Title of Invention

A METHOD FOR PREPARING CEFAZOLIN SODIUM PENTAHYDRATE CRYSTAL

Abstract The present invention relates to cefazolin sodium pentahydrate crystal and a method for assembly and preparation of the crystal molecule. The cefazolin sodium pentahydrate crystal molecule contains five water molecules, orthorhombic system, space group of C222(1), in which sodium ion is bonded to the cefazolin molecule with a coordinate bond. The method for assembly and preparation of cefazolin sodium pentahydrate crystal molecule are: adding a solvent to a reactor equipped with a jacket, adding cefazolin acid and a sodium salt, heating until the reaction solution is clear, stirring continuously adjusting pH, upon the completion of the reaction, transferring the liquid into a jacketed crystallizer, adding crystal seeds or nucleating spontaneously, controlling cooling, slowly adding a antisolvent. The particle size of cefazolin sodium pentahydrate crystal according to the present invention is adjustable, and the distribution of particle size is concentrated, the product has good flowability, smooth surface, high crystallinity, good stability, and rapid dissolving rate.
Full Text

Cefazolin sodium pentahydrate crystal and its molecular assembly
preparation method
Technical Field
The present invention belongs to crystallization technology field, particularly to
the structure of cefazolin sodium pentahydrate crystal molecule and a method
for assembly and preparation of the same.
Background Art
Cefazolin sodium, its full name is: Monosodium
(6R,7R)-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-(1 H-tetrazol-1 -yl)acet
ylamino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylate, its
chemical formula is C14H14N8O4S3, its pentahydrated compound has a
structure formula as shown in Fig. 1, being white or near white crystalline
powder, with a molecular weight of 566.57, and a theoretical water content of
15.9%; it is freely soluble in water, slightly soluble in methanol and ethanol,
and practically insoluble in isopropanol, acetone, chloroform, dichloromethane
and ethyl acetate; it has no fixed melting point, and its decomposition
temperature is 193±2°C.
Cefazolin sodium is the first generation of broad-spectrum antibiotic, it exhibits
excellent antibacterial activity to Gram-positive coccus, except enterococcus,
methicillin-resistant staphylococcus. Streptococcus pneumoniae and
streptococcus haemolytica are highly sensitive to this product.
Corynebacterium diphtheriae, bacillus anthracis, listeria and Clostridium are
also very sensitive to this product. This product has good antibacterial activity
to partial E.coli, proteus mirabilis and klebsiella pneumoniae, but has Sow
antibacterial activity to actistaphylococcus. Typhoid bacillus, shigella and
neisseria are sensitive to this product, but other enterobacteriaoeae

acinetobacter and P.aeruginosa are resistant to this product. PPNG Neisseria
gonorrheaeis resistant to this product. Haemophilus influenzae only exhibits
intermediate sensitivity. With the enhancement of the standard of living of
common people and domestic production level, recently, the demand of
cefazolin sodium has been increased continuously.
At present, it has been known that cefazolin sodium has 4 crystalline forms, i.e.,
α-crystal, β-crystal, γ-crystal, and amorphous crystal forms, in which a-crystal
of cefazolin sodium is present in needle crystal, with a specific rotation of -20°-
-25°, and absorbance index of 272-292. USP 4104470 describes a
method for the preparation of monohydrated cefazolin sodium. USP4146971
describes a method for the preparation of a rapidly dissolving cefazolin sodium
crystal. USP4898937 describes that cefazolin sodium is placed in moisture
environment to obtain a-crystals of cefazolin sodium. Above methods are not
suitable for bulk production, and the resulting products are easily dehydrated
to convert into other crystal forms.
CN1513854A discloses a method for preparing chelated cefazolin sodium. The
examples 1-5 and 6-8 of the invention describe a method to prepare chelated
cefazolin sodium from cefazolin acid by, after salt formation, adjusting pH in
isopropanol solvent or a mixed solvent. The solvent means isopropanol or
isopropanol + acetone, isopropanol + dichloromethane, isopropanol + ethyl
acetate. In these examples, the preparation of chelated cefazolin sodium
comprises following steps: 1) salt formation of cefazolin acid; 2) pH regulation;
3) addition of solvent. This invention has following problems: 1) long reaction
time; 2) small particle size of the product, it has been proved in practice that
the average particle size of the product obtained in the examples of this
invention is about 15 microns; 3) the chelated cefazolin sodium crystal
obtained in the examples of this invention is a monociinic crystal, with a space


group of P21.
Summary of the Invention
The present invention provides a novel cefazolin sodium pentahydrate crystal
and a method for assembly and preparation of the crystal molecule. The
structure of the novel cefazolin sodium pentahydrate crystal according to the
present invention is: the crystal molecule contains five water molecules,
orthorhombic system, space group of C222(1), in which sodium ion is bonded
to the cefazolin molecule with a coordinate bond.
Cefazolin sodium pentahydrate according to the present invention is
characterized that one sodium ion and N3 in two cefazolin molecules and
oxygen in four water molecules form sexadentate, another sodium has weak
bond action with 03W and 06W, cefazolin and water molecule, and water
molecules are linked with hydrogen bond to maintain a stable arrangement
under molecule crystalline state.
The assembly and preparation method of cefazolin sodium pentahydrate
crystal molecule according to the present invention are described as follows:
To a jacketed reactor is added 1-20 parts (preferably 1-10 parts) of crystallizing
solvent, 1 part of cefazolin acid and sodium salt with molar ratio of 1:1
(generally 2:1-1:2, preferably 1.3:1-1:1.3), heated and stirred until the solution
was clear, agitated for 10-60 minutes (preferably 20-40 minutes), pH is
adjusted to be 3-9 (preferably pH 4-7). Upon the completion of the reaction, the
liquid is transferred to a crystallizer equipped with a jacket, cooled by
controlling water bath, crystallized with a crystallizing agent and hold for 0.3-4
hours (preferably 0.5-2 hours) at 0.8-2.5 atmospheric pressure (preferably
1.1-2 atmospheric pressure). The preferred cooling region is controlled in the
range of 70-0°C (preferably 50-5°C), in the course is slowly added 3-15 pans

(preferably 5-10 parts) of a precipitating agent.
The crystallizing solvents used in the method for preparing a crystal according
to the present invention for are preferably selected from the mixtures of water
and organic solvents preferably selected from acetone, dichloromethane,
chloroform, methanol, ethanol, isopropanol, butanol, ethyl ether or ethyl
acetate, butyl acetate, or mixtures thereof. The water content in the
crystallizing solvent is >15%.
The sodium salts used in the method for preparing a crystal according to the
present invention are preferably selected from one of sodium carbonate,
sodium hydroxide, sodium acetate, trihydrated sodium acetate, sodium
isocaprylate, sodium methoxide, sodium bicarbonate, and sodium ethoxide, or
a mixture thereof.
The precipitating agents are oxygen-containing fatty hydrocarbons derivatives
or mixtures thereof, mainly including fatty acids, aliphatic alcohols or ketones
as well as their dibasic or polybasic mixtures. For example, the fatty acids are
formic acid or acetic acid, and the like; the aliphatic alcohols are methanol,
ethanol, n-propanol, isopropanol, n-butanol or isobutanol, and the like; the
ketones are acetone, isobutyl ketone or methyl ethyl ketone, and the like. The
preferred precipitating agents are ethanol, isopropanol, n-butanol, acetone,
isobutyl ketone or acetic acid, and the like. The preferred dibasic mixed
solvents as precipitating agents include: methanol and isopropanol, acetone
and ethanol, acetone and acetic acid, isobutyl ketone and isopropanyl,
n-propanol and formic acid, and the like, in a ratio of 20:1 to 1:20, preferably
10:1 to 1:10.
The crystallizing agents used in the method for preparing a crystal according to
the present invention are amino acids compounds, preferably lysine,

methionine, leucine, more preferably lysine, serine. The amount of the
crystallizing agents is preferably 0.1-0.5 ppm, more preferably 0.2-0.4 ppm.
The prepared cefazolin sodium pentahydrate crystal molecule according to the
present invention can be further subjected to post-treatments, including:
filtering, washing, drying and so on. The product can be selectively washed
with a detergent. The washed product is dried in air or vacuum at 5-80°C for
0.5-8 hours to finally give a product of cefazolin sodium pentahydrate.
The detergents are preferably oxygen-containing fatty hydrocarbons
derivatives or mixtures thereof, mainly including fatty acids, aliphatic alcohols
or ketones as well as mixtures of two or more solvents. For example, the fatty
acids a re formic acid or acetic acid, and the like; the aliphatic alcohols are
methanol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol, and the
like; the ketones are acetone, isobutyl ketone or methyl ethyl ketone, and the
like.
X-ray powder diffraction pattern showed that the cefazolin sodium
pentahydrate according to the present invention possess characteristic peaks
at about 4.8, 5.8, 6.3, 11.6, 13.5, 14.9, 15.9, 17.4, 18.7, 19.0, 19.6, 20.0, 20.8,
21.4, 27.3, 29.5 ( 20/ °C) and so on.
The infrared adsorption spectrum of cefazolin sodium pentahydrate according
to the present invention has characteristic absorption peaks at 3432(±5)cm"1,
3287(±5)cm-1, 1761(±5)cm-1, 1667(±5)cm-1, 1599(±5)cm-1, 1540(±5)cm-1,
1389(+5)cm-1, 1239(±5)cm-1, and 1184(±5)cm-1 and so on, measured by
infrared spectrophotometry (Chinese Pharmacopoeia 2000 Edition 2 Section,
Annex IVC).
The cefazolin sodium pentahydrate according to the present invention (which


is prepared by adding water into a solution containing 0.1 g per 1 ml) has a pH
value of 4.8-6.3, and a water content of 13.0-16.0%, measured by Chinese
Pharmacopoeia 2000 Edition 2 Section, Annex VIII M, First Method A.
DSC pattern showed that the temperature elevating rate of cefazolin sodium
pentahydrate according to the present invention is 5°C min-1, the product has
two dehydration peaks, the dehydration temperature is 93(±5)°C and 98(±5)°C;
cefazolin sodium directly decomposes without a melting adsorption peak, the
decomposition temperature is 193(±5)°C, and the decomposition heat is
-56(±5)kJ/mol.
The particle size of cefazolin sodium pentahydrate according to the present
invention i s adjustable (main s ize i s from 1 7 t o 5 00 um) b y a Itering s tirring
rotation speed and fluid adding rate, and the distribution of particle size is
concentrated, the surface of the particles is smooth, the product exhibits
excellent flowability, high crystallinity, good stability (it is identified by State
Food and Drug Administration to have a expiry date of 24 months, whereas the
expiry date of commercial cefazolin sodium at present is 18 months), and rapid
dissolving rate.

The Description of Accompanying Drawings
Fig. 1: Skeleton symbol of molecular structure of cefazolin sodium
pentahydrate;
Fig. 2: X-ray powder diffraction pattern of cefazolin sodium pentahydrate;
Fig. 3: Skiagraph of spatial structure of cefazolin sodium pentahydrate;
Fig. 4: Chart of accumulation of cefazolin sodium pentahydrate crystal cell in
the direction of a axis;
Fig. 5: Photograph of scanning electron microscope of cefazolin sodium
pentahydrate product (100 times enlarged).

Embodiments
The present invention is specifically explained by following examples:
Example 1
To a glass reactor equipped with a jacket were added 100 ml ethanol solution
(containing 20% water), 10.0 g cefazolin acid and 2 g sodium ethoxide, stirred
until the completion of the reaction, the finishing point pH was adjusted to be
4.5, the mixture was filtered into a jacketed crystallizer, agitated for 20 minutes,
cooled in water bath, added lysine and crystal seeds at about 60°C, turbidness
occurred in the crystallizer, hold for 0.8 hours. To the crystallizer were slowly
added isopropanol and acetone in a volume five times as much as the mixture
(in which the volume ratio of acetone is 5%) at 1.1 Mpa (optionally).
The resultant was filtered, washed with methanol, dried at 30°C for 4 hours to
give cefazolin sodium pentahydrate.
The structure of the single crystal of the product obtained in the example was
shown in table 1.
In the example, ethanol can be replaced by acetone, dichloromethane,
chloroform, methanol, isopropanol, butanol, ethyl ether or ethyl acetate, butyl
acetate.
Example 2
To a reactor equipped with a jacket were added 5 ml isopropanol, 5 mi water,
10 g cefazolin acid and 1.2 g sodium carbonate, stirred and heated to 50°C
until the solution was clear, the finishing point pH was adjusted to be 6.5, the
mixture was directly filtered into a glass crystallizer agitated, cooied to about
33°C, added serine, turbidness occurred in the solution, hold for 1.0
added anhydrous ethanol in an amount of 15 times as much as the

2MPa, cooled to 5-15°C and hold at the temperature for 1 hour.
The resultant was filtered, the filter cake was washed with ethanol, dried at 5°C
for 8 hours to give cefazolin sodium pentahydrate.
The structure of the single crystal of the product obtained in the example was
shown in table 1.
In the example, isopropanol can be replaced by methanol and isopropanol,
acetone and ethanol, acetone and acetic acid, isobutyl ketone and isopropanol,
n-butanol and formic acid.
Example 3
To a reactor equipped with a jacket were added 10 ml ethanol, 50 ml
dichloromethane, 20 ml water, 5 g cefazolin acid and 0.9 g sodium acetate,
stirred until the solution was clear, the finishing point pH was adjusted to be 7.4,
the mixture was directly filtered into a glass crystallizer, agitated for 60 minutes,
added dropwise about 20 ml of isopropanol and methanol mixed liquid (the
amount of methanol is 3%) and methionine, turbidness occurred in the solution,
hold for 4.0 hours, added isopropanol and methanol in a volume 10 times as
much as the mixture at 1.5MPa.
The resultant was filtered, the filter cake was washed with acetic acid, dried at
80°C for 0.5 hours to give cefazolin sodium pentahydrate.
The structure of the single crystal of the product obtained in the example was
shown in table 1.
In the example, ethanol can be replaced by formic acid,
n-propanol, isopropanol, n-butanol, isobutanol, acetone,


methyl ethyl ketone.

Example 4
The example illustrated a method to identify the structure of crystals. The
crystal of cefazolin sodium pentahydrate obtained in the invention is colorless
transparent needle type. The crystal had a dimension of 0.46x0.16x0.07mm,
measured by X-ray unit cell diffraction experiments. Diffraction strength data
were collected by means of Rigaku Rapid-ll surface detector, MoKa radiation,
graphic monochromator, pipe voltage, 50 kV, pipe current 90mA, ωscanning,
scanning scopes are chi=45°, phi=30°, to scanned from 130° to 190°; chi=45°,
phi=180°, ω scanned from 0° to 159°, oscillation angle was 3°, space was 3°,
73 pictures were taken in total, independent diffraction points were 3165,
observable points (>2sigma(l)) were 4566.
The structure of crystals was analyzed by computer by means of direct method
(SHELXS-97). The atomic positions were obtained from the pictures.
Difference Fourier method was used to acquire other non-hydrogen atoms, to
correct structural parameters and to determine the kinds of atoms. The

position of hydrogen atom was obtained by geometrical calculation method
and difference Fourier method, reliability factor R=8.16, finally the
stechiometric formula of each asymmetric unit was C14H13O4N8S3 , which
contained 6 water positions, in total five water molecules.
The skiagraph of spatial structure of cefazolin sodium pentahydrate molecular
according to the present invention was shown in fig. 3. One asymmetric unit in
crystal state contained one cefazolin molecule, five water molecules and 2
sodium ions (the position occupation degree of each sodium ion is 0.5).
Cefazolin molecules in crystal state were arranged into a tunnel cavity, water
molecules and sodium ions were present in the cavity. Sodium ions together
with two nitrogen atoms N3(N3') in two cefazolin molecules and four water
molecules of O1W(O1W) and O2W(O2W'), respectively, formed
6-coordinated hexagonal double cone, so that O1W, O2W were stable in
crystal state. Another sodium and O3W and O6W exhibited weak linkage
action. Cefazolin and water molecule, and water molecules were linked with
hydrogen bond to maintain a stable arrangement under molecular crystal state,
as shown in the chart of accumulation of molecule in the direction of a axis (fig.
4).
The X-ray powder diffraction pattern of cefazolin sodium pentahydrate
according to the present invention (Example 1) was shown in fig. 2, wherein
characteristic peaks occurred at 4.8,5.8,6.3,11.6,13.5,14.9,15.9,17.4,18.7,
19.0,19.6, 20.0, 20.8, 21.4, 27.3, 29.5 (29/°C), and so on.
Fig. 4 showed the chart of accumulation of cefazolin sodium pentahydrate
crystal cell according io the present invention (Example 1) in the direction of 3
axis, measured by single crystal X-ray diffraction scanner, and the chart of
accumulation was obtained by shelx software program analysis.


Fig. 5 showed the photographs of scanning electron microscope of cefazolin
sodium pentahydrate product. The product obtained in Example 1 was
analyzed and characterized by X-650 type scanning electron microscope
produced by Japan Hitachi Company to obtain scanning electron microscope
photographs.
The infrared adsorption spectrum of cefazolin sodium pentahydrate according
to the present invention had characteristic absorption peaks at 3432(±5)cm"1,
3287(±5)cm-1, 1761(±5)cm-1, 1667(±5)cm-1, 1599(±5)cm-1, 1540(±5)cm-1,
1389(±5)cm-1, 1239(±5)cm-1, and 1184(±5)cm-1 and so on, measured by
infrared spectrophotometry (Chinese Pharmacopoeia 2000 Edition 2 Section,
Annex IVC), pH was 4.8-6.3, and water content was 13.0-16.0%.
The results of the products obtained in Examples 2 and 3 were substantially
consistent with the results mentioned above.
DSC analytic results showed that cefazolin sodium pentahydrate according to
the present invention (Example 2) had two dehydration peaks at a temperature
elevating speed of 5°C/min, the dehydration temperature was 93(±5)°C and
98(±5)°C; cefazolin sodium directly decomposed without a melting adsorption
peak, and the decomposition temperature was 193(±5)°C, the decomposition
heat was -56(±5)kJ/mol. The results of the products obtained in Examples 1
and 3 were substantially consistent with the results mentioned above.
The present invention discloses the structure of cefazolin sodium pentahydrate
crystal and a method for assembly and preparation of crystal molecule.
According to the contents described in the present application, those skilled in
the art can achieve the present invention by appropriately altering raw
materials, technological parameters, and structural designs. The product and
method of the present invention were described in the preferred examples.


Those skilled in the art can obviously achieve the technology of the present
invention by modifying or appropriately altering and combining the method and
product described in the present invention without digressing from the contents,
essences and scopes of the present invention. It should be specifically pointed
out that all similar substitutions and alterations are obvious for those skilled in
the art. They are all regarded to be included in the protection scope of the
present invention.

We claim
1. A method for preparing cefazolin sodium pentahydrate crystal comprising: adding
1-20 parts of a solvent to a reactor equipped with a jacket; adding 1 part of
cefazolin acid and sodium salt in a molar ratio of about 1:1 to provide a reaction
solution; heating until the reaction solution is clear; adjusting pH to 3-9; upon the
completion of the reaction, transferring the liquid to a crystallizer equipped with
a jacket; cooling in water bath; adding 0.1 to 0.5 ppm of crystallization additives;
holding for 0.3-4 hours at 0.8-2.5 atmospheric pressure; cooling at the
temperature range of 0°C.-70°C, adding 3-15 parts of an antisolvent, filtering,
washing with a detergent, and drying to provide cefazolin sodium
pentahydrate.
2. The method as claimed in claim 1, wherein the solvent is a mixture of water and at
least one organic solvent, selected from the group consisting of acetone,
dichloromethane, chloroform, methanol, ethanol, isopro-panol, butanol, ethyl
ether, ethyl acetate, and butyl acetate, wherein the water content in the solvent is
greater than 15%.
3. The method as claimed in claim 1, wherein the sodium salt is selected from the
group consisting of sodium carbonate, sodium hydroxide, sodium acetate,
trihydrated sodium acetate, sodium isocaprylate, sodium bicarbonate, sodium
methoxide, sodium ethoxide and mixtures thereof.
4. The method as claimed in claim 1, wherein the antisolvent is an oxygen-containing
fatty hydrocarbon derivative selected from the group consisting of fatty acids,
aliphatic alcohols, ketones or mixtures thereof.

5. The method as claimed in claim 4, wherein the antisolvent is formic acid, acetic
acid, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol,
acetone, isobutyl ketone or methyl ethyl ketone.
6. The method as claimed in claim 4, wherein the antisolvent is ethanol,
isopropanol, n-butanol, acetone, isobutyl ketone or acetic acid.
7. The method as claimed in claim 4, wherein the antisolvent is methanol and
isopropanol, acetone and ethanol, acetone and acetic acid, isobutyl ketone
and isopropanol, or n-propanol and formic acid with a ratio of 20:1 to 1:20.
8. The method as claimed in claim 1, wherein the detergent is an oxygen-containing
fatty hydrocarbon derivative selected from the group consisting of fatty acids,
aliphatic alcohols, ketones and mixtures thereof, wherein the fatty acids are
formic acid, acetic acid; the aliphatic alcohols are methanol, ethanol, n-propanol,
isopropanol, n-butanol, isobutanol; and the ketons are acetone, isobutyl ketone or
methyl ethyl ketone.
9. The method as claimed in claim 1, wherein the crystallization additive is an amino
acid compound selected from the group consisting of lysine, serine, methionine,
and leucine, preferably lysine or serine.



ABSTRACT


CEFAZOLIN SODIUM PENTAHYDRATE CRYSTAL AND
ITS MOLECULAR ASSEMBLY PREPARATION METHOD

The present invention relates to cefazolin sodium pentahydrate crystal and a
method for assembly and preparation of the crystal molecule. The cefazolin
sodium pentahydrate crystal molecule contains five water molecules,
orthorhombic system, space group of C222(1), in which sodium ion is bonded to
the cefazolin molecule with a coordinate bond. The method for assembly and
preparation of cefazolin sodium pentahydrate crystal molecule are: adding a
solvent to a reactor equipped with a jacket, adding cefazolin acid and a sodium
salt, heating until the reaction solution is clear, stirring continuously adjusting pH,
upon the completion of the reaction, transferring the liquid into a jacketed
crystallizer, adding crystal seeds or nucleating spontaneously, controlling cooling,
slowly adding a antisolvent. The particle size of cefazolin sodium pentahydrate
crystal according to the present invention is adjustable, and the distribution of
particle size is concentrated, the product has good flowability, smooth surface,
high crystallinity, good stability, and rapid dissolving rate.

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Patent Number 257066
Indian Patent Application Number 2063/KOLNP/2008
PG Journal Number 36/2013
Publication Date 06-Sep-2013
Grant Date 30-Aug-2013
Date of Filing 22-May-2008
Name of Patentee SHENZHEN GOSUN PHARMACEUTICAL CO., LTD.
Applicant Address 2, KAIFENG ROAD, SHANGMEILIN, FUTIAN DISTRICT, SHENZHEN 518049
Inventors:
# Inventor's Name Inventor's Address
1 ZHANG, MEIJING 92 WEIJIN ROAD, NANKAI DISTRICT, TIANJIN 300072
2 WANG JINGKANG 92 WEIJIN ROAD, NANKAI DISTRICT, TIANJIN 300072
3 WU, JIEHUA 92 WEIJIN ROAD, NANKAI DISTRICT, TIANJIN 300072
4 YANG, ZHAN'AO 2, KAIFENG ROAD, SHANGMEILIN, FUTIAN DISTRICT, SHENZHEN 518049
5 QIAN, YUXIN 2, KAIFENG ROAD, SHANGMEILIN, FUTIAN DISTRICT, SHENZHEN 518049
PCT International Classification Number C07D 501/12
PCT International Application Number PCT/CN2006/002414
PCT International Filing date 2006-09-15
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 200510016123.5 2005-11-16 China