WO1997001563A1 - Stable bicozamycin benzoate crystals - Google Patents

Abstract

Stable bicozamycin benzoate crystals and a process for the production thereof.

Description

 Specification

Title of invention

 Stable crystals of vicosamycin benzoate.

Technical field

 The present invention relates to a novel and stable crystal of vicosamycin benzoate and a method for producing the same.

Background art

 Bicozamycin benzoate is a known substance (see, for example, JP-A-48-39497, U.S. Pat. No. 3,923,790, International Publication No. W094Z17073), and is currently sold as a marine medicine In addition, development as a terrestrial veterinary drug is being actively pursued.

 However, bicozamycin benzoate obtained by the methods described in these publications has drawbacks in terms of crystal yield, quality, handling, and the like.

 That is, crystal forms of vicosamycin benzoate include 020 type (stable type), 015 type (metastable type), F01 type (the above-mentioned JP-A-48-39497) and an amorphous type. However, it is desirable to obtain a 020 type crystal from the viewpoints of yield, quality, and crystal handling as described below.

 (1) Yield aspect

 The crystallization loss can be reduced because the solubility is smaller than that of the 015 type crystal.

 Since there is no adhesion and the fluidity is good, the dischargeability from the conical dryer is good and the adhesion loss is small.

 (2) Quality aspects

 Low contamination with impurities (dihydro-form of bicosamycin benzoate) and improved quality of purified crystals.

 (3) Operability

 The specific volume is small, the number of batches during drying is small, and the schedule can be shortened and the number of operating personnel can be reduced.

Furthermore, the 020 type crystal has the following advantages as compared with the conventional F01 type crystal. (1) Because it is stable without moisture absorption, it is easy to handle crystals under scale-up conditions.

 (2) Since there is no adhesion and the fluidity is good, the dischargeability from the conical dryer is good, so there is little adhesion loss and the operability is good.

 (3) The specific volume is small, the number of batches during drying and drying is reduced, and the schedule can be shortened and the number of personnel can be reduced.

 (4) It is less susceptible to static electricity than F01 type crystals, and there is less danger of ignition due to static electricity when handling crystals, and safety is improved.

 In view of the above, a challenge is to produce a stable crystal form of bicosamycin benzoate (type 020) with high purity and high yield.

Disclosure of the invention

 As a result of diligent research, the present inventors have dissolved the crude crystals of vicosamycin benzoate in hydroalcoholic alcohol, added vicosamycin benzoate crystals or powder as seed crystals, and added By crystallization at the above temperature, a new finding of bicozamycin benzoate, a new finding that a stable crystal (type 020) can be produced with high purity, was obtained, and the present invention was completed.

 Therefore, the present invention is characterized in that crude crystals of vicosamycin benzoate are dissolved in aqueous alcohol, and then crystals or powder of vicosamycin benzoate are added as seed crystals, followed by crystallization at a temperature of 3 ° C. or more. It is intended to provide a novel and stable crystal of kozamycin benzoate and a method for producing the same.

 The production of novel and stable crystals of bicozamycin according to the present invention is carried out by dissolving the crude crystals of bicozamycin besoleate in aqueous alcohol, and the aqueous alcohol includes methanol, ethanol, propanol, isopropanol, and the like. An aqueous solution such as butanol may be used. The concentration of the hydrous alcohol may be any concentration at which the bicozamycin benzoate is completely dissolved. ) May be in the concentration range of 20 to 40%.

Next, a crystal or powder of vicosamycin benzoate is added as a seed crystal to the solution of vicosamycin benzoate and crystallized at a temperature of 3 ° C or more. Here, the crystal form of vicosamycin benzoate used as a seed crystal is not limited. (020 type, 015 type, amorphous type, etc.) or powder.

 In addition, crystallization is performed by lowering the alcohol concentration in the solution by adding water. In the case of isopropanol, about 16% is best.

 Furthermore, the crystallization temperature is 3 ° C. or higher for hydrated isopropanol, preferably

Best results are obtained with a range of 3-5.

 According to the present invention, stable crystals of vicosamycin benzoate can be obtained with high yield.

The crystal (type 020) thus obtained has the following properties.

1 Table 1

(1) X-ray powder diffraction data

0 2 0 type 0 1 5 type F 0 1 type

Angle relative intensity Angle relative intensity Angle relative intensity 2Θ (') I / I…) 2Θ Ο I / I…) 2Θ (') I / In, ax (¾)

6.26 35.87 6.56 100.0 5.62 100.0 10.61 100.0 10.63 34.05 6.77 25.64 11.65 13.14 11.58 13.26 7.67 12.02 12.05 8.55 12.00 9.85 9.45 16.85

13.23 8.55 13.30 14.46 11.12 6.37 14.14 54.10 14.14 12.83 11.66 7.03

14.96 21.05 15.05 18.89 11.98 8.45 16.40 30.24 15.66 13.71 12.80 5.74 17.09 11.66 18.02 0.86 13.72 5.22

18.81 12.51 18.77 16.19 14.38 4.51

19.24 24.39 19.65 26.95 15.24 5.59

19.55 6.36 21.18 14.01 15.98 26.79

20.00 4.20 23.06 3.73 16.24 26.62 21.02 12.15 23.75 6.63 17.12 8.18 21.20 13.53 25.63 3.50 17.93 6.86 21.65 15.67 26.90 6.53 19.58 4.53 21.74 11.78 27.69 5.54 20.62 5.29 22.14 11.90 21.31 2.45

22.85 4.72 22.02 2.65

23.22 3.71 23.57 1.80

24.22 8.25 24.77 1.93 24.35 10.27 26.84 1.32 24.67 7.66 27.17 3.67

25.22 4.20 31.42 1.08

26.09 5.76

 26.50 11.31

 26.86 5.39

 27.78 14.31

 28.14 5.76

 30.09 5.51

31.70 4.13 Table 2

(2) Solubility in hydrous isopropanol

Table 4

(4) IR spectrum

 In the IR spectrum (Nudiol) of each crystal type, the peaks with significantly different absorption patterns are shown in comparison.

0 2 0 type 0 1 5 type F 0 1 type

(cm- ¹ ) (cm- ¹ ) (cm " ¹ )

3 2 5 7 ¾ 8 2 Q Q Q ί β υ

 3 2 6 5 3 2 4 5

1 7 1 0 1 7 1 4 1 7 2 6

 1 fi «ς 1« Q 1 β o Q q

 1 6 7 0

1 6 2 4 1 6 0 1 1 6 0 2

 1 6 0 1 1 5 8 5

1 4 5 6 1 4 5 8 1 4 6 2

 1 4 0 0 1 4 0 5 1 4 0 9

 1 3 7 9 1 3 7 9 1 3 7 9

1 2 8 6 1 2 8 6 1 2 7 3

1 2 6 3 1 2 5 9

W 97 1563

Table 5

 (5) hygroscopic

Next, the present invention will be described with reference to examples.

Example

 55 ml of pyridine and 0.91 g of 4-dimethylaminopyridine were charged and dissolved in a 300 ml 3 face corben. Next, 22.4 g of vicosamycin in terms of purity was charged, stirred at room temperature for about 30 minutes to dissolve, and then cooled to 0 to 5 ° C. 36.9 g of benzoic anhydride was charged and stirred at 15-20 ° C for 2 hours. After the reaction, 2.5 g of methanol was added and the mixture was stirred for 20 minutes. The reaction-terminated liquid was transferred to a 500 ml 3-face corvene, diluted with 125 ml of ethyl acetate, diluted with 75 ml of normal heptane at room temperature, and stirred for 1 hour to precipitate the desired crystal. Then, 175 ml of normal heptane was added dropwise over 30 minutes, and the mixture was further stirred for 1 hour. The precipitated crystals were filtered and washed successively with 50 ml of a mixture of ethyl acetate and normal heptane (1: 1) and 7.5 ml of water. Then, the crystals were dried under vacuum to obtain crude crystals of vicosamycin benzoate 34.5.

 In the same manner as above, another 10 g of crude crystals of vicosamycin benzoate were obtained.

 66 ml of isopropyl alcohol and 97 ml of water were charged into a 300 ml 3-faced corben, and the liquid temperature was adjusted to 20 to 25 ° C. Next, at the same temperature, 40 g of the crude crystal of bicozamycin benzoate obtained above was charged and stirred for 30 minutes to dissolve.

The lysate was clarified, and the 300 ml 3 face colben and the vessel were washed with 42 ml of water. The clarified solution and washing solution are stored in a 500 ml 3 ml corven and kept at 3-5 ° C. And cooled.

 260 mg of seed crystals were added to the above solution with stirring, and the mixture was stirred at 3 to 5 ° C for 2 hours to precipitate crystals of the target substance. Then, 20½1 of water cooled to 0 to 5 ° C was dropped over about 30 minutes, and the mixture was further stirred at 3 to 5 ° C for 3 hours.

The precipitated crystals were collected and washed with 120 ml of water cooled to 0 to 5 ° C. Then by vacuum drying the crystals to obtain 020 type crystal 28.3g of Bikozamaishin base Nzoe Bok (dehydrated product terms 99 ^2.3% 82.4% yield).

Claims

The scope of the claims

 Vicoza myzozoate having stable powder X-ray diffraction values as follows:

flip day

 Angle 2Θ) Relative intensity I / Imax (%)

 6.26 35.87

 10.61 100.0

 11.65 13.14

 12.05 8.55

 13.23 8.55

 14.14 54.10

 14.96 21.05

 16.40 30.24

 17.09 11.66

 18.81 12.51

 19.24 24.39

 19.55 6.36

 20.00 4.20

 21.02 12.15

 21.20 13.53

 21.65 15.67

 21.74 11.78

 22.14 11.90

 22.85 4.72

 23.22 3.71

 24.22 8.25

 24.35 10.27

 24.67 7.66

 25.22 4.20

26.09 5.76

26.50 11.31

 26.86 5.39

 27.78 14.31

 28.14 5.76

 30.09 5.51

 31.70 4.13

 2. Dissolve the crude crystals of vicosamycin benzoate in aqueous alcohol, add crystals or powder of vicosamycin benzoate as seed crystals, and crystallize at a temperature of 3 ° C or higher. A method for producing stable crystals.