Method of producing crystalline form of cephalexin hydrochloride monohydrate

专利摘要:
Crystalline cephalexin hydrochloride monohydrate, a useful antibiotic, can be prepared by the hydration of novel crystalline hydrochloride C1-4 alkanol solvates.
公开号:SU1251807A3
申请号:SU843815402
申请日:1984-11-26
公开日:1986-08-15
发明作者:Лоуэлл Энджел Гари；Майкл Инделикато Джозеф；Альберт Роуз Гарри；Джозеф Макшейн Лоренс；Санг Янг Куо
申请人:Эли Лилли Энд Компани (Фирма)；
IPC主号:

专利说明:

The invention relates to a method for preparing a crystalline form of cephalexin hydrochloride monohydrate — 7- (B-2-amio-2-phenylacetamido) -3-methyl-3-defem-4-carboxylic acid, which is an effective antibacterial agent.
The invention is aimed at obtaining a new crystalline form of a cephalosporin antibiotic, which has a poignant solubility in an aqueous medium with the formation of high osmotic pressure solutions,
Example I. Ethanol solvate cefalexin hydrochloride.
Cefalexin monohydrate (100 g) is suspended in 300 ml of absolute ethanol. The suspension is stirred at 25 (while hydrogen chloride is bubbled through the suspension until all the particles are in solution. The reaction mixture is stirred at 25 ° C for 2 hours and then cooled to 0 ° C and stirred for an additional 2 hours. The crystalline product is collected by filtration and washed with 200 ml of ethanol / ethyl acetate 1: 1 (by volume) and then 200 ml of ethyl acetate. The product is identified as ethanol cephalexin hydrochloride solvate. 53 g NMR (P, 0) : 61.2 (triplet, ЗН); (2.02 (singlet, 1Н); and 3.23 (quartet 2H); 53.63 (quartet, 2H);, 0 (doublet, 1H); 55.3 (singlet, IH); S 5.61 (doublet, 1H); 57.59 (singlet, 5H).
X-ray powder diffraction is performed using a diffractometer having a target tube and copper with nickel removed in the range of 1.5405 L.
Example 2, cefalexin hydrochloride monohydrate,
In a stirred suspension of 45 kg of cephalexin monohydrate in 168 l. absolute ethanol, portions of add 5.7 kg of hydrogen chloride over 30 minutes. The reaction mixture is stirred at 25 ° C for 30 minutes and then cooled to 10 ° C and stirred for another 2 hours. The crystalline precipitate that forms is collected by filtration and washed with 24 l of ethanol / / hexane 1: 1 and then 22 L of hexane. The filter cake is the ethanol solvate of cephalexin hydrochloride (m is consistent with the NMR of Example 1,
Calculated,%: C 50.29; H 5.63; N 9.77; S 7.46; C1 8.25;
С „Н„ N, 0, SHC1
CH CHjOH
Found,%: C 50.03; H 5.45; N 9.84; S 7.35; C1 8.37.
The filter cake of the ethanol solvate obtained above is kept for -2 weeks in the atmosphere of air at a relative humidity of -35% and a temperature of 25-30 0, resulting in a yield of 31.76 kg of cefalexin hydrochloride monohydrate.
NMR (DjO): 2.06 (singlet, GN); , 30 (quartet, 2H); S5.0 (doublet, F); 55.32 (singlet, 1H); 65.68 (doublet, 1H); b 7.6I (singlet, 5H.
IR (KBg) 3290; 3120; 1760; 1710; 1680; 1560; 1490.
Karl Fischer water analysis: 4.48% (consistent with the presence of approximately one mole of water. Residual ethanol is contained in a quantity of 0.6%.
Calculated,%: C, 47.82; H 5.02; N 10.46; S 7.98; C1 8.82;
С „Н„ N, -HCl Н, 0. Found,%: C 48.03; H 4.82; N 10.27; S 7.87; C1 8.90.
The compound has the following diffraction grating in the study of the x-ray powder in the X-ray tube of a copper target with nickel removed in the range of 1.5418 L:
40
45
50
55
Differential thermal analysis showed that this compound has a large and broad endotherm at 109 C, which indicates the removal of volatile materials, and an acute extremum discharge at, which indicates the decomposition of the NIN compound. Thermal gravimetric. the analysis indicated a weight loss that starts at 63 s and reaches 5.7 wt.% at. At 150 ° C, another weight reduction begins and continues until the end of the decomposition.
Example 3. The effect of moisture on the rate of formation of the target product.
The effect of moisture on the rate of conversion of ethanol sapvy cephalexin hydrochloride to cefalexin hydrochloride mogogidrat is examined using an analysis of the diffraction grating in x-rays of samples of ethanol solvate after storage at 25 ° C in chambers with different
-
to
15
20
25
thirty


35
40
45
50
8074
relative humidity. The transformation of the ethanol solvate into monohydrate occurs if the disappearance of the maximum in x-rays is observed.
) The rays having a value of d of approximately 7.34 A. The results of the study (at 25 C) are given in Table 1.
A sample of the ethanol solvate aged at a relative humidity of 70% can be completely dissolved. Within 24 hours
Example 4. The study of the stability of monohydrate hydrochloride cepha-lexic.
A sample of cefalexin hydrochloride monohydrate from example 2 was subjected to analysis using high pressure liquid chromatography. It was found that the sample contains 84.6% cefalexin (this is equivalent to a purity of about 99.2% for cefalexin hydrochloride monohydrate, the rest is essentially ethanol ). Samples of this material are stored at different temperatures for a prolonged period of time, periodically subjected to analysis with help. liquid chromatography (HPLC) and Karl Fischer titration (KFJ. The results of the study are shown in Table 2.
Example 5. Methanol solvate cefalexin hydrochloride.
Anhydrous methanol (100 ml) is cooled to give and treated with gaseous hydrogen chloride (8 g). Cephalexin monohydrate (35.2 g) is then added at room temperature. First, a solution of cefalexin monohydrate is formed, and then, for 15 minutes, the LYCIUM slurry of the target compound is formed. Output 18.0 g.
The X-ray diffraction structure of the material obtained in the presence of a stock solution using a Deb-Sherrer chamber of 114.6 mm and a copper target tube with nickel removed in the range of 1.5418 A in a hermetically sealed glass stock tube is shown below:
Interval, A
/ Relative I / I intensity.
13.97
1.00
7. 10
.49
Example 6 Cephalexin hydrochloride monohydrate.
Hydrogen chloride gas (7.0 g) is dissolved in methanol (100 MnJ
at koshatnoy temperature. Methanol is anhydrous (Karl Oischer Analysis) showed a water content of less than 0.12 wt.%. Then cephalexin monohydrate in solid form (35.2 g) is added to the reaction mixture. The dissolution process is observed. The process of crystallization of the methanol solvate of cefalexin hydrochloride begins within 15 minutes after priming with cefalexin hydrochloride monohydrate. The heat that is released during the crystallization process leads to a rise in temperature from 22 to. The mixture was kept for 3 hours at a coagulated temperature, and then the product was isolated by filtration and washed with cold methanol. NMR indicates the beginning of the formation of methanol solvate.
The methanol solvate obtained above is for three days
in contact with atmospheric air having a relative humidity of about 35% at 28 ° C, resulting in a yield of 18.1 g of crystalline cefalexin hydrochloride monohydrate,
 having NMR and IR spectra identical to the NMR and NK spectra of example 2.
Example 7. Cefalexin hydrochloride isopropanolate.
Prepare the sludge from disolvat
cefalexin dimethylformamide (300 g) in isopropanol (2.215 L), which is cooled to. Concentrated hydrochloric acid (190 mp) was quickly added dropwise to the reaction mixture at 13-17 ° C. Upon completion of the addition, a yellow solution is formed, which is heated to 20 ° C and stirred slowly. The cefaelexin isopropanol solpate hydrochloride crystallizes as a sticky slurry, which is stirred at room temperature for 2 hours, treated with hexane, 200 ml of isopropaiol is added, and then stirred for another 3 hours at room temperature, cooled and filtered. Next, the product is washed with a mixture of isopropanol / hexane 1: 1 (2 x. XUO ml). Output
An X-ray diffraction structure obtained for this material using a Deba-Sherrer camera and a double nickel target copper tube in the 1.5418 A range is shown below:
ten
15
Example 8. Cephalexin hydrochloride monohydrate.
Isopropanolate product (35 g)
of Example 7 is placed in a fluidized bed dryer sold under the trademark Label Line and moistened at 24 -. After 18.5 hours using the final NMR study
product found that the original isopropanolate was converted to crystalline hydrochloride monohydrate. Example 9. n-Propanol
cephalexy hydrochloride solvate.
Cephalexin monohydrate sludge (35.2 g) is prepared in anhydrous n-propanol (150 ml), cooled to
, and the sludge is treated with gaseous hydrogen chloride (6.1 g). The solution thus formed is seeded with the seed of the isopropanolate solvate prepared in Example 7. Then n-propanol (50 ml) is added and the reaction mixture is stirred at the same temperature for another 3 hours, while the desired n-propanol solvate is crystallized as sludge . The slurry is then cooled for 2 hours and the desired compound is precipitated. The yield is 39.1 g. Using NMR spectroscopy, it was established that this material is an n-propanolate solvate.
An X-ray diffraction grating, obtained in the same way as for methanolate, is shown below:
Stearinova
acid12,6
Magnesium Stearate 6.3 The above ingredients are mixed as in Example 11, and the mixture is compressed into tablets. Example 13. Cefalexin hydrochloride monohydrate (example 2), mg 617.7 Povidone, mg 12.6 Starch, mg 26.0 Stearic acid, mg 12.6 Magnesium stearate, mg 6.3 The ingredients are mixed as in Example 1 1. The resulting tablets are coated with hydroxypropylmethylcellulose for use as an antibacterial pharmaceutical composition for rapid release.
Example 14. Composition in the form of a capsule.
Cefalexin hydrochloride monohydrate, mg 450
Povidone, mg 10 Magnesium stearate, mg 5 The ingredients are thoroughly mixed and the mixture is filled with dried gelatin capsules.
Cefalexin hydrochloride monohydrate in the form of crystals, which is the subject of the invention, is used as active when osmotic. the use of antibacterial agent in the form of tablets n capsules.
Such pharmaceutical compositions containing from -10 to 98 wt.% The active ingredient, for example from 200 to mg of active ingredient
enta can be used to treat a person and prevent bacterial infections in single or multiple doses per day,
The amount of cephalexin hydrochloride monohydrate, which is antibacterially effective, ranges from I to mg / kg animal weight. Although cefalexin hydrochloride monohydrate has an activity profile very similar to that of cefalexin monohydrate, the former is more preferable because it is contained in blood in higher concentrations and its effect starts much faster than cefalexin monohydrate, which is It removes the high solubility of hydrochloride. Thus, the compound of the present invention is highly effective in the form of tablets with rapid release of the active ingredient.
Table 1
45
Note: - means
that the readings were not clear.

权利要求:
Claims (4)
[1]
1. METHOD FOR PRODUCING CRYSTALLINE FORM OF CEPHALEXIN HYDROCHLORIDE MONOHYDRATE, with the exception that C, - alkanol solvate of cephalexin crystalline hydrochloride is subjected to hydration.
[2]
2. The method according to claim 1, characterized in that they are used
C, -C ₂ ~ alkanol solvate of cephalexin crystalline hydrochloride.
[3]
3. The method of pop 1 and 2, characterized in that the hydration is carried out by contacting the solvate with the atmosphere with a relative humidity of 10 to 507.
[4]
4. The method according to PP, 2 and 3, characterized in that they use an ethanol solvate of cephalexin hydrochloride.
SU., »1251807>
CM

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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US06/556,887|US4600773A|1983-12-01|1983-12-01|Crystalline cephalexin hydrochloride monohydrate|

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