WO2011124124A1

WO2011124124A1 - Prasugrel hydrochloride acetic acid solvate and its crystalline, preparation method thereof

Info

Publication number: WO2011124124A1
Application number: PCT/CN2011/072448
Authority: WO
Inventors: 程兴栋; 袁哲东; 杨玉雷; 朱雪焱; 潘红娟; 童玲; 俞雄
Original assignee: 上海医药工业研究院
Priority date: 2010-04-08
Filing date: 2011-04-02
Publication date: 2011-10-13
Also published as: CN102212071A; CN102212071B

Abstract

Disclosed is a novel 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine hydrochloride acetic acid solvate or its crystalline, and the preparation method of the solvate or its crystalline. The Prasugrel hydrochloride acetic acid solvate or its crystalline has better stability and solubility than Prasugrel hydrochloride. Furthermore, its pharmaceutical preparation has better dissolution and bioavailability than commercial preparation.

Description

Prasugrel hydrochloride acetate solvate and crystallization and preparation method thereof

The present invention relates to a novel 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Hydrochloride acetate solvate and crystallization of the solvate and a process for the preparation thereof. Background technique

Prasugrel (2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c pyridine, compound of formula I A new class of ADP receptor antagonists, a new prodrug-type antiplatelet drug that is more potent than the market-proven ADP receptor antagonist clopidogrel, as induced by ADP in rats. Platelet aggregation, oral prasugrel produces ten times more potent than clopidogrel. Plage's active metabolite plasma concentration is also ten times higher than the active metabolite plasma concentration of clopidogrel, suggesting that pulage has a large market

(I)

The patent application of Chinese Publication No. CN1452624A discloses a hydrochloride and maleate salt of prasugrel, which has good oral absorption, metabolic activity and inhibition of platelet aggregation, low toxicity and good stability, however, The hydrochloride and maleate salts of prasugrel still have a problem of poor water solubility, which is to be solved by those skilled in the art. Summary of the invention

The inventors of the present application have intensively studied various acid addition salts of prasugrel and solvates thereof, and found that prasugrel hydrochloride acetate solvate or the solvate has crystals than prasugrel hydrochloride. Better stability and solubility, suitable for the production of drugs.

To achieve the above object, the technical solution provided by the present invention is as follows:

Prasugrel hydrochloride (Π) acetate solvate or crystals thereof.

(II)

Among them, the content of acetic acid is 0.1 to 2 mol/mol of the compound of the formula II. A compound of the formula II is preferably present in an amount of from 0.5 to 1.5 mol/mol. Most preferred is a compound of formula II in an amount of 1 mol/mol.

Among them, prasugrel hydrochloride acetate solvate or its crystal, in its powder X-ray diffraction pattern, at diffraction angle (2Θ) is 8.56°, 10.35°, 11.67°, 12.42°, 12.95°, 14.08 ° Characteristic peaks at 16.01 ° , 17.43 ° , 18.65 ° , 23.78 ° , 24.53 ° and 26.00 ° .

A process for the preparation of prasugrel hydrochloride acetate solvate or crystals thereof, comprising the steps of: (a) dissolving a compound of formula I in a solvent; (b) further adding hydrogen chloride and acetic acid thereto.

In addition, the solvent is not particularly limited as long as it does not inhibit the reaction and has a certain solubility in the raw material, and may be an aliphatic hydrocarbon such as hexane, cyclohexane, heptane, volatile oil or petroleum ether; benzene, toluene or two An aromatic hydrocarbon such as toluene; a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, An ether such as oxane, dimethoxyethane or diglyme; a ketone such as acetone, butanone or diethyl ketone; an ester such as ethyl acetate, propyl acetate or butyl acetate; a carboxylic acid such as acetic acid; or a nitrile such as acetonitrile or propionitrile. Preferred is acetic acid or ethyl acetate.

A process for the preparation of prasugrel hydrochloride acetate solvate or crystals thereof, comprising the steps of: (a) dissolving a compound of formula I in acetic acid; (b) further introducing hydrogen chloride gas thereto or adding hydrogen chloride. substance.

A process for the preparation of prasugrel hydrochloride acetate solvate or crystals thereof, comprising the steps of: (a) dissolving a compound of formula II in a solvent; (b) adding acetic acid thereto.

Wherein, the above preparation method further comprises the step (c). The obtained prasugrel hydrochloride acetate solvate or crystal thereof is recrystallized.

The reaction temperature varies depending on the reagent or the solvent, and may be a common temperature in the reaction in the art, as long as it is lower than the boiling point of the organic solvent, usually -20 ° C to 100 ° C, preferably 0 ° C to 70 ° C. More preferably, it is room temperature.

The reaction time varies depending on the reagent, the solvent or the reaction temperature, etc., and is usually from 5 minutes to 10 hours, preferably from 10 minutes to 5 hours. A drug of prasugrel hydrochloride acetate solvate or a crystal thereof as an active ingredient.

Use of prasugrel hydrochloride acetate solvate or crystals thereof for the manufacture of a medicament for preventing or treating a disease caused by thrombosis or embolism in a warm-blooded animal.

The present invention relates to a novel 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine a hydrochloride acetate hydrate, when used as a therapeutic or prophylactic agent for the above diseases, may be mixed with a suitable pharmacologically acceptable excipient, diluent, etc., in the form of tablets or capsules. Or granules, powders or syrups are administered orally or parenterally or injectables or suppositories.

These preparations can be produced by known methods using the following additives: excipients (e.g., sugar derivatives such as lactose, white sugar, glucose, mannitol, sorbitol, etc.; starch such as corn starch, potato starch, alpha starch, dextrin, etc.) Derivatives; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; organic excipients such as pullulan; and silicate derived from light silica anhydride, synthetic aluminum silicate, calcium silicate, magnesium aluminum silicate, etc. Phosphate such as calcium hydrogen phosphate; inorganic excipients such as carbonate such as calcium carbonate; and lubricants (such as stearic acid, calcium stearate, magnesium stearate, etc.; talc, etc.) , binders (such as hydroxypropyl cellulose, hydroxypropylmethylcellulose, etc.), disintegrants (such as: low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, etc.), emulsifiers (such as: twelve Anionic surfactants such as sodium alkyl sulfate and calcium stearate; cationic surfactants such as benzalkonium chloride and nonionic surfactants such as sucrose fatty acid esters; stabilizers such as methyl paraben; Flavor Thinner.

The prasugrel hydrochloride acetate solvate or the crystal thereof provided by the invention has better stability and solubility, is more advantageous for the application in preparation of the pharmaceutical preparation, and is also very simple in preparation process, and is suitable for industrial application. .

The compound of the formula I used in the present invention is obtained by reference to Reference Example 1 in the patent application of the Chinese Patent Publication No. CN1452624A.

The hydrazine compound of the present invention is commercially available or is produced according to Example 1 of the patent application of Chinese Patent Publication No. CN1452624A.

DRAWINGS

In order to more clearly understand the objects, features and advantages of the present invention, the preferred embodiments of

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a powder X-ray diffraction pattern of the product prasugrel hydrochloride acetate solvate of Example 2 of the present invention. Figure 2 is a powder X-ray diffraction pattern of the product prasugrel hydrochloride acetate solvate of Example 5 of the present invention.

detailed description

Example 1

2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-0 |pyroline hydrochloride acetate Object

2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-0 |pyridine (compound of formula I) (2 g) was dissolved in 16 ml of acetic acid, and an acetic acid solution containing 1 equivalent of hydrogen chloride was added dropwise with stirring at room temperature, and crystals were precipitated at about 10 minutes, and stirred at the same temperature for 2 hours. The precipitated crystals were filtered, washed with ethyl acetate, and dried under reduced pressure at 60 ° C for 4 hrs to afforded to afforded white crystals (yield: 87.3%). Example 2:

Dissolving 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-0 |pyridine (2g) in In a mixed solvent of 8 ml of acetic acid and 8 ml of ethyl acetate, an ethyl acetate solution containing 1 equivalent of hydrogen chloride was added dropwise with stirring at room temperature, a small amount of seed crystals (crystals obtained in Example 1) was added, and the mixture was stirred at the same temperature for 2 hours. The precipitated crystals were filtered, washed with ethyl acetate, and dried under reduced pressure at 60 ° C for 4 hrs to give the title compound (yield: 91.3%). Example 3:

Dissolving 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-0 |pyridine (2g) in In 16 ml of acetic acid, an aqueous solution containing 1 equivalent of hydrogen chloride was added dropwise with stirring at room temperature, a small amount of seed crystals (crystals obtained in Example 1) was added, and the mixture was stirred at the same temperature for 2 hours. Filtration of precipitated crystals, B After washing with ethyl acetate, it was dried under reduced pressure at 60 ° C for 4 hours to obtain 2.2 g of the title compound as white crystals (yield: 87.3%). Example 4:

0.4 g of the white crystal obtained in Example 2 was dissolved in 4 ml of acetic acid, heated to 70 ° C and stirred for 10 min, and then naturally cooled to room temperature and stirred for 2 hours. The precipitated crystals were filtered, washed with ethyl acetate and dried under reduced pressure at 60 ° C for 4 hours to give the title compound as white crystal. (0.34 g, yield 85%) Example 5:

Dissolving 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-0 |pyridine (200 g) in In a mixed solvent of 800 ml of acetic acid and 800 ml of ethyl acetate, an equivalent of hydrogen chloride in ethyl acetate was added dropwise with stirring at room temperature, a small amount of seed crystals (crystals obtained in Example 1) was added, and the mixture was stirred at the same temperature for 2 hours. The precipitated crystals were filtered, washed with ethyl acetate, and dried under reduced pressure at 60 ° C for 4 hr to afford 235 g (yield: 91. Effect embodiment

1, powder X-ray diffraction pattern

An appropriate amount of the prasugrel hydrochloride acetate solvate crystal obtained in Example 2 was subjected to powder X-ray diffraction pattern.

Determined using a Bruker D8 ADVANCE instrument. The measurement conditions were as follows: Light source: CuKa 40kV 40mA, graphite monochromator, divergence slit (DS): 1°; anti-scatter slit (SS): 1°; LynxEye array detector, scanning method: θ/θ, continuous scanning Scan range: 3 ° ~ 45 °, scan speed 8 min.

The results of the measurement are shown in Figure 1 and Table 1.

Table 1 Powder of prasugrel hydrochloride acetate solvate crystals X-ray diffraction data Sequence 2-Theta d(A) Height 1% Area 1% FWHM No.

1 8.556 10.3257 3949 21.9 31110 15.3 0.151

2 10.350 8.5397 3260 18.1 21900 10.8 0.134 9LV0 178£9 L 86^1 SLZVZ LPVZP 9P

V6V0 1-1 OZSZ ξ 6£6

I IV

£6 0 19611 9'L 179£1 V£OZ'Z £Z6'0V

ζΚ'Ο O 801 Ο'ί 09^1 bZ ZZ 108"6£ £V

Z6V0 £ οεΐ9 69 ζνζι L9i'6i zv

6£ 0 Li 8 ςιπ ίβΖί'Ζ

Ζζ Ο 9·ει ςοΐίζ 9·ει Z9VZ 618£ 9£ L£ ov

Γ L 9 9 9 9 9 9 9

1Ό1 6LUZ ε·6 9L91 Z99'V£ Li

ΖΙΖΌ 8·Α 56851 ε-π 1£0Ζ 1619^ LOZ'Vi 9£

1780Ό O εεΐΐ Li 8 \Ζ 'Ζ ξ £

58Γ0 ς-οι ς-ς\ 96LZ £01ί'Ζ ε^ο'εε V£

9£ 0 LOZ£l ΙΌΐ 9181 0£S Z 9£VZ£ ££

ILVO 50501 66 16 016Ό£ Z£

90£Ό 9 Ι 5-Π OSOZ £096τ ξ9Γ0£ l£

£ΙΖΌ ε·9 £98^1 ΟΌΐ £081 9θΐο-ε 6W6Z 0££

LSVO ΐ7ΐ 17-81 ^εε ς£πτ 69£'SZ 61 ξ9Υ0 6 Μ)8ε V9 9511

LiLLZ sz

9£ 0 8"5 508 Π Γ6 8£9ΐ βννζτ V9VLZ LI

9ξΥ0 VIZ ZISZV Ι £ £095 ι ε'ε \L Z 91

60£Ό 8· 9S0Z£ Γΐ7ΐ 9 ςζ £99£τ ςςν9ζ ςζ

176Γ0 8"ΐΐ7

9£ZV£500"9S z

£VZ'0 6 96 VZLI Π9'ξΖ £Z ΐΌ 99ζ£ΐ ς-π ς\9ζ 9ζιςτ £0&VZ zz εθΓΟ ΟΌΟΐ 696 6·86 6£SLl ιζς' ζ IZ

179Γ0 9ΐ7θΐ£

818£ 6069'£ Z60'VZ oz ζςνο 9·6ε ΐ7ΐ£08 ιτς e ζβατ 9LLiZ 61

Ο^ΟΌ νζ- 179617- L L6ZI £66 £ ςβ£τζ 81 εΐ ΐΌ ιτι VZS9Z 6ξί£ 6Μ)0·ΐ7 SLVZZ LI

6VZO

6 991 06Πζ 91 ξ£Υ0 ε 1598 66 16 LOSVV V£Z'IZ ς\ ζζνο Ο 0661 νς ΙΖ6 8£8 ΐ7 SI OZ n

L£VO 9'VZ

09179 1089"ΐ7 9l76"81 £1 ζςνο VLL 11 51 ΟΌΟΐ 017081 3⁄49"81 Zl

£80Ό νο Ζ16 νς £Ζ6 LO Ll 01

6£1Ό £-ς\ LOOK 9'VZ 9£VV 0£VLI 6

ΐΌ &ς 096 Π £Ό1 1581 160· 8

£17ΪΌ ς-0£ 619 ιτν \SLL 60£ς-ς ΠΟ'91 L

L6V0 ε·εε Ζ Ζ9 9W9 SLO'Vl 9

εεΐΌ ςτι Ζζ£ξΖ £VL£ 661VL

6ΠΌ 6·ε 6£SL 6 1591 Ζίίξ'ί 699· 11 £ oz OAV 47 43.159 2.0943 1133 6.3 5835 2.9 0.223

48 43.514 2.0781 1118 6.2 7840 3.9 0.286

49 43.959 2.0581 1013 5.6 3853 1.9 0.160

50 44.375 2.0397 916 5.1 3091 1.5 0.190

Peak Search Report (50 Peaks, Max P/N = 64.5)

[Xl-AcOH.raw]

PEAK: 35-pts/Parabolic Filter, Threshold=3.0, Cutoff=0.1%, BG=3/1.0, Peak-Top=Summit As can be seen from Fig. 1 and Table 1, the product obtained in Example 2 was in powder X-ray diffraction. In the spectrum, there are characteristic peaks at diffraction angles (2Θ) of 8.56°, 10.35 °, 11.67°, 12.42°, 12.95 °, 14.08 ° , 16.01 ° , 17.43 ° , 18.65 ° , 23.78 ° , 24.53 ° and 26.00 ° . .

2. Determination of acetic acid content by HPLC

2.1 An appropriate amount of the prasugrel hydrochloride acetate solvate obtained in Example 2 was crystallized.

Column: octadecylsilane bonded silica, mobile phase A is acetonitrile; mobile phase B is 10 mM potassium dihydrogen phosphate solution (pH adjusted to 3.0 with phosphoric acid); gradient elution; 0-5 min, 5% A, 95 %B _; 5-15min, A from 5% to 60%, B from 95% to 40%; 15-20min, 60%A, 40%B _; detection wavelength 210nm.

Found: Acetic acid content was 12.8 wt %, theoretical value: acetic acid content was 12.8 wt%.

2.2 An appropriate amount of the prasugrel hydrochloride acetate solvate obtained in Example 5 was crystallized.

The detection method is the same as above (2.1 method).

Found: acetic acid content 12.92 wt %, theoretical value: acetic acid content 12.8 wt%

3, elemental analysis

3.1 An appropriate amount of the prasugrel hydrochloride acetate solvate obtained in Example 2 was crystallized.

Oxygen cylinder combustion method, silver acetate titration of chlorine content.

Found: The content of chlorine is 7.6%. Theoretical value: The content of chlorine is 7.6 wt%.

3.2 The appropriate amount of the prasugrel hydrochloride acetate solvate obtained in Example 5 was crystallized.

Found: The content of chlorine is 7.45%, theoretical value: the content of chlorine is 7.6wt%

4, solubility analysis

4.1 A suitable amount of prasugrel hydrochloride acetate solvate crystals and prasugrel hydrochloride samples obtained in Example 2 were obtained. The experimental results are shown in Table 2. Table 2 Solubility of the solvate obtained in Example 2 and prasugrel hydrochloride

XI lg/10ml 0.1N hydrochloric acid

Slightly soluble in X2 lg/44ml XI almost insoluble > lg/10000ml water

X2 is almost insoluble > lg / 10000 ml wherein XI is the solvate obtained in Example 2, and X2 is prasugrel hydrochloride.

It can be seen that the prasugrel hydrochloride acetate solvate obtained in Example 2 has a better solubility in 0.1 equivalent of hydrochloric acid which is close to the human gastric juice environment than prasugrel hydrochloride.

4.2 Take appropriate amount of the prasugrel hydrochloride acetate solvate crystal and prasugrel hydrochloride salt sample obtained in Example 5. The experimental results are shown in Table 3.

Table 3 Comparison of the solubility of the solvate obtained in Example 5 with prasugrel hydrochloride Test substance Solubility

Prasugrel hydrochloride B

Lg/10ml

0.1N hydrochloric acid acid complex

Prasugrel hydrochloride slightly soluble lg/44ml prasugrel hydrochloride B

Dissolved lg/12ml absolute ethanol acid

Prasugrel hydrochloride slightly soluble lg/37ml prasugrel hydrochloride B

Almost insoluble > lg/10000ml water acid complex

Prasugrel hydrochloride is almost insoluble> lg / 10000 ml Conclusion: The solubility of prasugrel hydrochloride acetate solvate obtained in Example 5 in 0.1 equivalent of hydrochloric acid and absolute ethanol close to human gastric juice environment is better than that of Pula Gray hydrochloride is good.

5, stability analysis

5.1 An appropriate amount of prasugrel hydrochloride acetate solvate crystals and prasugrel hydrochloride samples obtained in Example 2 were tested under the following conditions. The experimental results are shown in Table 4. HPLC conditions:

Instrument: Agilent 1100

Column: Phenomenex Hyperclone 5 μ BDS C 18

Mobile phase: acetonitrile: KH ₂ P0 ₄ ( 10 mM) = 70: 30

Column temperature: 25 °C

Flow rate: l .Oml/min

Wavelength: 220nm

Table 4 Comparison of the stability of the solvate obtained in Example 2 with prasugrel hydrochloride Conditions Substance Purity (HPLC area

XI 99.74

0 days

X2 99.08

XI 99.62

60 degrees 5 days

X2 98.89

XI 99.36

60 degrees 10 days

X2 98.29

XI 99.46

Light 5 days

X2 98.49

XI 99.47

Light 10 days

X2 98.20

RH92.5% XI 99.55

5 days X2 98.39

RH92.5% XI 99.40

10 days X2 98.20

Wherein XI is the solvate obtained in Example 2, X2 is prasugrel hydrochloride, and RH is relative humidity.

The test results showed that the prasugrel hydrochloride acetate solvate (XI) obtained in Example 2 was compared with the existing prasugrel salt hydrochloride (X2) under light, 60 ° C and RH 92.5%, respectively. It is stable and more conducive to the application in the preparation of pharmaceutical preparations.

5.2 (1) Influencing factors test

An appropriate amount of the prasugrel hydrochloride acetate solvate crystals and prasugrel hydrochloride samples obtained in Example 5 were placed in an open weighing bottle and protected from light at 60 V, 25 V relative humidity RH 92.5 %, respectively. , 4500Lux light irradiation for 5 days, 10 days, test under the following conditions, to assess the purity and content of the sample. The experimental results are shown in Table 5.

HPLC conditions Instrument: Agilent 1100

Column: Phenomenex Hyperclone 5 μ BDS C 18

Mobile phase: acetonitrile: KH ₂ P0 ₄ ( 10 mM) = 70: 30

Column temperature: 25 °C

Flow rate: l .Oml/min

Wavelength: 220nm

Table 5 Evaluation results of influencing factors

Purity (HPLC method) 3 liters Condition

(area normalized %) (HPLC external standard method %) prasugrel hydrochloride acetate 99.80 99.65

0 days

Prasugrel hydrochloride 99.08 99.49 Prasugrel hydrochloride acetate 99.70 99.62

60 degrees 5 days

Prasugrel hydrochloride 98.89 99.30

60 degrees 10 prasugrel hydrochloride acetate 99.43 99.41

Day prasugrel hydrochloride 98.29 99.02

Prasugrel hydrochloride acetate 99.51 99.70 light 5 days

Prasugrel hydrochloride 98.49 99.50 Prasugrel hydrochloride acetate 99.49 99.68 Light 10 days

Prasugrel hydrochloride 98.20 99.42

RH92.5% prasugrel hydrochloride acetate 99.59 99.58

5 days prasugrel hydrochloride 98.39 99.24

RH92.5% prasugrel hydrochloride acetate 99.43 99.46

10 days Prasugrel hydrochloride 98.20 99.05 where RH stands for relative humidity.

The test results showed that the prasugrel hydrochloride acetate solvate obtained in Example 5 was more stable than the prasugrel salt hydrochloride under the conditions of light, 60 ° C and RH 92.5%. Conducive to the application in the preparation of pharmaceutical preparations.

(2) Accelerated test and long-term stability test

The prasugrel hydrochloride acetate solvate obtained in Example 5 was sealed in an aluminum plastic packaging bag, and the temperature was set at a constant temperature. In the box, the temperature is 40 ° C, the relative humidity is 75%, the acceleration is 3 months, 6 months, the purity of the sample is evaluated by the above HPLC conditions; the prasugrel hydrochloride acetic acid solvate is sealed in the aluminum plastic packaging bag. Inside, in an incubator, the temperature was 25 V, and the relative humidity was 60%. The room was allowed to stand for 3 months, 6 months, and 12 months at room temperature. The purity and content of the samples were evaluated by the above HPLC conditions. The results are shown in Table 6 below.

Table 6 Accelerated test and long-term stability test results

The test results show that the prasugrel hydrochloride acetate solvate obtained in Example 5 has good stability under accelerated conditions (40 V/75% RH) and long-term stability (25 °C/60% RH). Sex, suitable for the preparation of pharmaceutical preparations.

6. Preparation of preparations

Formulation and dissolution studies were carried out using the prasugrel hydrochloride acetate solvate prepared in Example 5.

Prescription Raw material name Prasugrel hydrochloride acetate solvate 12.6g (equivalent to prasugrel 10g)

Microcrystalline cellulose 175

Lactose 22.5

Sodium Carboxymethyl Starch 10.0

Magnesium Stearate 1.0 The main drug and auxiliary materials in the above prescription were obtained through a 100 mesh sieve and tableting machine to prepare about 220 mg per tablet. tablet.

The tablets obtained in the above examples were combined with the commercially available prasugrel hydrochloride tablets (EfientTM lot number: A594158, manufactured by Lilly) in three different media (0.1 mol/l hydrochloric acid solution, pH 4.5 acetic acid-sodium acetate buffer). Comparative study of dissolution in liquid, pH 6.8 phosphate buffer). The results are shown in the following Table 7: Table 7 Comparison of Dissolution of Homemade Tablets and EfientTM Tablets in 0.1 mol/1 Hydrochloric Acid Solution Dissolution Q ( % )

Tablet lot number

3 minutes 5 minutes 10 minutes 20 minutes 30 minutes

Efient 74.1 79.5 85.0 88.4 88.9 Homemade tablets 80.2 85.5 88.3 88.9 90.3

Table 8 Comparison of Dissolution of Homemade Tablets and Listed EfientTM Tablets in pH 4.5 Acetic Acid-Sodium Acetate Buffer

Dissolution Q ( % )

Tablet lot number

3 minutes 5 minutes 10 minutes 20 minutes 30 minutes

Efient 15.6 18.5 27.8 35.5 38.6 Homemade tablets 30.6 41.3 45.8 49.3 49.5 Table 9 Dissolution of homemade tablets and marketed EfientTM tablets in phosphate buffer pH 6.8 Dissolution Q ( % )

Tablet lot number

3 minutes 5 minutes 10 minutes 20 minutes 30 minutes

Efient 6.5 12.4 14.3 16.1 16.4 Homemade tablets 18.6 30.3 38.6 41.5 41.8 The results show:

In the three dissolution media, the self-made prasugrel hydrochloride acetate solvate tablets in the O.lmol / L hydrochloric acid solution, the dissolution rate is significantly faster than the listed hydrochloride tablets Efient ^TM dissolution rate, the dissolution is basically the same ; The self-made prasugrel hydrochloride acetate solvate tablets in the pH 4.5 acetic acid-sodium acetate buffer and pH 6.8 phosphate buffer, the dissolution rate and dissolution are significantly better than the listed hydrochloride tablets Efient ^TM

Conclusion: The dissolution test suggests that prasugrel hydrochloride acetate solvate tablets have better dissolution rates and dissolution rates.

7. Results of comparative study on animal pharmacokinetics

Six male beagle dogs were randomly divided into two groups according to body weight, and two-period crossover design was used. After fasting for 12 hours, the test preparation (preparation preparation example 6) was administered by gavage. 1 tablet (containing prasugrel 10 mg) or a reference preparation (EfientTM) 1 tablet (containing prasugrel 10 mg), and the two groups were cross-administered with another preparation after 1 week of washing. Blood samples were taken at multiple points within 12.0 h after each administration, and plasma was separated by centrifugation. The peak area of prasugrel metabolites and internal standards was determined by LC-MS/MS method, and the plasma concentration was calculated by area ratio. Plasma concentration related data were analyzed by DAS 2.1.1 software. The relevant pharmacokinetic parameters were calculated and the bioequivalence of the two formulations was evaluated. The results are as follows:

From the results of the pharmacokinetic test of Beagle dogs, it can be seen that the half-life t _{1/2 of the} homemade prasugrel hydrochloride acetate solvate tablets is slightly shorter than the reference preparation tablets (EfientTM tablets), and the peak value is slightly higher; The peak time is slightly shorter, and the AUC value under the plasma concentration-time curve is roughly equivalent, suggesting that prasugrel hydrochloride acetate solvate may have an advantage over prasugrel hydrochloride.

Claims

Claims Prasugrel hydrochloride (Π) Acetate solvate or crystals thereof.

The prasugrel hydrochloride acetate solvate or the crystal thereof according to claim 1, which has an acetic acid content of 0.1 to 2 mol/mol of the compound of the formula II.

The prasugrel hydrochloride acetate solvate or the crystal thereof according to claim 2, which has an acetic acid content of 0.5 to 1.5 mol/mol of the compound of the formula II.

The prasugrel hydrochloride acetate solvate or crystal thereof according to claim 3, which has an acetic acid content of 1 mol/mol of the compound of the formula II.

The prasugrel hydrochloride acetate solvate or crystal thereof, or the acetic acid solvate of the formula II or a crystal thereof, according to any one of claims 1 to 4, in a powder X-ray diffraction pattern thereof, The diffraction angles (2 Θ) have characteristic peaks at 8.56°, 10.35°, 11.67°, 12.42°, 12.95°, 14.08°, 16.01 °, 17.43°, 18.65°, 23.78°, 24.53° and 26.00°, respectively.

6. The method for preparing prasugrel hydrochloride acetate solvate or crystal thereof according to claim 1, comprising the steps of: (a) dissolving the compound I in a solvent; (b) adding hydrogen chloride thereto. And acetic acid.

(I)

The method for producing prasugrel hydrochloride acetate solvate or a crystal thereof according to claim 6, wherein the solvent is acetic acid or ethyl acetate.

8. The method for preparing prasugrel hydrochloride acetate solvate or crystal thereof according to claim 1, comprising the steps of: dissolving a compound of formula I in acetic acid; (b) further introducing hydrogen chloride gas thereto or O 2011/124124 substances. PCT/CN2011/072448

9. The method for preparing prasugrel hydrochloride acetate solvate or crystal thereof according to claim 1, comprising the steps of: (a) dissolving a compound of formula II in a solvent; (b) adding thereto again. Acetic acid.

The method for producing prasugrel hydrochloride acetate solvate or crystal thereof according to any one of claims 6 to 9, further comprising the step (c) of obtaining the acetic acid solvate of the compound of the formula II or The crystals are recrystallized.

The prasugrel hydrochloride acetate solvate or the crystallization thereof according to claim 1 as an active ingredient.

12. Use of prasugrel hydrochloride acetate solvate or a crystal thereof according to claim 1 for the manufacture of a medicament for preventing or treating a disease caused by thrombosis or embolism in a warm-blooded animal.