP 2 003 136 Al. The interplanar distances d of the same values, ie. 6,6; 6,1 ; 4,0; 3,5 i 3,4 A, for both crystalline forms Bl and B2, presented therein were determined by X-ray powder diffraction obtained with copper radiation source of Koc 1 ,54 A wave length.

In EP 2 145 890 Bl X-ray powder diffraction pattern of polymorphic form B has been presented. Recalculation of d values into their corresponding diffraction angles 2Θ in the presented XRPD pattern proved its identity to XRPD patterns of polymorphic forms Bl and B2 disclosed in EP 2 003 136 Al. WO 2009/062044 discloses the other polymorphic forms C, D and E of prasugrel hydrochloride. Prasugrel hydrochloride crystalline form C was obtained by the addition of the compound being the hydrochloride source to prasugrel free base dissolved in butan-2- ol, followed by collecting and drying of the precipitated crystals. In the similar manner crystalline forms D and E were obtained, carrying out the reaction in propan-2-ol or ethyl acetate, respectively.

In the International patent application WO 2010/070677 amorphous form and two further crystalline forms Gl and G2 of prasugrel hydrochloride have been described. Crystalline form Gl was obtained by dissolving prasugrel hydrochloride in a solvent or in the solvents mixture selected from a group comprising methyl alcohol, dichloromethane, ethyl acetate, isobutyl acetate, acetonitrile, THF, 1,4-dioxane or the mixture thereof with water, followed by the solid precipitation induced by non-polar anti-solvent addition, wherein anti-solvent was selected from a group including, inter alia, n-hexane, n-heptane, cyclohexane, toluene or the mixtures thereof. In the enclosed preparative example, addition of cyclohexane to the solution of prasugrel hydrochloride in dichloromethane yielded crystalline form Gl . Crystalline form G2 was obtained under similar conditions, i.e. by dissolving prasugrel hydrochloride in a solvent or in a mixture of solvents selected from a group comprising methyl alcohol, ethanol, isopropanol, dichloromethane, ethyl acetate, isobutyl acetate, acetonitrile, THF, 1,4-dioxane or the mixture thereof with water and adding anti-solvent selected from the group comprising n-hexane, n-heptane, cyclohexane, toluene or the mixture thereof. In the example, crystalline form G2 was obtained by the addition of hexane as anti-solvent to the solution of prasugrel hydrochloride in isopropyl alcohol under reflux.

In the International patent application WO 2011/117782 formation of another prasugrel hydrochloride crystalline form, characterized by X-ray powder diffraction pattern, IR spectrum and differential scanning calorimetry thermogram, obtained by the addition of hydrochloride solution in isopropyl alcohol to the solution of prasugrel hydrochloride in methyl ketone, has been described.

The attempts to reproduce the aforementioned methods, enabled the authors of the present invention to determine the actual number of existing polymorphic and pseudo- polymorphic forms of prasugrel hydrochloride on the basis of comparative analysis of X- ray powder diffraction patterns (XRPD). The comparative analysis of X-ray powder diffraction patterns of polymorphic form A, presented in the patent application EP 2 003 136 Al and polymorphic form C disclosed in WO 2009/062044 as well as Gl and G2 forms disclosed in WO 2010/070677, is depicted on Fig. 1. Additional peaks, which appear on XRPDs of polymorphic forms C, Gl and G2 in comparison with polymorphic form A X-ray diffraction pattern are circled and pointed with arrows. The presence of additional peaks on polymorphic forms C, Gl and G2 XRPDs, which are not observed on polymorphic form A XRPD pattern, may be attributed to the presence of some crystalline contaminations. For crystalline forms A, C, Gl and G2 the differences of diffraction angle 20 values are at the error range (±0,2°), acceptable by the European Pharmacopeia. It proves the identity of those four crystalline forms, which will be denominated under the common name as polymorphic form A through the following description.

On Fig. 2 two XRPD patterns of polymorphic forms B 1 and B2 reproduced from the patent application EP 2 003 136 Al and XRPD patterns of polymorphic forms D and E from WO 2009/062044 as well as XRPD patterns of polymorphic form B from EP 2 145 890 Al are depicted for comparative analysis. All XRPD patterns of the aforementioned crystalline forms show close resemblance. Additional peaks, which appear on polymorphic forms D and E XRPD patterns are pointed with arrows. On account of low quality of the XRPD patterns and low intensities of additional peaks, the absence of these peaks on the other polymorphic forms XRPD patterns cannot be ascertained. The differences of diffraction angle 20 values of polymorphic form Bl and B2 (recalculated from interplanar distance d values), and polymorphic form D and E are at the error range (±0,2°), acceptable by the European Pharmacopoeia and prove the identity of those four crystalline forms, which will be denominated under the common name as polymorphic form B through the following description.

Experimental work carried out by the authors of the present invention has proved that prasugrel hydrochloride can exist in two polymorphic forms: A and B, amorphous form and as the solvate with acetonitrile, which was disclosed in EP 2 145 890 B.

Analysis of XRPD and DSC data obtained in the stability experiments performed undeLnormal and accelerated aging conditions of the crystals, indicate, that among the other polymorphic forms, form B shows the highest stability under thermal and photolytical degradation conditions as well as the lowest hygroscopicity. Considering these physicochemical properties, form B only meets the requirements for active substance to be used in an output of solid oral dosage forms of the pharmaceutical products.

To encompass the discussed difficulties, the authors of the present invention aimed at working out the large-scale synthesis of pharmaceutically favorable prasugrel hydrochloride polymorphic form B of high purity, which will meet the demands for active pharmaceutical ingredients.

According to European Medicines Agency guidelines authorized by International Conference on Harmonisation, Harmonised Tripartite Guideline. Q3A(R2), Impurities in new drug substances, and Q3C(R4), Impurities: Guideline for Residual Solvents, approved in Geneva in 2006, active pharmaceutical ingredient must fall into line with the particular specification regarding purity, which means, the content of impurities and residual solvents cannot exceed acceptable limits. For the pharmaceutical substances, which are not disclosed in monographs of the European Pharmacopoeia, acceptable content of a single identified impurity is <0.15% and of an unidentified impurity is <0.10%.

Generally, crystalline prasugrel hydrochloride may be obtained following standard methodology, comprising the addition of equimolar or small molar excess of concentrated aqueous solution (c.a. 36%) of hydrochloric acid, or gaseous hydrochloride or its solution in organic solvent to prasugrel base or its salt dissolved in organic solvent. Addition of anti-solvent, like for example ether, may be necessary to induce precipitation of the product.

However, synthesis of prasugrel hydrochloride having both the high pharmaceutical purity and pharmaceutically favorable polymorphic form free of other crystalline forms impurities or amorphous inclusions according to this general method turned out to be very difficult.

During the reaction of prasugrel base with hydrochloric acid under acidic conditions deacetylation occurs, resulting in formation of 5-[2-cyclopropyl-l-(2- fluorophenyl)-2-oxoethyl]-5,6,7,7a-tetrahydrothieno[3,2-c]py ridin-2(4H)-on, which is the main impurity referred to as OXTP in patent application EP 2 003 136 Al, along with its tautomers. The final product may also be contaminated with the side reactions stereoisomeric products.

in die patent application EP 2 003 136 A 1 the process for preparation of prasugrel hydrochloride having decreased content of OXTP contamination has been disclosed. This process encompasses dissolving prasugrel base in acetone, adding half of the appropriate (usually equimolar) amount of concentrated hydrochloric acid to this solution within 2-10 minutes, optionally seeding, followed by slow (30 minutes to 2 hours) addition of the remaining amount of hydrochloric acid. The mixture is being left for crystallization, the crystals are collected, dried and optionally purified following one of the routinely used methods, for example, recrystallization or chromatography. The polymorphic purity of thus obtained product has not been given.

WO 2011/069473 discloses synthesis of prasugrel hydrochloride containing low level of impurities. Prasugrel base dissolved or suspended in organic solvent is treated with hydrochloric acid dissolved in organic solvent or water, and resulting product crystallizes, optionally due to addition of co-solvent, such as acetic acid ester, preferably ethyl or isopropyl acetate. In the examples given, to the solution of prasugrel base in ethyl acetate or isopropyl acetate hydrochloric acid in ethanol is added. It is reported that purity of prasugrel hydrochloride polymorphic form B thus obtained is higher than 99.6% and the content of deacetylation product, (5-[2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]- 5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-on), is below 0.1%. According to another example, in reaction of prasugrel base dissolved in methyl ethyl ketone and hydrochloric acid in ethanol, prasugrel hydrochloride polymorphic form B is obtained without addition of seed crystals.

In EP 2 145 890 Bl, the method for preparation of salts with hydrochloric acid and basic pharmaceutical substances containing primary, secondary and tertiary amine groups, eliminating OXTP impurity generation has been described. Preferably, the reaction is carried out under strictly anhydrous conditions to furnish expected polymorphic form. According to this methodology illustrated, inter alia, by the example of prasugrel hydrochloride polymorphic form B preparation, hydrochloride is generated in situ due to addition of trialkylsilyl chloride to the solution of amine in protic solvent, or in a mixture of organic aprotic solvent and protic solvent, at least at equimolar amount in relation to the amount of amine. Protic solvents allowing generation of hydrochloride from trialkylsilyl chloride are aliphatic and aromatic alcohols, silanoles, ketones undergoing enolization or carbonic acids. Aprotic solvents, such as for example, esters, nitriles, ethers, chlorinated and aromatic solvents and alkanes are not susceptible to silylation and are used to dissolve or suspend amine and enable crystallization of favorable crystalline form. To obtain prasugrel hydrochloride polymorphic from B, the preferred aprotic solvent is acetone and acetic acid is used as protic solvent. The prior art methods are useful as far as reduced amounts of the forming impurities are concerned, but they are not suitable for selective crystallization of prasugrel hydrochloride polymorphic from B. A plethora of experiments carried out by the authors of the present invention following published procedures proved, the formation of prasugrel hydrochloride polymorphic from A is being favored in different solvents and mixtures thereof, even when seeding with form B crystals. It was observed that selective crystallization of form B occurs in acetone, using concentrated aqueous solution of hydrochloric acid (about 36%) and seeding with form B crystals.

However, presence of water in the reaction mixture which favors crystallization of prasugrel hydrochloride polymorphic from B, at the same time influences increased formation of deacetylated by-product. On the other hand, carrying out the addition reaction under non-hydrolytic conditions, eg. using gaseous hydrogen chloride or its solutions in organic solvents, does not warrant formation of pure polymorphic form B. Summary of the invention

The authors of the present invention have solved this problem, running the addition reaction of hydrogen chloride to prasugrel base under non-hydrolytic conditions, in presence of some amount of polar solvent, such as methyl alcohol, and seed crystals of prasugrel hydrochloride polymorphic form B to induce nucleation of expected crystalline form B.

It turned out, selectivity of prasugrel hydrochloride crystallization depends not only on addition of methyl alcohol and seed crystals of form B, but it is also strongly influenced by the mixture of solvents used in addition reaction and crystallization. The selective crystallization of prasugrel hydrochloride of expected and pharmaceutically accepted polymorphic form B is favored in the mixtures of solvents at particular compositions. Exemplary solvents mixtures are collected in Table 1.

Table 1. Effect of addition reaction conditions on selective crystallization of prasugrel hydrochloride crystalline forms

Sample Solvent Seeding with Addition of Product crystalline form

No form B crystals methyl alcohol

1 MTBE No No B + amorphous form 2 MTBE No Yes B + amorphous form

3 MTBE Yes No B + amorphous form

4 MTBE Yes Yes B + amorphous form

5 Acetone/MTBE No No Hydrate + impurity

2: 1

6 Acetone/MTBE No Yes A + impurity

2:1

7 Acetone/MTBE Yes No B + impurity/amorphous

2: 1 form

8 Acetone/MTBE Yes Yes B

2: 1

9 IPA/MTBE No No A

2: 1

10 IPA/MTBE No Yes A

2: 1

11 IPA:MTBE Yes No A

2: 1

12 IPA.-MTBE Yes Yes A + B

2: 1

13 EtOAc No No B + amorphous form

14 EtOAc No Yes B + impurity

15 EtOAc Yes No B + impurity

16 EtOAc Yes Yes B

MTBE = methyl tert-butyl ether;

IPA = propan-2-ol;

EtOAc = ethyl acetate

For example, using the mixture of propan-2-ol / methyl rt-butyl ether in all reaction variations, i.e. without seeding and addition of methyl alcohol, with seeding but without addition of methyl alcohol, with no seeding but with addition of methyl alcohol, with seeding and addition of methyl alcohol, polymorphic form A is obtained. In the last reaction variant only, with seeding and addition of methyl alcohol, polymorphic form A containing some amount of expected form B is formed. It has been observed, that concomitant addition of methyl alcohol and form B seed crystals results in crystallization of pure polymorphic form B, free of detectable impurities (including polymorphic form A co-crystals) and amorphous inclusions. Pure polymorphic form B is obtained in the mixture of acetone / methyl tert-butyl ether and ethyl acetate / methyl tert-butyl ether, among others. Using the same mixtures of solvents but altering reaction conditions, obtained prasugrel hydrochloride crystals do not meet demands of polymorphic purity.

As used herein, the term 'pure prasugrel hydrochloride polymorphic form B' relates to the substance in polymorphic form B free of other polymorphic or pseudo-polymorphic impurities at amounts detected by routinely used analytical methods, such as X-ray powder diffraction and infrared absorption, ie. including less than 2%, preferably less then 1% of other polymorphic forms contaminations. In addition, 'pure prasugrel hydrochloride polymorphic form B' refers to the substance of chemical purity, evaluated, for example, by high performance liquid chromatography (HPLC), that is higher than 99%, preferably higher than 99.5%. Prasugrel hydrochloride polymorphic form B is characterized by X-ray powder diffraction pattern, recorded on the diffractometer equipped with the copper anode of Κα λ = 1.54056 A wave length, and represented as relative intensities of diffraction peaks I/I ₀ , diffraction angles 2Θ and interplanar distances d, which substantially resembles the X-ray powder diffraction pattern of polymorphic form B reproduced in patent application EP 2 003 136 Al .

Detailed description of the invention

Process for preparation of prasugrel hydrochloride polymorphic form B of pharmaceutical purity according to the present invention comprises the steps of:

(a) dissolving parasugrel base in organic solvent selected from group I comprising ketones, aliphatic esters, and aliphatic or cyclic ethers,

(b) adding 0.1-10% volume of methyl alcohol in relation to the initial volume of the organic solvent and seed crystals of prasugrel hydrochloride polymorphic form B,

(c) adding 1 - 1.1 molar equivalent of hydrogen chloride,

(d) optionally, when the solvent is selected from a group of ketones or aliphatic esters, adding anti-solvent selected from group II of aliphatic or cyclic ethers,

(e) separating crystalline product from the post-reaction mixture and drying to a constant weight, (f) optionally, grinding the pre-dried crystalline product and additional drying to remove residual solvents to the level below 5000 ppm.

Preferably, organic solvent selected from group I is acetone.

The other organic solvent selected from the group I is ethyl acetate.

When organic solvent selected from group I of ketones or aliphatic esters is used as the first solvent, preferably, to the reaction mixture anti-solvent, selected from group II of aliphatic or cyclic ethers is added to facilitate precipitation of the product.

Preferably, organic solvent selected from group II of aliphatic or cyclic ethers is methyl tert-butyl ether.

Seed crystals of polymorphic form B are added at amount of 1-5% by weight in relation to prasugrel base.

In the preferred embodiment of the invention, to the solution of prasugrel base in acetone, 1-2% (by volume in relation to acetone amount) of methyl alcohol, 1-5% (by weight in relation to prasugrel base used) of seed crystals of prasugrel hydrochloride form B, 1 - 1.1 molar equivalent of hydrogen chloride in methyl tert-butyl ether and finally methyl tert-butyl ether as anti-solvent, are added.

After addition of anti-solvent and initiation of precipitation, the reaction mixture is stirred at room temperature until crystallization process is completed. The crystalline product is separated by means of one of routinely used methods, for example, filtration, decantation or solvent evaporation. Then, obtained crystals are washed with inert solvent, preferably aliphatic or cyclic ether. The crystalline product thus obtained is dried to the constant weight under reduced pressure at 30-50°C, preferable at 40°C.

Acid addition reaction yields prasugrel hydrochloride polymorphic B, crystals of which are of irregular shape and tend to agglomerate. Crystals obtained in different batches are characterized by volume moment mean (De Broucker mean) D[4,3] at 45-50 μ ^η ι range and d(0.9) of about 90 μιτι. On account of the product properties, usually during the attempts to reduce, by simple drying, content of the residual solvents to the level accepted by ICH guidelines, some difficulties are met.

The results of microscopic imaging and measurements of particle size distribution indicate, neither shape nor size of the crystals are substantially changed following additional drying and/or maceration in another inert solvent, what may suggest, the properties of crystals are not influenced by simple drying process. Hence, if the content of residual solvents after drying the product to the constant weight exceeds 5000 ppm, the crystal size reduction is necessary, either by grinding or micronization followed by additional drying of the micronized crystals.

According to the present invention, process for preparation of prasugrel hydrochloride of pharmaceutical purity can be achieved, preferably, due to obtaining crystals of uniform particle size, reducing volume moment mean D[4,3] to less than 10 μιη, more preferably less than 5 μηι.

Grinding and micronization as well as particle size distribution measurements methods are well known to those skilled in the art. Usually, when grinding in a ball mill, for example, the particles of size no less than 30-40 μπι are obtained. Reduction of particle size to less than 10 μηι can be achieved in micronization process performed, for example, in a mill with fluidal beads, in a ball mill, colloid or jet mill or by spray-drying.

Preferably, the substance of demanded pharmaceutical purity can be obtained due to drying prasugrel hydrochloride to the constant weight under reduced pressure, at 30-50°C, preferable at 40°C, followed by micronization to obtain volume moment mean D[4,3] less than 10 μηι, more preferably less than 5 μηι, and additional drying.

Characteristic microscopic images of prasugrel hydrochloride crystals obtained according to the present invention are depicted on Fig. 4A - before pre-drying, Fig. 4B - before micronization, and Fig. 4C - after micronization.

Particle size volume distribution of prasugrel hydrochloride prepared according to the present invention measured by laser diffraction method before and after micronization are depicted on Fig. 5A and Fig. 5B, respectively.

Preferably, prasugrel hydrochloride obtained according to the present invention, after micronization has volume moment mean D[4,3] at 2.00 - 3.50 μηι range and d(0.5) at 0.18-0.20 μηι range, 10% of particles have size below 0.10 μη (d(0.1) < 0.10 μ ^η ι), and 90% below 5.00 μηι (d(0.9)<5.00 μιη).

Prasugrel hydrochloride prepared by the process according to the invention is characterized by X-ray powder diffraction pattern (XRPD), recorded on the diffractometer equipped with the copper anode of Κα λ = 1,54056 A wave length, represented as relative intensities of diffraction peaks I/I ₀ , diffraction angles 2Θ and interplanar distances d, with scanning range from 3 to 40°, scanning rate 0,5 min and step size 0,02°. The data are collected in Table 2. Table 2. X-ray powder diffraction pattern of prasugrel hydrochloride

Exemplary X-ray powder XRPD pattern of prasugrel hydrochloride obtained according to the present invention is depicted on Fig. 6.

Infrared spectrum of prasugrel hydrochloride obtained according to the present invention, performed in KBr tablet is depicted on Fig. 7.

Prasugrel hydrochloride DSC profile obtained using differential scanning calorimetry, under dynamic heat regime ranging from 25 to 250 °C at heating rate 10 °C/min, is presented on Fig. 8, it is characterized by one endothermic peak. Melting point measured as onset is 185°C, enthalpy is about 157 J/g.

On TG curve obtained from thermogravimetric (TGA) analysis, under dynamic heat regime ranging from 25 to 250 °C at heating rate 10 °C/min, represented as full line on Fig. 9, the effect of 0,4% loss of mass at temperature range from 30°C to about 160°C is observed. Comparison of the effects shown on TGA and SDTA {Single Differential Thermal Analysis) (broken line) curves indicates, the first effect is attributed to evaporation of superficially absorbed solvent and the base line sloping down reflects melting and concomitant decomposition of the sample.

The present invention provides the preparation method of prasugrel hydrochloride polymorphic form B, which is stable and contains impurities and residual solvents at the level meeting the demands for active pharmaceutical ingredients.

The present invention is illustrated by the following examples.

Examples

Analytical methods

• X-ray powder diffraction (XRPD)

X-ray powder XRPD patterns were recorded on X-ray powder diffractometer type MiniFlex by Rigaku, with the following parameters:

> Radiation: CuKal, λ=1, 54056 A

> Scanning range 2Θ: from 3 to 40°

> Step size: 0,02°

> Scanning rate: 0,5°/min

> Detector: scintillating counter. · Infrared spectroscopy (IR)

IR spectra were performed in pressed KBr tablets, containing about 1,5 mg of tested substance and about 200 mg of KBr, on Nicolet Impact 410 spectrometer at measurement range from 4000 to 400 cm ^"1 and 4 cm ^"1 resolution. · Differential scanning calorimetry (DSC)

DSC measurements were performed in the furnace sample chamber DSC822 ⁶ by Mettler Toledo, under following conditions: _f

> Melting pot: aluminum, 40 μΐ, capacity,

> Purge gas: N ₂ , flow rate 60 mL/min,

> Measurement conditions: the samples were heated under dynamic regime ranging from 25 to 250 °C at heating rate 10 °C/min,

> Samples preparation: the crystalline substances weighting from 5 to lO mg were placed in the melting pots without prior preparation. The melting pots were air-tight pressed and punctured before the measurement.

• Thermogravimetry (TGA)

TGA measurements were performed in the furnace sample chamber TGA/SDTA851 ⁶ by Mettler Toledo, under following conditions:

> Melting pot: aluminum, 40 μί, capacity,

> Purge gas: N ₂ , flow rate 60 mL/min,

> Measurement conditions: the samples were heated under dynamic regime ranging from 25 to 250 °C at heating rate 10 °C/min,

> Samples preparation: the crystalline substances weighting from 5 to

10 mg were placed in the melting pots without prior preparation. The melting pots were air-tight pressed and punctured before the measurement. The empty pot correction was included in the measurements. On each thermogram the following curves are depicted: TGA (full line) and SDTA

(broken line). TGA curve represents the changes of a sample mass as a function of temperature or time. On the differential SDTA curve, the effects of solvent evaporation and a substance melting are shown.

• Gas chromatography (GC)

Determination of propan-2-ol, n-hexane and methyl alcohol residues was performed by GC method.

Instrument and measurement conditions:

Gas chromatograph equipped with flame ionization detector

Column: DB624 (60 m x 0,32 mm)

Column temperature: 100°C (2°C/min) -» 120°C (40°C/min) - 240°C (3 min)

Feeder: 240° C, carrier gas - nitrogen (100 kPa), split 5 : 1, sensitivity -5

Detector: 260° C, hydrogen 45 mL/min, air 450 mL/min

Headspace conditions:

Oven: 100° C, Needle: 110° C, Transfer line: 120° C, Column, Injection: 140 kPa

Thermostat: 30 min, Pressurize: 1 min, Inject: 0,05 min, Withdraw: 0,2 min • Microscopic and particle size analysis

Particle size distribution was measured by laser diffraction method with particle size distribution analyzer Mastersizer 2000, Malvern and dispersion adapter Hydro 2000S, Malvern. Microscopic visualization was performed with automated microscopic analyzer Morphologi G3s Malvern in diascopic light.

Measurement conditions:

Laser diffraction

Device/dispersion adapter Mastersizer 2000 / Hydro 2000S Malvern Ultrasound (us) 0%

Stirring speed 2800 rpm

Dispersion medium sunflower oil

Single measurement time 0.5 s

Background measurement time 10 s

Refraction coefficient of tested particles 1.6

Refraction coefficient of dispersant 1.469

Absorption coefficient 0.01

Obscuration 5-25%

Microscopic analysis

Device/dispersion adapter: Morphologi G3S / -, Malvern

Dispersion medium:

Example 1

To the solution of 1 g of prasugrel base in acetone (10,00 mL) methyl alcohol (0,13 mL) and prasugrel hydrochloride form B seed crystals (0,03 g) were added. While stirring at room temperature, to the slurry the solution of hydrochloride in methyl tert-butyl ether (4,8 M; 0,61 mL) and methyl tert-butyl ether (4,40 mL) were added. The resulting mixture was stirred at room temperature for 2 h. The thick solid was filtered off, washed three times with methyl tert-butyl ether (3 x 2 mL) and dried to dry mass at 40°C under reduced pressure for 5 h. The crystalline solid was micronized in a jet mill and dried at 40°C under reduced pressure for 5 h. Prasugrel hydrochloride form B was obtained as white crystals (yield 0,83 g, 76%). Purity (HPLC): 99,80%. The content of single impurities <0,10%, the content of residual solvents: acetone - 3413 ppm, MTBE - 2659 ppm.

Example 2

To the solution of 1 g of prasugrel base in ethyl acetate (10,00 mL) methyl alcohol

(0,13 mL) and prasugrel hydrochloride form B seed crystals (0,03 g) were added. While stirring at room temperature, to the slurry the solution of hydrochloride in methyl tert-butyl ether (4,8 M; 0,61 mL) and methyl tert-butyl ether (4,40 mL) were added in succession. The resulting mixture was stirred at room temperature for 120 min. The thick solid was filtered off, and washed three times with methyl tert-butyl ether (3 x 2 mL). Further workup was performed as described in example 1. Prasugrel hydrochloride form B was obtained as white crystals (yield 0,92 g, 84%). Purity (HPLC): 99,41%.

Example 3 (comparative)

To the solution of 1 g of prasugrel base in propan-2-ol (10,00 mL) methyl alcohol

(0,13 mL) and prasugrel hydrochloride form B seed crystals (0,03 g) were added. While stirring at room temperature, the solution of hydrochloride in methyl tert-butyl ether (4,8 M; 0,61 mL) and methyl tert-butyl ether (4,40 mL) were added to the slurry in succession. The resulting mixture was stirred at room temperature for 2 h. The thick solid was filtered off, and washed three times with methyl tert-butyl ether (3 2 mL). Further work-up was performed as described in example 1. Prasugrel hydrochloride form A containing some amount of form B was obtained as white crystals (yield 0,80 g, 73%). Purity (HPLC): 99,71%. Example 4

The influence of drying and micronization parameters on the contents of residual solvents and particle size distribution was determined.

The results are collected in Tables 3 and 4 and depicted on Fig. 4 and Fig. 5. Table 3. The influence of drying and micronization on the residual solvents content

After double drying at 40°C under reduced pressure, the content of residual solvents was not reduced and reached >5000 ppm, when acetone was used as the first solvent.

Following micronization and additional drying, the content of two residual solvents was reduced to <5000 ppm.

Table 4. Particle size distribution