Field of the invention

The present invention relates to the field of pharmaceuticals. Especially, it is related to a new crystal form of cefoperazone sodium. The present invention also is related to a method for preparing crystalline cefoperazone sodium.

Background of the invention

Cefoperazone sodium belongs to the class of third generation cephalosporins and has many advantages including a broad antimicrobial spectrum, resistance to β-lactamases, low toxicity and strong antibiotic activity. The compound is widely applied in clinical therapy.

Cefoperazone sodium has been provided in amorphous or crystalline forms. So far, the crystalline forms include Crystal Form A and Crystal Form B (See Chinese Patent Application No. CN 1970561A (publication date May 30, 2007, entitled "A new crystal form of cefoperazone sodium and its production method"); and Xue J., Chang- qin H., Li-hong Y., Rui-ping W., Jian-wen L, et al. (201 1 ) Journal Addiction Research & Therapy, 2:1 16. doi:10.4172/2155-6105.10001 16 "Relationship between Crystal Form of Cefoperazone Sodium and Its Stability"). Crystal Form A belongs to the triclinic crystal system, and Crystal Form B belongs to the monoclinic crystal system.

The present invention provides a new crystal form of cefoperazone sodium, referred to as Crystal Form C. Crystal Form C belongs to the orthorhombic crystal system. The present invention also provides a method for making Crystal Form C of cefoperazone sodium. Detailed description of the invention

In a first aspect, the present invention provides a new crystal form of cefoperazone sodium, hereafter referred to as crystal Form C, the XRD spectrum of which is given in Figure 1 .

Crystal Form C is an orthorhombic crystal, distinguishing from the crystal forms in the prior art documents, i.e. Crystal Forms A and B. Based on the cell parameter of the crystal system, the orthorhombic crystal system has the following characteristics: a≠b≠c and all angles = 90°.

In one embodiment, the unit cell dimensions are a=52.0±0.5A, b=52.0±0.5A, c=5.0±0.5A with the proviso that a≠b≠c. In another embodiment the ratio a:b:c=(1.00±0.05):(1 .00±0.05):(0.10±0.01 ) with the proviso that a≠b≠c. In a preferred embodiment a=52.15A, b=51 .87A and c=4.95A. In a most preferred embodiment a=52.1516038A, b=51 .8713984A and C=4.9455441A. The space group is F222.

In a second aspect, the present invention provides a method for selecting good crystals of cefoperazone sodium.

The selection is based on the diffractograms, formed by X-ray powder diffraction. The term 'good crystals of cefoperazone sodium' refers to crystals having a high crystallinity and a large crystal size. For crystals with a larger size, one can read from the diffractogram a narrower peak width and also better separation of the otherwise overlapping diffraction peaks.

For peak width (full width at half maximum, FWHM), the peak at -29=7.5 ^° (Peak no 8 in Table 1 ) is used. The term 'FWHM' refers to the degree of the angle between the two points on the diffractogram at half of the peak height, with the unit in degrees (°). Preferably, the FWHM is less than 0.3. More preferably, the FWHM is less than 0.2. Most preferably, the FWHM is less than 0.19.

For estimation of the peak separation, the two peaks at -29=13.9 ^° (Peak no 12 in Table 1 ) and -29=14.4 ^° (Peak no 2 in Table 1 ) are used. As an indicator, the ratio of the intensity at the minimum (l _min ) between these two peaks, at approximately 29=14.1 ^° (see also Figure 2), and intensity (l ₃ ) of the peak at -29=13.9 ^° is used. The ratio of the intensity of the peak at -29=7.5 ^° (l ₂ ) to the peak at -29=3.3 ^° ( _, ;Peak no 1 in Table 1 ), as a side indicator, is used. Preferably, the ratio of I _min /l3 is less than 90%. More preferably, the ratio of I _min /l3 is less than 80%. Most preferably, the ratio of I _m m/l3 is less than 70%. Still most preferably, the ratio of I _min /l3 is less than 65%. Preferably, the ratio of l ₂ / is less than 40%. More preferably, the ratio of l ₂ /li is less than 30%. Most preferably, the ratio of l ₂ /li is less than 20%. Still most preferably, the ratio of l ₂ /li is less than 15%.

The method comprises the following steps:

• Preparing a crystal of cefoperazone sodium;

• Placing the crystal in an X-ray powder diffractometer to record a diffractogram;

• With the FWHM, I _min /l3 and l ₂ /li, determining the quality grade of the crystal The three parameters, namely, the FWHM, I _min /l3 and l ₂ / can be changed independently. In other words, if a crystal has a small FWHM and a relatively high l ₂ /li, it may still be regarded as a good crystal.

In a third aspect, the present invention provides a method of making a crystal form of cefoperazone sodium from cefoperazone acid. Thus, the third aspect of the present invention provides a method for the preparation of Crystal Form C of cefoperazone sodium comprising the steps of:

(a) mixing cefoperazone acid with an organic solvent and adding a sodium source;

(b) adding an anti-solvent to the mixture obtained in step (a) followed by isolating the solid material from the mixture thus obtained.

The method comprises two phases: reaction (salt-forming) and crystallization (anti-solvent crystallization).

The term 'reaction' refers to transferring the raw material cefoperazone acid into cefoperazone sodium with a salt-forming agent. The term 'crystallization' refers to forming a crystal with a solvent and an anti-solvent.

In the first phase of the method of the third aspect, cefoperazone acid is suspended in an organic solvent, preferably a ketone, more preferably acetone or a mixture of acetone and water and into the suspension a sodium source is added in portions or drop wise. A suitable sodium source is sodium bicarbonate which may be added as solid or as a solution of sodium bicarbonate in water. The temperature is controlled within the range of 0-50°C, preferably within the range of 15-23°C. After the addition of the solution of sodium bicarbonate in water, stirring is continued for a certain time. The pH is adjusted in the range of 5.5 to 7.0, preferably within the range of 6.5 to 6.6, through the addition of the solution of sodium bicarbonate in water. The cefoperazone acid, also referred to as cefoperazone free acid may be obtained from a commercial source. Alternatively, cefoperazone acid may be obtained directly from a synthetic process leading to cefoperazone acid. If so, it may exist in a reaction liquid together with other substances, such as impurities. Sodium bicarbonate functions as a salt-forming agent. Other salt-forming agents can be used, such as sodium acetate, sodium carbonate, sodium ethylhexanoate, sodium hydroxide or sodium isooctanoate. The salt-forming agents may be formulated into a solution with water and/or acetone. Preferably, the salt-forming agent is formulated into an aqueous solution. For example, sodium bicarbonate may be added as a solution in water, at a concentration of 0.08 g/ml (8% (w/v)), or 0.04 g/ml (4% (w/v)).

In the second phase of the method of the third aspect, the temperature is brought to 20-25°C. Subsequently an anti-solvent is added, such as acetone or isopropanol or, preferably, a mixture of acetone and isopropanol. Alternatively, a mixture of acetone and ethanol is added. Or, only acetone may be added. Other suitable anti-solvents are a mixture of acetone and acetonitrile, a mixture of acetone and isopropyl acetate, a mixture of acetone and 1 ,2-dichloroethane, and the like. The term 'anti-solvent' refers to the substance(s) that is added to initiate the formation of crystal. The anti-solvent may be added in portions. For example, if acetone is used, the acetone may be added in three portions, a first portion, a second portion and a third portion.

The temperature may be changed, with several platforms. For example, the temperature at the beginning of crystallization may be a temperature of 20 to 25°C, then the temperature may be lowered to 18°C, and then in the end, the temperature may be further lowered to a range of 10-15°C.

In a fourth aspect, the present invention provides a pharmaceutical composition comprising Crystal Form C of cefoperazone sodium.

Crystal Form C of cefoperazone sodium can be used to treat the diseases that are treated with cefoperazone sodium or cefoperazone acid, preferably in a suitable formulation. Any composition comprising Crystal Form C is within the scope of the present invention.

In a fifth aspect, the present invention provides the use of Crystal Form C of cefoperazone sodium in the preparation of an anti-infective medicament.

Legend to the Figures

Figure 1 is the XRD spectrum of Crystal Form C of cefoperazone sodium. X-axis: 2-theta value (deg). Y-axis: intensity (cps). The following 25 strongest peaks are given below in Table 1 .

Table 1 : Peak position (in 2-theta and d spacing) and relative peak intensity for the 25 strongest peaks used for the indexing

Peak no 2-Theta (deg) d Spacing (A) l/lo (%)

1 3.299 26.76 100

2 14.350 6.167 86.69

3 19.838 4.472 83.83

4 20.422 4.345 63.06

5 17.992 4.926 59.93

6 21 .521 4.126 56.93

7 18.624 4.760 49.83

8 7.505 1 1 .77 41 .26

9 4.712 18.74 36.16

10 25.071 3.549 31 .26

1 1 26.455 3.366 27.46

12 13.941 6.347 30.49

13 10.107 8.745 27.79

14 26.010 3.423 23.82

15 19.238 4.610 20.24

16 9.527 9.275 18.36

17 6.710 13.16 17.67

18 24.1 13 3.688 17.64

19 22.080 4.023 17.49

20 20.666 4.295 16.79

21 23.628 3.762 15.56

22 10.663 8.290 14.06

23 27.339 3.260 1 1 .96

24 15.137 5.849 10.35

25 16.931 5.233 8.1 16 Figure 2 is the determination of l _min (position marked with arrow) from the XRD spectrum of Crystal Form C of cefoperazone sodium. X-axis: 2-theta value (deg). Y-axis: intensity in arbitrary units (a.u.).

EXAMPLES

The present invention is further illustrated below with reference to the concrete examples. It is to be understood that these examples are to describe the present invention, not to limit the scope of the present invention. It is also to be understood that those skills in the art may make various modifications or alterations after reading the content taught by the present invention. These equivalents also fall within the scope limited by the claims of this application.

Example 1

To a suspension of 10.0 g of cefoperazone free acid in 40 ml acetone, stirred at 15-20°C, 15.4 ml of 8% sodium bicarbonate in water was added drop wise in 30 min, to a final pH of 6.5-6.6. The resulting solution was kept stirring for 10 min and subsequently transferred into a crystallization reactor after which 35 ml of a mixture acetone:isopropanol (2:1 ) was added in 10 min with vigorous stirring (stirring speed at about 250 rpm). The temperature was kept at 20-25°C. The mixture was then stirred for 30 min at 80 rpm. Another portion of 75 ml acetone:isopropanol (2:1 ) mixture was added at the same temperature and the stirring speed was adapted to 100 rpm. After stirring for 40-50 min, 80 ml acetone:isopropanol (2:1 ) mixture was added in 15 min and the temperature was adjusted to 10-15 °C, after which stirring was continued at 80 rpm for approximately 30 min. The slurry was filtered and washed twice with 50 ml acetone each time. The resulting white solid was dried for 20 h at room temperature. The dried white solid was used as crystal seed for Examples 2-6.

Example 2

To a suspension of 10.0 g of cefoperazone free acid in 40 ml acetone, stirred at 15-20°C, 15.4 ml of 8% sodium bicarbonate in water was added drop wise in 30 min, to a final pH of 6.5-6.6. The resulting solution was kept stirring for 10 min and subsequently transferred into a crystallization reactor after which 35 ml of a mixture acetone:isopropanol (2:1 ) was added in 10 min with vigorous stirring (stirring speed at about 250 rpm). The temperature was kept at 20-25°C. Seed crystals from Example 1 were added and the mixture was stirred for 30 min at 80 rpm. Another portion of 75 ml acetone:isopropanol (2:1 ) was added at the same temperature and the stirring speed was adapted to 100 rpm. After stirring for 40-50 min, 80 ml acetone:isopropanol (2:1 ) mixture was added in 15 min after which the temperature was adjusted to 10-15°C and stirring was continued for approximately 30 min at 80 rpm. The resulting slurry was filtered and washed twice with 50 ml acetone each time. The resulting white solid was dried in vacuum at 40 °C. The isolated yield was approximately 9.3 g (89.9%).

Example 3

This crystallization experiment was performed as described above for Example 2. The anti-solvent used was acetone:isopropanol (10:1 ). The isolated yield was approximately 10.1 g (97.6%).

Example 4

The crystallization experiment was performed as described above for Example 2. The anti-solvent used was acetone:ethanol (2:1 ). The isolated yield was approximately 9.0 g (87.0%).

Example 5

The crystallization experiment was performed as described above for Example 2. The anti-solvent used was acetone:ethanol (10:1 ). The isolated yield was approximately 9.8 g (94.8%).

Example 6

To a suspension of 10.0 g of cefoperazone free acid in 40 ml acetone and 5 ml water, stirred at 15-20°C, 15.4 ml of 8% sodium bicarbonate in water was added drop wise in 30 min, to a final pH of 6.5-6.6. The resulting solution was kept stirring for 10 min and subsequently transferred into a crystallization reactor after which 50 ml of acetone was added in 10 min with vigorous stirring (stirring speed was approximately 120 rpm). The temperature was kept at 20-25°C. Seed crystals from Example 1 were added and the mixture was stirred for 30 min at 80 rpm. Another portion of 100 ml acetone was added at the same temperature and the stirring speed was kept at 80 rpm. After stirring for 30 min, 100 ml acetone was added in 15 min and the temperature was adjusted to 10-15°C, after which stirring was continued for approximately 30 min at 80 rpm. The resulting slurry was filtered and washed twice with 50 mL acetone each time. The resulting solid was dried in vacuum. The isolated yield was approximately 10.15 g (98.1 %).

Example 7

For the crystals obtained in Examples 2-6, the X-ray powder diffractograms were recorded on an X-ray powder diffractometer from BRUKER, D8 ADVANCE, which uses copper Ka radiation and has a VANTEC array detector with divergence slit angle set at

0.3°. The scanning angle 2Θ ranged from 2 ^° to 60 ^° , with step (in 2Θ) around 0.007 ^° , and the count time 1 s/step. The sample rotated at 15 rpm during the measurement. The measurements were carried out at room temperature and ambient humidity.

For the crystal prepared in Example 2, the FWHM is 0.188 ^° , the l ₂ / is 29.7%, and the

Imin l3 is 63.7%. The quality of the crystal was marked as Grade 1 .

For the crystal prepared in Example 4, the FWHM is 0.182 ^° , the l ₂ / is 28.4%, and the

Imin l3 is 58.9%. The quality of the crystal was marked as Grade 1 .

Example 8

The indexing of the X-ray powder data was carried out using program TOPAS 4-2 from Bruker. The crystal prepared in Example 2 was tested by HPLC and confirmed the purity of >99%, in respect of organic impurities. The X-ray powder diffraction data of this crystal was used for the indexing. The data was recorded on the same diffractometer as for Example 7, but using a position sensitive detector (PSD) (i.e. scintillation counter). The count time was 20s/step. The data was additionally corrected in sample displacement error by an extra measurement using silicon powder (NIST SRM 640d) as an external standard. The thus collected data, which were used as input for indexing the crystal structure, are summarized in Table 1 (see Legend to Figure 1 ). The conclusion from the above indexing was that the crystal belongs to an orthorhombic crystal system with space group F222, unit cell dimensions are a=52.1516038A, b=51.8713984A and C=4.9455441A.