WO2013034087A1

WO2013034087A1 - Doripenem hydrate crystal and preparation method therefor

Info

Publication number: WO2013034087A1
Application number: PCT/CN2012/081064
Authority: WO
Inventors: 安晓霞; 吕峰; 胡猛; 周吴; 王光华
Original assignee: 上海希迈医药科技有限公司; 江苏迪赛诺制药有限公司
Priority date: 2011-09-08
Filing date: 2012-09-06
Publication date: 2013-03-14
Also published as: CN102285988B; CN102285988A

Abstract

Disclosed are a doripenem hydrate crystal and preparation method therefor. The X-ray diffraction spectrogram of the crystal powder is basically as represented in figure 1, and the measured water content is 4.4 to 5.5%. The doripenem hydrate crystal of the present invention has high purity, low residual solvent, good stability, and application safety. Additionally, the preparation method for the doripenem hydrate crystal of the present invention has simple techniques and low preparation cost, and is suitable for industrial production.

Description

Doripenem hydrate crystal and preparation method thereof

Technical field

The invention relates to a doripene hydrate crystal and a preparation method thereof, and belongs to the field of organic chemistry technology. Background technique

Doripenem is a new beta-methyl carbapenem antibiotic developed by Japan's Yanyeyi Pharmaceutical Co., Ltd., which was launched in Japan on September 16, 2005 under the trade name Finibax. Doripenem was approved by the US FDA on October 15, 2007 for the clinical treatment of complex intra-abdominal infections and complex urinary tract infections. By inhibiting cell wall synthesis, it exhibits broad-spectrum, high-efficiency antibacterial activity, and is particularly active against Pseudomonas aeruginosa than existing carbapenem antibiotics.

The Chinese patent (Patent No. ZL92111069. 3 and ZL95104834. 1) discloses the preparation method of amorphous doripenem. It is well known that amorphous substances are generally less stable than crystalline substances and are difficult to preserve. To overcome these defects, Japan Yanye Yiyi Pharmaceutical Company has successively disclosed four kinds of doripenem crystals (Form I, Form II, Form III and Form IV) and preparation methods thereof. The specific information of the four crystal compounds is shown in Table 1. .

Table 1

Patent Literature Form X Diffraction Pattern 2 Θ Angle Main Peak Water Content

2. 14%

7. 32, 14. 72, 16. 62, 20. 42, 21. 1.

Crystal form I 0. 5 molecular crystal

22. 18, 23. 88, 29. 76

Water

ZL95193672. 7

6. 65%

6. 06, 12. 2, 14. 56, 17· 0, 18. 38, 20. 68,

Crystal Form II 1. 65 Molecular Crystallization

24. 38, 24. 60, 25. 88, 30. 12

Water

6. 78, 6. 96, 15. 74, 17. 92, 21. 16, 7. 74%

ZL01810309. X Crystal Form III

23. 56, 25. 8 2 molecular water 13. 01, 14. 98, 15. 88, 16. 62, 20. 62,

4. 28% Form IV 21. 06, 22. 18, 23. 90, 26. 08, 28. 22,

1 molecule of crystal water

28 98

Among the above four crystal forms, the stability of the three crystal forms I, II and III is not good. Only the crystal form IV is the crystal form with the best stability. However, the form IV cannot be directly obtained, and the crystal must be obtained first. After the type III, it is obtained by drying under reduced pressure, and there are undoubted defects such as complicated preparation process and high preparation cost.

The Chinese patent (patent number ZL200610028746. 9) has successively disclosed two kinds of doripenem crystals (crystal form V and crystal form VI) and preparation methods thereof. The specific information of the two kinds of crystal compounds is shown in Table 2. .

Table 2

The Chinese patent (Patent No. ZL200710127224. 9) discloses another form of Dominican form V containing 2 molecules of water of crystallization. The specific information of the crystalline compound is shown in Table 3.

table 3

Despite the reports of various crystal forms mentioned above, it is still necessary to study the new crystal form of Donibene which is convenient, easy to obtain, and has good thermodynamic stability and can be smoothly industrialized to ensure the preparation and storage of the drug substance and its preparation. The stability of the drug to improve the quality and clinical efficacy of doripenem. Summary of the invention

The object of the present invention is to provide a Dominican hydrate crystal having high purity, low residual solvent and good stability, and a method for preparing the crystal which is simple in process, low in preparation cost and suitable for industrial production.

+1 In order to achieve the above object, the technical solution adopted by the present invention is as follows:

o ο

According to the doripenem hydrate crystal of the present invention, the powder has a powder X-ray diffraction spectrum of 3 or more (preferably 3-18, or 5-18, or 7-18, most Good place is 18) 2 selected from the group below

Θ Characteristic peak: 6.43° ±0· 2° , 13 .02° ±0, .2° ±0· 2° , 15. 27. ±0· 2° o

±0· 2° , 17. 46° ±0.2° , 20.60° ±0· 2° ,

±0· 2° , 22.18° ±0 oO· 2° , 23 .88° ±0 , 2° , 25.35° ±0· 2° , 26. 04° ±0· 2° o

28.19° ±0.2° , 29.00° ±0· 2° , 31. 65° ±0.2° , 34.09° ±0· 2° , 34.90°

±0.2°, and the moisture in the crystal is measured 1+ 4.4~5.

The o value is 5%.

The powder X-ray diffraction spectrum of the doripenem hydrate crystal of the present invention is basically as shown in FIG. 1, and the measured value of moisture in the crystal is 4.4 to 5.5%, and more preferably O is 4.7 to 5.1%. More preferably 4.8-5.0%.

In another preferred embodiment, the moisture in the crystal is substantially or entirely crystalline water.

Further, the Dominican hydrate crystal 1+ inch body of the present invention further has the DSC spectrum shown in FIG. 2,

O o o

The TG spectrum shown in Fig. 3 and the IR spectrum shown in Fig. 4 are shown. O

Furthermore, the doripenem hydrate crystal of the present invention is under 2+ powder X-ray diffraction at 2 Θ o

Is 6.43. ±0.2° O ±0. 2° , 15. 85°

O L

±0.2. , 17.46° ±0· 2. , 20.60° ±0.2° , 21. 04° ±0· 2°

22.18° ±0.2° , 23.88° ±0.2° , 25.35° ±0.2° , 26.04° ±0· 2° , 28. 19°

±0· 2 ^ο , 29.00° ±0.2. , 31.65 ° ± 0.2. 34.09° ±0.2° , 34.90° ±0· 2° There is a main peak at 2 Θ of 10.86. ±0.2° ±0 .2° , , 18. 43°

±0· 2. 23. 40° ±0· 2°

33.34 ° ± 0.2. , 36.44° ±0.2° , ±0.2° , 38.04° ±0· 2° , 39. 77°

±0.2. , 41.22 ° ± 0.2. There are secondary peaks at 45.22° ±0.2°.

Further, the residual amount of isopropanol in the crystal of doripenem hydrate of the present invention is 500 ppm. Further, the residual amount of isopropanol in the crystal of doripenem hydrate of the present invention is 300 ppm. A method for preparing a doripenem hydrate crystal according to the present invention comprises the following steps:

a) Dissolving the crude product of doripenem in water at 40~70 ° C (preferably 50~60 ° C);

b) Cooling to 0~25 °C (preferably 10~25 °C), adding activated carbon, stirring and decoloring for 5~15 minutes; c) filtering, cooling the filtrate to 0~10 °C, solid precipitation, stirring and stirring 1 ~2 hours;

d) Filter and wash the filter cake with isopropanol / water = 4:1;

e) The measured value of moisture in the crystal dried at 40 to 60 ° C, 5 to 10 mmHg is 4.4 to 5.5% (preferred) 4〜5. 2%), that is, the described doripenem hydrate crystal.

Alternatively, the method for preparing the doripenem hydrate crystal of the present invention comprises the following steps: a) dissolving the crude doripenem in water at 40 to 70 ° C (preferably 50 to 60 ° C);

b) cooling to 0~25 ° C (preferably 10~25 ° C), adding activated carbon, stirring and decoloring for 5~15 minutes; C) filtering, adding the doripenem hydrate crystal of the invention to the filtrate as a seed crystal, a solid precipitated, stirring 0. 5~1 hour, adding organic solvent, cooling to -5~15 ° C, stirring is continued for 1 to 2 hours;

d) Filter and wash the filter cake with isopropyl alcohol / water = 4:1;

〜。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。 Pein hydrate crystals.

The crude doripenem may be either amorphous or known in any crystal form.

The HPLC purity of the crude doripenem is preferably 95%.

The mass ratio of the crude product of doripenem to water in the step a) is preferably 1:10 to 1:30.

The organic solvent is preferably any one of a C ₄ lower alcohol (e.g., methanol, ethanol, isopropanol, n-butanol, etc.), tetrahydrofuran, acetone, and acetonitrile; preferably isopropanol.

The ratio of the volume ratio of the organic solvent to the water used in the step a) is preferably 0.1:1 to 3:1; preferably 0.44:1~

twenty one.

The invention also provides a pharmaceutical composition comprising:

(a) a doripenem hydrate crystal according to the invention;

(b) a pharmaceutically acceptable carrier or excipient.

The invention also provides the use of the novel doripene hydrate crystal of the invention in preparing an antibacterial medicament, in particular for preparing an antibacterial agent for inhibiting Pseudomonas aeruginosa.

Compared with the prior art, the doripenem hydrate crystal provided by the invention has the following advantages: high purity (HPLC purity greater than 99.8%); low residual solvent (isopropanol residual amount not exceeding 500 ppm, generally lower than 300ppm), far below the ICH limit for isopropyl alcohol solvent residue not exceeding 5000ppm, which greatly guarantees the safety of docepinan preparation; good stability, at 40 ° C and relative humidity of 75% After being placed in the environment for 6 months, there was no significant change in the traits, contents, related substances and moisture of the samples examined. In addition, the preparation method of the doripene hydrate crystal provided by the invention has the advantages of simple process, low preparation cost, and suitable for industrial production. DRAWINGS

Figure 1 is a powder X-ray diffraction spectrum of the doripenem hydrate crystal of the present invention;

Figure 2 is a DSC spectrum of the doripenem hydrate crystal of the present invention;

Figure 3 is a TG spectrum of the doripenem hydrate crystal of the present invention;

Figure 4 is an infrared (IR) spectrum of the doripenem hydrate crystal of the present invention. detailed description

The present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention. The experimental methods in which the specific conditions are not specified in the following examples are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, the percentages and parts are percentages by weight and parts by weight. The crude doripenem used in the examples may be either amorphous or known in any form, preferably 95% by HPLC. For the preparation method, refer to ZL92111069. 3, ZL95104834. 1, ZL95193672. 7 , ZL01810309. X , ZL200610028746. 9, ZL200710127224. 9 and other documents.

The measurement of the powder X-ray diffraction spectrum is: 1. 5460 angstroms (A) of the wavelength α 1 , 1. 54439 angstroms (Α) of the wavelength of i 2 radiation source, the intensity ratio α 1 / (1 2 is 0.5 Dedye-Scherrer INEL CPS-120 with a voltage of 40 kV and a current of 30 mA. The measurement error of the diffraction angle 2 Θ is approximately ± 0.2.

DSC measurement conditions: In a closed vessel, a nitrogen flow of 50 ml/min was used, and the heating rate was 10 ° C/min at 20 to 320 ° C, using a DSC Q 2000 (TA company, USA) equipment.

TGA measurement conditions: In a closed vessel, a nitrogen flow of 100 ml/min was used, and the heating rate was 10 ° C/min at 20 to 320 ° C, using an SDT Q600 (TA company, USA) equipment.

The infrared (IR) spectrum was measured under the conditions of 24 and 40% humidity in a PE Spectrum RX apparatus after tableting with potassium bromide. Example 1

5克多尼培南粗品 Dissolved in 100~55 ° C of lOOmL distilled water, and then cooled to 25 ° C in a water bath, added 0. 5g activated carbon, stirring and decoloring for 15 minutes; suction filtration, the filtrate is cooled to about 0~10 ° C, a solid precipitated, stirred for two hours, suction filtration, washing the filter cake with isopropyl alcohol / water = 4: 1; drying at 50 ~ 60 ° C, 5mmHg 1. 5 hours, get 2g of the present invention Niperan hydrate crystals. The HPLC purity of the obtained crystal was measured by the method described in "Journal of Chromatography B, 853 (2007), 123~126"; the test was carried out by the method described in "Chinese Journal of Antibiotics, 3 (31), 2006, 187~189". The residual amount of isopropanol in the crystal.

As a result of the measurement, the crystal purity of the crystal obtained in this example was 99.85%, and the residual amount of isopropyl alcohol was 219 ppm.

The water content in the crystal was determined by Karl Fischer (KF) method to be 4.83%.

The powder X-ray diffraction spectrum of the crystal obtained in this example is shown in Fig. 1: at 2Θ, 6.43°, 13.02°, 14.96°, 15.27°, 15.85°, 16.60°, 17.46°, 20.60°, 21.04°, 22.18°. , 23.88°, 25.35°, 26.04°, 28.19°, 29.00°, 31.65. , 34.09. , 34.90. There is a main peak; at 2 Θ, it is 10.86°, 11.22°, 18.05°, 18.43°, 18.92°, 19.62°, 23.10°, 23.40°, 33.34. , 36.44. , 37.21° , 38.04. , 39.77° , 41.22° , 45.22° There are secondary peaks.

The DSC spectrum of the crystal obtained in this example is shown in Fig. 2: There is an endothermic peak at 110~160 °C, the Onset value (starting temperature) is 137.17 ° C; there is an exothermic peak at 170~200 ° C, Onset The value (starting temperature) was 179.02 °C.

The TG spectrum of the crystal obtained in this example is shown in Fig. 3: The measured value of the thermogravimetric analysis is 4.86%. The infrared (IR) spectrum of the crystal obtained in this example is shown in Fig. 4:

Absorption peak wave number (cm - absorption peak intensity group and vibration type

3541.1 s intramolecular hydrogen bond association 0-H stretching vibration

3393.8 m pyrrole ring N-H stretching vibration

3261.5 s intramolecular hydrogen bond association 0-H stretching vibration

3083.5 m C-H asymmetric stretching vibration connected to nitrogen atom

2977.7 m methyl group C-H asymmetric stretching vibration

2964.5 m

1715.7 s carboxyl group C=0 stretching vibration

1635.6 m β-lactam C=0 stretching vibration

1568.9 s C=C stretching vibration

Asymmetric deformation vibration of C-H in 1456.2 m methyl group

C-H symmetric deformation vibration in 1364.7 m methyl group

Symmetrical deformation vibration of CH in 1366.6 m methyl group 1350. 4 m

1279 m -so ₂ - Asymmetric stretching vibration

1264. 2 m

1162. 6 m -so ₂ -symmetric stretching vibration

1091. 7 m secondary alcohol c- o stretching vibration

1071. C-N stretching vibration of 9 m tertiary amine

930. 1 m carboxyl group 0H non-planar angular vibration

765. 1 m pyrrole ring N-H non-planar rocking Example 2

10 g of the crude product of doripenem was dissolved in 200 mL of distilled water at 50-55 ° C, then cooled to 25 ° C in a water bath, added with 1.0 g of activated carbon, and decolorized by stirring for 15 minutes; filtered to reduce the filtrate to about 0 to 10 ° C, the 0. lg crystal obtained in Example 1 was used as a seed crystal, and a solid precipitated. After stirring for 1 hour, 100 ml of isopropanol was added dropwise, and the mixture was stirred for 2 hours, and then suction filtered, using isopropanol/water = 4:1. 2克晶体。 The filter cake was dried at 50~60 ° C, lOmmHg for 2 hours, gave 8. 2g crystals.

The test has a HPLC purity of 99.86%, wherein the residual amount of isopropanol is 205 ppm, and the moisture measured by the Karl Fischer (KF) method is 4.79%; The powder X-ray diffraction spectrum shown, the DSC spectrum shown in Fig. 2, the TG spectrum shown in Fig. 3, and the infrared (IR) spectrum characteristics shown in Fig. 4 are shown. Example 3

The lg obtained in Example 1 was added to the solution obtained in Example 1. The lg obtained in Example 1 was added to the sol. The crystal was used as a seed crystal, and a solid precipitated. After stirring for 1 hour, 200 ml of isopropanol was added dropwise, and the mixture was cooled to 0 to 5 ° C. After stirring for 2 hours, it was suction filtered, and the filter cake was washed with isopropyl alcohol/water = 4:1. 0克晶体。 The crystallization was carried out at 0. 0g.

The test has a purity of 99. 83%, the residual amount of isopropyl alcohol is 259 ppm, and the moisture measured by the Karl Fischer (KF) method is 4.81%; The powder X-ray diffraction spectrum shown, the DSC spectrum shown in Fig. 2, the TG spectrum shown in Fig. 3, and the infrared (IR) spectrum characteristics shown in Fig. 4 are shown. Example 4

The lg obtained in Example 1 was added. The lg obtained in Example 1 was added to the mixture obtained in Example 1. The lg obtained in Example 1 was added. The crystal is used as a seed crystal, and a solid precipitates. After stirring for 1 hour, 200 ml of isopropanol is added dropwise, and the mixture is cooled to 10 to 15 ° C. After stirring for 2 hours, it is filtered with suction, and the filter cake is washed with isopropyl alcohol/water = 4:1. And lg crystals were obtained by drying at 40 to 50 ° C, 5 mmHg for 3 hours.

The sample has a HPLC purity of 99. 84%, wherein the residual amount of isopropyl alcohol is 235 ppm, and the moisture measured by the Karl Fischer (KF) method is 4.76%; The powder X-ray diffraction spectrum shown, the DSC spectrum shown in Fig. 2, the TG spectrum shown in Fig. 3, and the infrared (IR) spectrum characteristics shown in Fig. 4 are shown. Example 5

The lg obtained in Example 1 was added to the solution obtained in Example 1. The lg obtained in Example 1 was added to the mixture obtained in Example 1. The lg obtained in Example 1 was added. The crystal was used as a seed crystal, and a solid precipitated. After stirring for 1 hour, 300 ml of isopropanol was added dropwise, and the mixture was cooled to 0 to 5 ° C. After stirring for 2 hours, it was suction filtered, and the filter cake was washed with isopropyl alcohol/water = 4:1. 0克晶体。 After drying at 50~55 ° C, lOmmHg for 2 hours, gave 8. 0g crystals.

The test has a HPLC purity of 99. 87%, wherein the residual amount of isopropanol is 165 ppm, and the moisture measured by the Karl Fischer (KF) method is 4.78%; The powder X-ray diffraction spectrum shown, the DSC spectrum shown in Fig. 2, the TG spectrum shown in Fig. 3, and the infrared (IR) spectrum characteristics shown in Fig. 4 are shown. Example 6

Dissolve 10 g of the crude product of doripenem in 300 mL of distilled water at 50-55 ° C, then cool to 10 ° in a water bath.

15°C, adding l. Og of activated carbon, stirring and decoloring for 15 minutes; suction filtration, adding 0. lg crystals obtained in Example 1 as a seed crystal, solid precipitation, stirring for 1 hour, adding 200 ml of isopropanol, dropping and cooling The crystallization of 7. 8g of crystals was obtained by pulverizing the granules. The granules were washed with isopropyl alcohol/water = 4:1, and dried at 40 to 45 ° C, lOmmHg for 5 hours to obtain 7.8 g of crystals.

The detection of the crystals of the present example has a purity of 99.88%, wherein the residual amount of isopropanol is 265 ppm, the moisture measured by the Karl Fischer (KF) method is 5.01%; and has the powder X-ray diffraction spectrum shown in FIG. 1, the DSC spectrum shown in FIG. 2, and the TG spectrum shown in FIG. The infrared (IR) spectrum features shown in Figure 4 and Figure 4. Example 7

10 g of the crude product of doripenem was dissolved in 200 mL of distilled water at 50-55 ° C, then cooled to 20 to 25 ° C in a water bath, added with 1.0 g of activated carbon, and decolorized by stirring for 15 minutes; filtered to reduce the filtrate to about 0~ 5 克, added the 0. lg crystal obtained in Example 1 as a seed crystal, a solid precipitated, stirred for 1 hour, 200 ml of isopropanol was added dropwise, and the mixture was cooled to -5 to 0 ° C, stirred for 2 hours, and then filtered. The crystals were washed with isopropyl alcohol/water = 4:1, and dried at 55 to 60 ° C, 5 mmHg for 1 hour to obtain 7.88 g of crystals.

The test has a HPLC purity of 99. 82%, wherein the residual amount of isopropyl alcohol is 275 ppm, and the moisture measured by the Karl Fischer (KF) method is 4.87%; The powder X-ray diffraction spectrum shown, the DSC spectrum shown in Fig. 2, the TG spectrum shown in Fig. 3, and the infrared (IR) spectrum characteristics shown in Fig. 4 are shown. Example 8

10 g of the crude product of doripenem was dissolved in 250 mL of distilled water at 55-65 ° C, and then cooled to 20 to 25 ° C in a water bath, added with 1.0 g of activated carbon, and decolorized by stirring for 15 minutes; filtered to reduce the filtrate to about 0~ 5 。 l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l The crystals were washed with methanol/water = 4:1, and dried at 50 to 55 ° C, 5 mmHg for 1 hour to obtain 7.95 g of crystals.

5%; and having the moisture content of the sample obtained by the Karl Fischer (KF) method of 4. 53%; The powder X-ray diffraction spectrum, the DSC spectrum shown in Fig. 2, the TG spectrum shown in Fig. 3, and the infrared (IR) spectrum characteristics shown in Fig. 4. Example 9

10 g of the crude product of doripenem was dissolved in 200 mL of distilled water at 60 to 70 ° C, and then cooled to 20 to 25 ° C in a water bath, added with 1.0 g of activated carbon, and decolorized by stirring for 15 minutes; filtered to reduce the filtrate to about 0~ 5 ° C, the 0. lg crystal obtained in Example 1 was used as a seed crystal, and a solid precipitated. After stirring for 1 hour, 300 ml of tetrahydrogen was added dropwise. The crystals were dried, and the mixture was cooled to -5 to 0 ° C. After stirring for 2 hours, the mixture was filtered, and the filter cake was washed with tetrahydrofuran, and dried at 50 to 55 ° C, 5 mmHg for 1 hour to obtain 7.97 g of crystals.

The test has a HPLC purity of 99. 73%, wherein the residual amount of tetrahydrofuran is 175 ppm, and the moisture measured by the Karl Fischer (KF) method is 4.78%; The powder X-ray diffraction spectrum, the DSC spectrum shown in Fig. 2, the TG spectrum shown in Fig. 3, and the infrared (IR) spectrum characteristics shown in Fig. 4. Example 10

10 g of the crude product of doripenem was dissolved in 200 mL of distilled water at 60-65 ° C, and then cooled to 20 to 25 ° C in a water bath, added with 1.0 g of activated carbon, and decolorized by stirring for 15 minutes; filtered to cool the filtrate to about 0~ 5 克, added the 0. lg crystal obtained in Example 1 as a seed crystal, a solid precipitated, after stirring for 1 hour, 400 ml of acetone was added dropwise, and the mixture was cooled to -5 to 0 ° C, stirred for 2 hours, and then suction filtered. The crystals of 8.03 g were obtained by drying the filter cake, and drying at 50 to 55 ° C, 5 mmHg for 1 hour.

15%; and having a moisture content of 515 ppm, a 5% by weight of the acetone, using a Karl Fischer (KF) method, and having a moisture content of 5.2 ppm; The powder X-ray diffraction spectrum, the DSC spectrum shown in Fig. 2, the TG spectrum shown in Fig. 3, and the infrared (IR) spectrum characteristics shown in Fig. 4. Example 11

Dissolve 10 g of crude fennipan in 200 mL of distilled water at 40~50 °C, then cool to 20~ in a water bath.

Lg, the addition of l. Og of activated carbon, stirring and decoloring for 15 minutes; suction filtration, the filtrate was cooled to about 0~5 ° C, adding 0. lg crystals obtained in Example 1 as a seed crystal, solid precipitation, stirring for 1 hour After the dropwise addition of 400 ml of acetonitrile, the mixture was cooled to -5 to 0 ° C, stirred for 2 hours, and then filtered, and the cake was washed with acetonitrile, and dried at 50 to 55 ° C, 5 mmHg for 1 hour to obtain 7.89 g of crystals.

The HPLC purity of the crystal obtained in this example was 99.59%, and the residual amount of acetonitrile was

175 ppm, the moisture measured by the Karl Fischer (KF) method is 4.95%; and has the powder X-ray diffraction spectrum shown in Fig. 1, the DSC spectrum shown in Fig. 2, and the TG spectrum shown in Fig. 3. The infrared (IR) spectrum features shown in Figure 4 and Figure 4. Investigating the stability of the doripenem hydrate crystal of the present invention: The obtained doripene hydrate crystal of the present invention is placed in a drier having a relative humidity of 75%, and placed in a constant temperature drying oven at 40 ° C, respectively Samples were taken after 0, 1, 2, 3, and 6 months to analyze the traits, contents, related substances, and moisture of the analyzed samples. The results are shown in Table 4.

Table 4

It can be seen from Table 4 that the Dominican hydrate crystal of the present invention has no significant change in properties, content, related substances and moisture during the 6-month investigation period, and has good stability. Example 13 Pharmaceutical Composition

100 g of the donatenan hydrate crystals obtained in any of Examples 1 to 11 were mixed with 4 times by weight of the starch, and then tablets were prepared in a usual manner. All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entirety in the the the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art after the above-described teachings of the present invention, which are also within the scope defined by the appended claims.

Claims

Rights request

A doripene hydrate crystal characterized by: a powder X-ray diffraction spectrum of the crystal having 3 or more 2 Θ characteristic peaks selected from the group consisting of 6.43° ± 0.2°, 13.02 ° ± 0.2 ° , 14.96 ° ± 0.2 ° , 15.27 ° ± 0.2 ° , 15.85 ° ± 0.2 ° , 16.60 ° ± 0.2 ° , 17.46 . ±0.2° , 20.60° ±0.2° , 21.04° ±0.2° , 22.18° ±0.2° , 23.88° ±0.2° , 25.35° ±0.2° , 26.04° ±0.2° , 28.19° ±0.2° , 29.00° ±0.2 °, 31.65. ±0.2°, 34.09° ±0.2°, 34.90. ±0.2°, and the measured value of moisture in the crystal is 4.4 to 5.5%.

2. A doripene hydrate crystal, characterized in that the powder X-ray diffraction spectrum of the crystal is substantially as shown in Fig. 1, and the measured value of moisture in the crystal is 4.4 to 5.5%.

The doripene hydrate crystal according to claim 1 or 2, wherein the crystal further has a DSC spectrum shown in FIG. 2, a TG spectrum shown in FIG. 3, and a TG spectrum shown in FIG. IR spectrum.

The doripenem hydrate crystal according to claim 1 or 2, wherein the residual amount of isopropanol in the crystal is 500 ppm.

5. A method of preparing a doripenem hydrate crystal according to claim 1 or 2, wherein the method comprises the steps of:

a) Dissolve the crude product of doripenem in water at 40~70 °C;

b) Cool to 0~25 ° C, add activated carbon, stir and discolor for 5~15 minutes;

c) Filtration, the filtrate is cooled to 0~10 ° C, a solid precipitates, and the mixture is stirred for 1 to 2 hours; d) filtered, and the filter cake is washed with isopropyl alcohol / water = 4:1;

e) The measured value of moisture in the crystals dried at 40 to 60 ° C, 5 to 10 mmHg, is 4.4 to 5.5%, that is, the donatenan crystals are obtained.

6. The method for preparing a doripenem hydrate crystal according to claim 5, wherein the operation of step c) is as follows:

Filtration, adding the crystal of doripenem hydrate according to claim 1 or 2 to the filtrate as a seed crystal, solid precipitation, stirring for 0.5 to 1 hour, adding an organic solvent, and cooling to -5 to 15 ° C Continue to stir for 1 to 2 hours.

The method for preparing a doripenem hydrate crystal according to claim 5, wherein the crude doripenem is amorphous or known in any crystal form.

The method for preparing a doripenem hydrate crystal according to claim 5, wherein: The crude purity of the crude doripenem was 95%.

The method for preparing a doripenem hydrate crystal according to claim 5, wherein the mass ratio of the crude product of doripenem to water in the step a) is 1:10 to 1:30.

The method for preparing a doripenem hydrate crystal according to claim 6, wherein the organic solvent is any one of methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, acetone and acetonitrile. One.

The method for preparing a doripenem hydrate crystal according to claim 6, wherein the volume ratio of the organic solvent to the water used in the step a) is 0.1:1 to 3:1.

12. A pharmaceutical composition, characterized in that the composition comprises:

(a) the doripenem hydrate crystal of claim 1 or 2;

(b) a pharmaceutically acceptable carrier or excipient.