Clathrate of azithromycin hydrate with 1,2-propyleneglycol, production thereof and pharmaceutical composition containing the same

FIELD: organic chemistry, pharmaceutical industry.

SUBSTANCE: invention relates to clathrate of azithromycin hydrate with 1,2-propyleneglycol of formula I , wherein m =1-2 and n = 0.20-0.40. Method for production of target compound includes azithromycin dissolution in acetone followed by addition of 1,2-propyleneglycol and water in solution, formed crystal filtering, washing with water and drying. Also disclosed is pharmaceutical composition for microbial infection treatment based on clathrate of formula I.

EFFECT: azithromycin with reduced hygroscopicity and increased storage stability.

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The technical field

This invention relates to a new clathrate hydrate azithromycin 1,2-propylene glycol, the method of its production and pharmaceutical composition containing the clathrate.

The level of technology

Azithromycin, 9 deoxo-9a-Aza-9a-methyl-9a-homoerythromycin And (N-methyl-11-Aza-10-deoxo-10-dihydroergotamine: IUPAC formula (II)described in U.S. patent No. 4517358 and 4474768, is a semi-synthetic macrolide antibiotic azalides type used for treatment of bronchial infections, sexually transmitted infections, and dermatological infections (see Kirste and Sides. Antimicrob. Agents Chemother., 33, 1419 (1989)).

(II)

It is known that azithromycin exists in three forms: anhydrous, monohydrate and dihydrate. These forms are identified by powder x-ray and differential scanning calorimetry.

The anhydride of azithromycin, which is described in U.S. patent No. 4517359, is not crystalline product, and, thus, its high absorbency makes it unacceptable for pharmaceutical compositions.

Further, the monohydrate azithromycin (so pl. 136° (C)described in U.S. patent No. 4474768 and international publication WO No. 89/00576 is crystalline, but also hydroscopic, making it difficult to preserve in it the water content at the permanent level.

In international publication WO No. 89/000576 describes a method for dihydrate azithromycin (so pl. 126° (C) of the monohydrate azithromycin by recrystallization from a mixture of tetrahydrofuran, water and5-C7aliphatic hydrocarbon. Although dehydrate less hygroscopic than monohydrate, water content must be maintained during stage vacuum drying at a relatively low temperature. Such control of the water content, however, is not sufficient to remove toxic aliphatic hydrocarbon solvent, necessarily used in the process of recrystallization. On the other hand, vacuum drying at higher temperatures can lead to the formation of dihydrate azithromycin with unwanted water content.

Therefore, it was made many attempts to develop a new crystalline or solvate form of azithromycin. For example, in the publication EP No. 0984020 described the clathrate monohydrate azithromycin with isopropanol formula (III).

(III)

In international publication WO No. 00/32203 described MES with ethanol hydrate azithromycin of formula (IV)

(IV)

However, there is still a need for improved crystalline form crystal azithromycin suitable for receipt of the pharmaceutical compositions.

Brief description of the invention

Therefore, the object of this invention is a new form of azithromycin which can be used for getting medicines for the treatment of various microbial infections.

In accordance with this invention presents a new clathrate hydrate azithromycin 1,2-propylene glycol of the formula (I)

(I)

where m is from 1 to 2 and n is from 0.20 to 0.40.

The present invention also presents a method of producing clathrate formula (I), comprising the stage of: (1) dissolving azithromycin in acetone and then adding to a solution of 1,2-propylene glycol and water to obtain a crystalline product, and (2) filtration of the formed crystals, washing the crystals with water and drying to obtain crystals of clathrate azithromycin.

The present invention also presents a pharmaceutical composition for treating microbial infections comprising the clathrate of the formula (I) and a pharmaceutically acceptable carrier.

Brief description of drawings

The above and other objects of this invention become clear from the following descriptions of the present invention in conjunction with the drawings, which depict, respectively:

Figure 1: powder x-ray connection in accordance with this invention.

Figure 2: powder roentgenogram the mA monohydrate azithromycin.

Figure 3: powder x-ray dihydrate azithromycin.

Figure 4: chart of differential scanning calorimetry compounds in accordance with this invention.

Figure 5: chart of differential scanning calorimetry monohydrate azithromycin.

6: chart of differential scanning calorimetry dihydrate azithromycin.

Fig.7: a comparative hygroscopic properties of the compounds in accordance with this invention, the anhydride, monohydrate and dihydrate azithromycin.

Detailed description of the invention

The compound of formula (I) can be obtained (1) by dissolving azithromycin in a suitable amount of acetone, preferably from 2 to 10 ml of acetone per 1 g of azithromycin, adding to the resulting solution of 1,2-propylene glycol in the amount of from 0.25 to 2.5 ml per 1 ml of acetone at a temperature from room temperature (K.T.) up to the boiling point of acetone, adding water in an amount of from 1 to 3 ml per 1 ml of acetone by stirring the mixture for 30 minutes to 4 hours at a temperature of from 0°C to room temperature, filtered fallen crystals, washing the crystals with water and drying for 12 to 24 hours at a temperature of from 40°C to 45°C.

1,2-propylene glycol part of clathrate in accordance with this invention is essentially non-toxic (LD50: 25 ml/kg when peroral is the first introduction in rats) and can exist in the form of a racemate, The S-isomer or R-isomer.

Azithromycin is used to obtain clathrate in accordance with this invention may be anhydrous, monohydrate, dihydrate, clathrate azithromycin with isopropanol or MES azithromycin with ethanol, known in the art, or their mixture, and it can be obtained by any method described in U.S. patent No. 4517359 and 4474768 and the patent application Korea No. 2001-14659.

New clathrate compound in accordance with this invention is melted at a temperature of approximately 130°C has an endothermic peak on the chart DSK when 150,8°and heat 104,42 j/g, as shown in figure 4. These thermal characteristics are completely different from the characteristics monohydrate (endothermic peak 145,55°C; heat 137,7 j/g) or dihydrate (endothermic peak 142,72°C; heat 160,15 j/g), shown in figure 5 and 6 respectively.

Crystal structure of the clathrate compounds in accordance with this invention differs from the crystal structure of the monohydrate and dihydrate, as shown by powder x-ray figure 1, figure 2 and figure 3, respectively.

The water content of the clathrate in accordance with this invention, certain water analyzer Karl-Fischer is from 2.3 to 4.6%, preferably from 3.0 to 4.0%, more preferably from 3.1 to 3.7%, the content of 1,2-propylene glycol, certain gas chromatography or1H-NMR spectroscopy, is from 2.1 to 4.1%, preferably from 2.4 to 3.8%.

The clathrate of the formula (I) in accordance with this invention preferably has a value of 1,5 m±0.2 and the value of n 0,30±0,06.

The clathrate compound in accordance with this invention are much less hygroscopic than the anhydrous azithromycin or monohydrate azithromycin, and water content remains more or less constant during storage in humid conditions unlike dihydrate azithromycin.

The clathrate compound in accordance with this invention can be used for various pharmaceutical compositions for the treatment of various microbial infections. Such compositions contain a clathrate in accordance with this invention together with pharmaceutically acceptable excipients and carriers and can be administered orally, by injection, rectally, transdermally, transbukkalno or nasal. Suitable forms for oral administration include tablets, compressed or coated pills, tablets, sachets of powder for recovery, hard or soft gelatin capsules, syrups and emulsions, and others. Suitable forms for parenteral administration include aqueous or nonaqueous solutions, emulsions; suitable forms for rectal injection include suppose the Oria with hydrophilic or hydrophobic media. For local injection, the invention provides ointments or sprays, are known in the art; for percutaneous introduction presents a suitable delivery system known in the art. For nasal introduction presents appropriate aerosol delivery systems known in the art.

The invention will be better understood from the following examples. These examples illustrate but do not limit the invention. Specialist in the art will easily understand, that presents certain methods and results are only illustrative for the present invention, which is more fully described in the claims.

Example 1

100 g of the anhydride of azithromycin is dissolved in 300 ml of acetone and to the solution add 100 ml of 1,2-propylene glycol. The solution is stirred for 10 minutes at K.T. and added dropwise to 500 ml of water to precipitate crystals of azithromycin. The solution is stirred for 2 hours at K.T. and the precipitate is filtered, thoroughly washed with water and then dried at a temperature of 40°C for 20 hours to obtain 96 g of clathrate hydrate azithromycin 1,2-propylene glycol.

So pl. from 129 to 131°C.

The water content, specific water analyzer, Karl-Fischer, 3.5 wt.%, the content of 1,2-propylene glycol, certain gas chromatograph is it to 3.3 wt.%.

Example 2

20 g of the monohydrate azithromycin is dissolved in 100 ml of acetone and to the solution add 15 ml of 1,2-propylene glycol. The solution is stirred for 10 minutes at K.T. and added dropwise to 200 ml of water to precipitate crystals of azithromycin. The solution is stirred for 2 hours at a temperature of from 0 to 5°and the precipitate is filtered, thoroughly washed with water and then dried at a temperature of 40°C for 20 hours to obtain 18.2 g of clathrate hydrate azithromycin 1,2-propylene glycol.

So pl. from 130 to 132°C.

The water content of 3.4 wt.%.

The content of 1,2-propylene glycol: 3.2 wt.%.

Example 3

20 g of the monohydrate azithromycin is dissolved in 120 ml of acetone and to the solution add 15 ml of 1,2-propylene glycol. The solution is stirred for 10 minutes at K.T. and added dropwise to 180 ml of water to precipitate crystals of azithromycin. The solution is stirred for 3 hours at a temperature of from 0 to 5°and the precipitate is filtered, thoroughly washed with water and then dried at a temperature of 40°C for 20 hours to obtain 17.6 g of clathrate hydrate azithromycin 1,2-propylene glycol.

So pl. from 130 to 132°C.

The water content of 3.4 wt.%.

The content of 1,2-propylene glycol 3.5 wt.%.

Sample analysis 1

The compound obtained in example 1, monohydrate and dihydrate azithromycin obtained by methods described in U.S. patent No. 586629, examined by the method of differential scanning calorimetry (heating rate 10°C/min). Connection in accordance with this invention obtained in example 1 shows an endothermic peak at 150,8°and heat 104,42 j/g, as shown in figure 4. On the other hand, monohydrate azithromycin shows an endothermic peak at 145,55°and heat 137,7 j/g (figure 5), and the dihydrate azithromycin shows an endothermic peak at 142,72°and heat 160,15 j/g (6).

Next, x-rays, the above compounds are shown in figure 1, figure 2 and figure 3 respectively. The x-rays are presented in table 1 indicate that the compound in accordance with this invention has a crystalline structure that is completely different from the structures of the known compounds.

Hygroscopic properties of the compound obtained in example 1 (1), dihydrate azithromycin (2), monohydrate azithromycin (3) and anhydrous azithromycin (4) determine the location of each sample in terms of relative humidity 25%, 50%, 75% or 100% for 7 days and measuring the water content in each sample by the method of Karl Fischer. The results are shown in table 2 and figure 7.

Table 1
Radiation: Cu K-

Differences is: 1° < / br>
Scattering: 1°

Perception: 0.15mm min
Mode: 40 kV/mA 126

Scanning method: continuous

Scan rate: 5°/min

Step scan of 0.02°
2 theta (°2θ)the value of d (A)I/Io(≥2)2 theta (°2θ)the value of d (A)I/Io(≥2)
6,20014,2437318,3004,84393
7,30012,0996518,5004,79205
7,82011,29623219,0404,657312
8,22010,7474219,6604,51189
9,7409,073310019,9804,440312
10,2208,6482 220,4004,349810
11,1407,93602920,8604,25498
11,9007,4308721,7404,08464
12,2207,2369622,3203,97983
12,5007,07542222,6403,92425
13,8806,37491223,2203,82752
14,6406,04561623,5403,77623
15,2205,81651223,9603,71093
15,4005,7490123,62744
15,7005,6398624,7203,59853
15,9405,5554625,2603,52282
16,6205,3296625,5003,49023
16,9605,22351026,2003,39854
17,2205,1452928,4403,13572
17,4605,07501131,0802,87512
18,0604,9078233,6002,66502
Table 2
 (1)(2) (3)(4)
Start3,504,58(4,1)2,30(3,2)0,22
Relative humidity 100%4,066,11(5,2)6,29(7,2)7,00
Relative humidity 75%3,555,10(4,6)5,41(6,6)4,33
Relative humidity 50%3,504.25 in(4,6)5,13(5,6)2,85
Relative humidity 25%3,014,20(2,5)3,35(2,3)1,11
(33%)    
The calculated water content (%)3,381)4,602,35 0,00
Found-intended-0,37~+0,68-0,4~+1,51+1~+3,94+1,11~+7,00
(difference %) (of-2.1~+0,6)(to-0.05~+4,84) 
Interval differences (%)1,051,91(2,7)3,94(4,9)7,00
Note:

1) the Calculation is based on m=1.5 and n=0,30 in the formula (I)

2) Numbers in parentheses are the values obtained after 3 days at the appropriate relative humidity.

Table 2 clearly shows that the new clathrate compound in accordance with this invention are much less hygroscopic than other compounds.

Although variations of this invention is described and illustrated, it is obvious that can be done various changes and modifications within the scope of this invention which is limited only by the scope of the claims.

1. The connection of the clathrate hydrate azithromycin 1,2-propylene glycol of the formula (I)

(I)

where m is from 1 to 2 and n is from 0.20 to 0.40.

2. The compound according to claim 1, in which the water content is from 2.3 to 4.6% and the content of 1,2-propylene glycol is from 2.1 to 4.1%.

3. The method of obtaining compounds of clathrate azithromycin of formula (I) according to claim 1, comprising the stages of (1) dissolving azithromycin in acetone and then adding to a solution of 1,2-propylene glycol and water to obtain a crystalline product, and (2) filtration of the formed crystals, washing the crystals with water and drying to obtain crystals of clathrate azithromycin.

4. The method according to claim 3, in which 1 g of azithromycin use from 2 to 10 ml of acetone.

5. The method according to claim 3, in which 1 ml acetone applied from 0.25 to 2.5 ml of 1,2-propylene glycol.

6. The method according to claim 3, in which 1 ml of acetone is used from 1 to 3 ml of water.

7. Pharmaceutical composition for treating microbial infections comprising the clathrate compound of azithromycin of formula (I) under item 1 and a pharmaceutically acceptable carrier.



 

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