CN103288851B - The preparation method of Sodium flucloxacillin crystal form II I - Google Patents
The preparation method of Sodium flucloxacillin crystal form II I Download PDFInfo
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Abstract
The invention discloses the preparation method of a kind of Sodium flucloxacillin crystal form II I.Sodium flucloxacillin bulk drug 1.0g is dissolved in 13mL acetone, magnetic agitation, heat 0.5h under boiling condition after, filtered while hot, 5-15 DEG C of cooling crystallization, collects crystal and 50 DEG C of freeze-day with constant temperature after crystal is separated out, and after dry 12 hours, normal temperature sealing is kept in moisture eliminator.Sodium flucloxacillin crystal form II I prepared by the present invention all has higher solubleness in neutral environment (pH=6.8), thus shows higher bioavailability.
Description
This case application is June 17 2011 applying date, application number 2011101650164, and invention and created name is: the divisional application of the preparation method of the amorphous and three kinds of polymorphic forms of Sodium flucloxacillin.
Technical field
The present invention relates to the preparation method of the amorphous crystal formation thing of Sodium flucloxacillin and three kinds of polymorphic forms.
Background technology
Sodium flucloxacillin [chemical name: (2S, 5R, 6R)-6-[[3-(the chloro-6-fluorophenyl of 2-)-5-methyl isophthalic acid, 2-oxazole-4-formyl] amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid sodium salts] be known as a kind of semi-synthetic penicillins antimicrobial drug.Same drug adopts different solvents, and crystallization processes crystallization makes the crystal of generation have different space structures, and we are referred to as medicine heteromorphism.Medicine polycrystalline it is generally acknowledged Four types: conformation polymorphic, configuration polymorphic, look polymorphic, pseudo-polymorphic.The crystal that Molecule in Crystal is formed in the arrangement difference of lattice vacancy is called conformation polymorphic, and the crystal formation of most medicine all belongs to this type of.The crystal that atom in crystal position difference is in the molecule formed is called configuration polymorphic.Medicine during crystallization, forms the crystal of different colours in different solvents, and this is that optical property is also different, thus creates distinct colors, and this crystal is called look polymorphic because crystal formation is different.Medicine is when crystallization, and solvent molecule stoichiometrically ratio is combined in lattice and forms molecular complex, claims pseudo-polymorphic, is also called solvent addition.Known many organic compound generally have polymorphic form, and this depends on the kind of recrystallization solvent, recrystallization temperature, the difference of the factors such as pressure.
Sodium flucloxacillin bulk drug is the mixture having amorphous and unknown crystal formation by analysis, and dissolving properties is unstable.
Summary of the invention
The object of this invention is to provide the preparation method of the amorphous and three kinds of polymorphic forms of Sodium flucloxacillin.
One, Flucloxacillin sodium crystal I-III and unbodied preparation method are:
Sodium flucloxacillin bulk drug 1-2g is dissolved in 10-20mL organic solvent, magnetic agitation, filtered while hot heat 0.5h under 50-55 DEG C of condition after, collect filtrate, room temperature cooling crystallization, after crystal is separated out, collect crystal and 50 DEG C of freeze-day with constant temperature, after dry 12 hours, normal temperature sealing is kept in moisture eliminator;
Described organic solvent is the one in Virahol, ethyl acetate, ethanol, acetone, methyl alcohol and tetrahydrofuran (THF).
Two, Flucloxacillin sodium crystal I-III and to be unbodiedly characterized as:
1, the feature of Flucloxacillin sodium crystal I:
In differential scanning calorimetric analysis curve, there is endotherm(ic)peak in 60 ° of C; Exothermic peak is had at about 65 ° of C; ?
165 ° of C have crystal conversion and melting hump; Decomposition peak is had at 210 ° of C; In X-ray powder diffraction, there is the strongest diffraction peak (I/I in 2 θ=19.3375 °
0=100), in 2 θ=6.799; 15.0499; Also there is stronger diffraction peak at 21.1936 ° of places; In infrared spectra about 783; 901; 1250; 1340; 1500; 1600; 1770; 2980; 3370; 3520cm
-1there is characteristic absorbance.
2, the feature of Sodium flucloxacillin crystal form II:
In differential scanning calorimetric analysis curve, there is endotherm(ic)peak in 40 ° of C and 100 ° C; Put at about 65 ° of C
Thermal spike; Crystal conversion and melting hump is had at 145 ° of C and 165 ° C; Decomposition peak is had at 210 ° of C; In X-ray powder diffraction, there is the strongest diffraction peak (I/I in 2 θ=8.9858 °
0=100); In infrared spectra about 785; 899; 1330; 1400; 1510; 1600; 1670; 1770; 3370cm
-1there is characteristic absorbance.
3, the feature of Sodium flucloxacillin crystal form II I:
In differential scanning calorimetric analysis curve, there is endotherm(ic)peak in 65 ° of C; Exothermic peak is had at about 150 ° of C; ?
170 ° of C and 190 ° C have crystal conversion and melting hump; Decomposition peak is had at 230 ° of C; In X-ray powder diffraction, there is the strongest diffraction peak (I/I in 2 θ=6.4951 °
0=100); In infrared spectra about 781; 899; 1250; 1330; 1410; 1500; 1610; 1660; 1770; 3370; 3510cm
-1there is characteristic absorbance.
4, the unbodied feature of Sodium flucloxacillin:
In differential scanning calorimetric analysis curve, there is endotherm(ic)peak in 25 ° of C; Exothermic peak is had at about 150 ° of C; ?
180 ° of C have melting hump; Decomposition peak is had at 220 ° of C; In X-ray powder diffraction, there is no crystalline diffraction peak, there is amorphous feature steamed bun peak at 2 θ=10-30 ° place; In infrared spectra about 787; 899; 1250; 1400; 1450; 1510; 1600; 1660; 1740; 3400cm
-1there is characteristic absorbance.
Amorphous and three kinds of polymorphic Sodium flucloxacillins equal tool in neutral environment (pH=6.8) prepared by the present invention
There is higher solubleness, thus show higher bioavailability.
Accompanying drawing explanation
Fig. 1 is differential scanning calorimetric analysis (DSC) curve of Flucloxacillin sodium crystal I of the present invention.
In figure: show 60 ° of C and there is endotherm(ic)peak in DSC curve, have exothermic peak at about 65 ° of C and have crystal conversion and melting hump at 165 ° of C, have decomposition peak at 210 ° of C.In X-ray powder diffraction, there is the strongest diffraction peak (I/I in 2 θ=19.3375 °
0=100), in 2 θ=6.799; 15.0499; Also there is stronger diffraction peak at 21.1936 ° of places, and this is obviously different from crystal form II, III and amorphous.
Fig. 2 is differential scanning calorimetric analysis (DSC) curve of Sodium flucloxacillin crystal form II of the present invention.
In figure: show 40,100 ° of C and there is endotherm(ic)peak in DSC curve, have exothermic peak at about 65 ° of C and have crystal conversion and melting hump at 145,165 ° of C, have decomposition peak at 210 ° of C.In X-ray powder diffraction, there is the strongest diffraction peak (I/I in 2 θ=8.9858 °
0=100), this is obviously different from crystal formation I, III and amorphous,
Fig. 3 is differential scanning calorimetric analysis (DSC) curve of Sodium flucloxacillin crystal form II I of the present invention.
In figure: show 65 ° of C and there is endotherm(ic)peak and have exothermic peak and 170 at about 150 ° of C in DSC curve
A ° C and 190 ° C has crystal conversion and melting hump, has decomposition peak at 230 ° of C.In X-ray powder diffraction, there is the strongest diffraction peak (I/I in 2 θ=6.4951 °
0=100), this is obviously different from crystal formation I, II and amorphous,
Fig. 4 is the unbodied differential scanning calorimetric analysis of Sodium flucloxacillin of the present invention (DSC) curve.
In figure: show 25 ° of C and there is endotherm(ic)peak in DSC curve, have exothermic peak and 180 at about 150 ° of C
° C has melting hump, has decomposition peak at 220 ° of C.In X-ray powder diffraction, there is amorphous feature steamed bun peak at 2 θ=10-30 ° place, this is obviously different from crystal formation I, II and III.
Fig. 5 is the X-ray powder diffraction pattern of Flucloxacillin sodium crystal I of the present invention.
In figure: infrared spectra shows, 3090, cm
-1to have on phenyl ring=C-H stretching vibration, 1460,1500,1600cm
-1there is phenyl ring skeletal vibration, 984cm
-1for C-H in-plane bending vibration on trisubstituted benzene ring, 783,847cm
-1there are three adjacent=C-H out-of-plane deformation vibrations on phenyl ring at place, 3520cm
-1molecule is interior, intermolecular hydrogen bonding O-H stretching vibration, 3370cm
-1N-H stretching vibration, 2980cm
-1place is CH
3c-H asymmetrical stretching vibration, 1770cm
-1for carbonyl C=O stretching vibration on beta-lactam ring, 1660cm
-1the stretching vibration being absorbed as by force conjugation C=O and with C=C stretching vibration mixing peak, 1600cm
-1that phenyl ring skeletal vibration and C=N stretching vibration lotus root close Ou He peak, peak, 1410cm
-1-CH3 on hydrogenation thiazole ring, asymmetric bending is vibrated, 1340cm
-1comparatively strong absorption be the C-H asymmetric bending vibronic coupling peak of-CH3 on C-C skeletal vibration and thiophene oxime ring ring, 1250cm
-1for thiophene oxime ring C-O stretching vibration, 901cm
-1for N-O stretching vibration on thiophene oxime ring.
Fig. 6 is the X-ray powder diffraction pattern of Sodium flucloxacillin crystal form II of the present invention.
In figure: infrared spectra show, 1450,1510,1600cm
-1there is phenyl ring skeletal vibration, 987cm
-1for C-H in-plane bending vibration on trisubstituted benzene ring, 785,841cm
-1there are three adjacent=C-H out-of-plane deformation vibrations on phenyl ring at place, 3370cm
-1N-H stretching vibration, 2970cm
-1place is CH
3c-H asymmetrical stretching vibration, 1770cm
-1for carbonyl C=O stretching vibration on beta-lactam ring, 1670cm
-1the stretching vibration being absorbed as by force conjugation C=O and with C=C stretching vibration mixing peak, 1600cm
-1that phenyl ring skeletal vibration and C=N stretching vibration lotus root close peak, 1400cm
-1the CH asymmetric bending vibration of-CH3 on hydrogenation thiazole ring, 1330cm
-1comparatively strong absorption be the C-H asymmetric bending vibronic coupling peak of-CH3 on C-C skeletal vibration and thiophene oxime ring ring, 899cm
-1for N-O stretching vibration on thiophene oxime ring.
Fig. 7 is the X-ray powder diffraction pattern of Sodium flucloxacillin crystal form II I of the present invention.
In figure: infrared spectra show, 1450,1500,1610cm
-1there is phenyl ring skeletal vibration, 995cm
-1for C-H in-plane bending vibration on trisubstituted benzene ring, at 781cm
-1there are three adjacent=C-H out-of-plane deformation vibrations on phenyl ring at place, 3510cm
-1molecule is interior, intermolecular hydrogen bonding O-H stretching vibration, 3370cm
-1N-H becomes stretching vibration, 2970cm
-1place is CH
3c-H stretching vibration, 1770cm
-1for carbonyl C=O stretching vibration on beta-lactam ring, 1660cm
-1the stretching vibration being absorbed as by force conjugation C=O and with C=C stretching vibration mixing peak, 1610cm
-1that phenyl ring skeletal vibration and C=N stretching vibration lotus root close peak, 1410cm
-1the CH asymmetric bending vibration of-CH3 on hydrogenation thiazole ring, 1330cm
-1comparatively strong absorption be the C-H asymmetric bending vibronic coupling peak of-CH3 on C-C skeletal vibration and thiophene oxime ring ring, 1250cm
-1for being thiophene oxime ring C-O stretching vibration; 899cm
-1for N-O stretching vibration on thiophene oxime ring.
Fig. 8 is the unbodied X-ray powder diffraction pattern of Sodium flucloxacillin of the present invention.
In figure: infrared spectra show, 1450,1510,1600cm
-1there is phenyl ring skeletal vibration, 978cm
-1for C-H in-plane bending vibration on trisubstituted benzene ring, at 787cm
-1there are three adjacent=C-H out-of-plane deformation vibrations on phenyl ring at place, 3400cm
-1N-H becomes stretching vibration, 1770cm
-1for carbonyl C=O stretching vibration on beta-lactam ring, 1660cm
-1the stretching vibration being absorbed as by force conjugation C=O and with C=C stretching vibration mixing peak, 1600cm
-1that phenyl ring skeletal vibration and C=N stretching vibration lotus root close peak, 1450cm
-1phenyl ring skeletal vibration and-CH3 symmetric curvature vibronic coupling peak, 1250cm
-1for being thiophene oxime ring C-O stretching vibration; 899cm
-1for N-O stretching vibration on thiophene oxime ring.
Fig. 9 is the infrared absorption spectrum of Flucloxacillin sodium crystal I of the present invention.
In figure: calculate according to TG curve diagram data, Flucloxacillin sodium crystal I of the present invention contains the Bound moisture of 1 molecule, and planar water and crystallization moisture account for 0.53% and 3.34% of total mass respectively, and 210 ° of about C decompose
Figure 10 is the infrared absorption spectrum of Sodium flucloxacillin crystal form II of the present invention.
In figure: calculate according to TG curve diagram data, Sodium flucloxacillin crystal form II of the present invention contains the Bound moisture of 1 molecule, and planar water and crystallization moisture account for 1.21% and 3.31% of total mass respectively, and 230 ° of about C decompose.
Figure 11 is the infrared absorption spectrum of Sodium flucloxacillin crystal form II I of the present invention.
In figure: calculate according to TG curve diagram data, Sodium flucloxacillin crystal form II I of the present invention contains the Bound moisture of 1 molecule, and planar water and crystallization moisture account for 0.51% and 3.14% of total mass respectively, and 220 ° of about C decompose.
Figure 12 is the unbodied infrared absorption spectrum of Sodium flucloxacillin of the present invention.
In figure: calculate according to TG curve diagram data, Sodium flucloxacillin of the present invention is amorphous not containing Bound moisture, and planar water accounts for 3.89% of total mass, and 220 ° of about C decompose.
Figure 13 is thermogravimetric-difference quotient thermogravimetric (TG-DTG) curve of Flucloxacillin sodium crystal I of the present invention.
Figure 14 is thermogravimetric-difference quotient thermogravimetric (TG-DTG) curve of Sodium flucloxacillin crystal form II of the present invention.
Figure 15 is thermogravimetric-difference quotient thermogravimetric (TG-DTG) curve of Sodium flucloxacillin crystal form II I of the present invention.
Figure 16 is the unbodied thermogravimetric of Sodium flucloxacillin of the present invention-difference quotient thermogravimetric (TG-DTG) curve.
In figure: shown in calculating according to TG curve and data, Flucloxacillin sodium crystal I-III contains an one's share of expenses for a joint undertaking Bound moisture, amorphous not containing Bound moisture.In pure water, amorphous and crystal form II I has higher solubleness.During 35 ° of C, the solubleness of each crystal formation is respectively (g/kg water): crystal formation I542.824; Crystal form II 462.406; Crystal form II I934.864; Amorphous 965.021.Amorphous and crystal form II I is almost the twice of crystal formation I and II.
Figure 17 is the dissolution characteristics of each crystal formation of Sodium flucloxacillin of the present invention.
Embodiment
embodiment 1:
One, Flucloxacillin sodium crystal I is prepared:
1.0g Sodium flucloxacillin bulk drug and 17mL Virahol is added, magnetic agitation, stirring velocity 20r/min in 50mL there-necked flask.Filtered while hot heat 0.5h under 50-55 DEG C of condition after, collects filtrate, room temperature cooling crystallization, collects crystal and 50 DEG C of freeze-day with constant temperature after crystal is separated out, and after dry 12 hours, normal temperature sealing is kept in moisture eliminator.
Two, the confirmation of Flucloxacillin sodium crystal I:
1. ultraviolet spectrophotometry:
Adopt Sodium flucloxacillin standard substance and the Flucloxacillin sodium crystal I solution of the phosphate buffer soln configuration 1g/L of pH=6.8, quartz colorimetric utensil, the phosphate buffer soln of pH=6.8 makes blank reagent.
Operational condition:
Detector: UV-2450 ultraviolet spectrophotometer
As a result, the Flucloxacillin sodium crystal I obtained as described in Example 1 and standard substance to go out peak position consistent.
2. infrared spectroscopy:
Adopt KBr compressing tablet process test sample, agate grinds ware grinding, 12kPa tableting pressure.
Operational condition:
Detector: ShimadzuFTIR-8400 type infrared spectrometer
Result: contrast with 2009 editions European Pharmacopoeias, 2000-400cm
-1mainly go out peak position difference in scope little, the intensity at part peak is variant, and this is relevant with crystal formation and instrument.
The instrumental analysis (DSC curve, X-ray powder diffraction and infrared spectra) of Flucloxacillin sodium crystal I
With the Flucloxacillin sodium crystal I that DSC curve (NETZSCH, DSC204 type), X-ray powder diffraction (Shimadzu, XpertPRO type) and infrared spectra (Shimadzu, FTIR-8400 type) are analyzed.Result is shown in Fig. 1,5,9.
Three, Flucloxacillin sodium crystal I moisture determination:
Thermogravimetric analyzer (NETZSCH, STA-449) is adopted to test the crystal water content of Flucloxacillin sodium crystal I.
This instrument of result records Bound moisture content 3.34%, planar water content 0.53%.With the relative molecular mass 475.87 of Sodium flucloxacillin, based on the relative molecular mass 18 of water, find that Flucloxacillin sodium crystal I contains a part Bound moisture.
Four, the solubility test of Flucloxacillin sodium crystal I:
Adopt the solubleness of stationary method test Flucloxacillin sodium crystal I in pure water, first adopt standard substance drawing standard curve, obtain typical curve equation y=6.1301x-0.8546, r=0.9989, configure the saturated solution of Flucloxacillin sodium crystal I under differing temps again, measure absorbancy at 286nm place, substitute into typical curve Solving Equations and obtain Flucloxacillin sodium crystal I solubleness at different temperatures.
Operational condition:
Water: second distillation
Detector: UV-2450 ultraviolet spectrophotometer
Solution temperature 20,25,30,35,40 ° of C
As a result, the Flucloxacillin solubleness of sodium crystal I in pure water increases along with the rising of temperature, and detailed content is shown in Figure 17.
embodiment 2:
One, Sodium flucloxacillin crystal form II is prepared:
2.0g Sodium flucloxacillin bulk drug and 20mL ethanol is added, magnetic agitation, stirring velocity 20r/min in 50mL there-necked flask.Heat 0.5h under boiling condition after, filtered while hot, Slow cooling crystallization, collects crystal and 50 DEG C of freeze-day with constant temperature after crystal is separated out, and after dry 12 hours, normal temperature sealing is kept in moisture eliminator.
Two, the confirmation of Sodium flucloxacillin crystal form II:
1. ultraviolet spectrophotometry:
Adopt Sodium flucloxacillin standard substance and the Sodium flucloxacillin crystal form II solution of the phosphate buffer soln configuration 1g/L of pH=6.8, quartz colorimetric utensil, the phosphate buffer soln of pH=6.8 makes blank reagent.
Operational condition:
Detector: UV-2450 ultraviolet spectrophotometer
As a result, the Sodium flucloxacillin crystal form II obtained as described in Example 6 and standard substance to go out peak position consistent.
2. infrared spectroscopy
Adopt KBr compressing tablet process test sample, agate grinds ware grinding, 12kPa tableting pressure.
Operational condition:
Detector: ShimadzuFTIR-8400 type infrared spectrometer
Result: contrast with 2009 editions European Pharmacopoeias, 2000-400cm
-1mainly go out peak position difference in scope little, the intensity at part peak is variant, and this is relevant with crystal formation and instrument.
The instrumental analysis (DSC curve, X-ray powder diffraction and infrared spectra) of Sodium flucloxacillin crystal form II
With DSC curve (NETZSCH, DSC204 type), X-ray powder diffraction (Shimadzu, XpertPRO type) and infrared spectra (Shimadzu, FTIR-8400 type) analysis Sodium flucloxacillin crystal form II as described in Example 6.Result is shown in Fig. 2,6,10.
Three, Sodium flucloxacillin crystal form II moisture determination:
Thermogravimetric analyzer (NETZSCH, STA-449) is adopted to test the crystal water content of Sodium flucloxacillin crystal form II.
This instrument of result records Bound moisture content 3.31%, planar water content 1.21%.With the relative molecular mass 475.87 of Sodium flucloxacillin, based on the relative molecular mass 18 of water, find that Sodium flucloxacillin crystal form II contains a part Bound moisture.
Four, the solubility test of Sodium flucloxacillin crystal form II:
Adopt the solubleness of stationary method test Sodium flucloxacillin crystal form II in pure water, first adopt standard substance drawing standard curve, obtain typical curve equation y=6.1301x-0.8546, r=0.9989, configure the saturated solution of Sodium flucloxacillin crystal form II under differing temps again, measure absorbancy at 286nm place, substitute into typical curve Solving Equations and obtain Sodium flucloxacillin crystal form II solubleness at different temperatures.
Operational condition:
Water: second distillation
Detector: UV-2450 ultraviolet spectrophotometer
Solution temperature 20,25,30,35,40 ° of C
As a result, the solubleness of Sodium flucloxacillin crystal form II in pure water increases along with the rising of temperature, and detailed content is shown in Figure 17.
embodiment 3:
One, Sodium flucloxacillin crystal form II I is prepared:
1.0g Sodium flucloxacillin bulk drug and 13mL acetone is added, magnetic agitation, stirring velocity 20r/min in 50mL there-necked flask.Heat 0.5h under boiling condition after, filtered while hot, lesser temps cooling crystallization (5-15 DEG C), collects crystal and 50 DEG C of freeze-day with constant temperature after crystal is separated out, and after dry 12 hours, normal temperature sealing is kept in moisture eliminator.
Two, the confirmation of Sodium flucloxacillin crystal form II I:
1. ultraviolet spectrophotometry:
Adopt Sodium flucloxacillin standard substance and the Sodium flucloxacillin crystal form II I solution of the phosphate buffer soln configuration 1g/L of pH=6.8, quartz colorimetric utensil, the phosphate buffer soln of pH=6.8 makes blank reagent.
Operational condition:
Detector: UV-2450 ultraviolet spectrophotometer
As a result, the Sodium flucloxacillin crystal form II I and the standard substance that obtain as described in embodiment 11 to go out peak position consistent.
2. infrared spectroscopy:
Adopt KBr compressing tablet process test sample, agate grinds ware grinding, 12kPa tableting pressure.
Operational condition:
Detector: ShimadzuFTIR-8400 type infrared spectrometer
Result: contrast with 2009 editions European Pharmacopoeias, 2000-400cm
-1mainly go out peak position difference in scope little, the intensity at part peak is variant, and this is relevant with crystal formation and instrument.
The instrumental analysis (DSC curve, X-ray powder diffraction and infrared spectra) of Sodium flucloxacillin crystal form II I
Flucloxacillin sodium crystal III is analyzed with DSC curve (NETZSCH, DSC204 type), X-ray powder diffraction (Shimadzu, XpertPRO type) and infrared spectra (Shimadzu, FTIR-8400 type).Result is shown in Fig. 3,7,11.
Three, Sodium flucloxacillin crystal form II I moisture determination:
Thermogravimetric analyzer (NETZSCH, STA-449) is adopted to test the crystal water content of Sodium flucloxacillin crystal form II I.
This instrument of result records Bound moisture content 3.14%, planar water content 0.51%.With the relative molecular mass 475.87 of Sodium flucloxacillin, based on the relative molecular mass 18 of water, find that Sodium flucloxacillin crystal form II I contains a part Bound moisture.
Four, the solubility test of Sodium flucloxacillin crystal form II I:
Adopt the solubleness of stationary method test Sodium flucloxacillin crystal form II I in pure water, first adopt standard substance drawing standard curve, obtain typical curve equation y=6.1301x-0.8546, r=0.9989, configure the saturated solution of Sodium flucloxacillin crystal form II I under differing temps again, measure absorbancy at 286nm place, substitute into typical curve Solving Equations and obtain Sodium flucloxacillin crystal form II I solubleness at different temperatures.
Operational condition:
Water: second distillation
Detector: UV-2450 ultraviolet spectrophotometer
Solution temperature 20,25,30,35,40 ° of C
As a result, the solubleness of Sodium flucloxacillin crystal form II I in pure water increases along with the rising of temperature, and detailed content is shown in Figure 17.
embodiment 4:
One, Sodium flucloxacillin is prepared amorphous:
1.0g Sodium flucloxacillin bulk drug and 17mL methyl alcohol (or 6mL tetrahydrofuran (THF)) is added, magnetic agitation, stirring velocity 20r/min in 50mL there-necked flask.Filtered while hot heat 0.5h under boiling condition after, room temperature cooling crystallization or use Rotary Evaporators evaporating solvent, collect crystal and 50 DEG C of freeze-day with constant temperature after crystal is separated out, and after dry 12 hours, normal temperature sealing is kept in moisture eliminator.
Two, the unbodied confirmation of Sodium flucloxacillin
1. ultraviolet spectrophotometry:
Adopt Sodium flucloxacillin standard substance and the amorphous solution of Sodium flucloxacillin of the phosphate buffer soln configuration 1g/L of pH=6.8, quartz colorimetric utensil, the phosphate buffer soln of pH=6.8 makes blank reagent.
Operational condition:
Detector: UV-2450 ultraviolet spectrophotometer
As a result, Sodium flucloxacillin amorphous with standard substance to go out peak position consistent.
2. infrared spectroscopy:
Adopt KBr compressing tablet process test sample, agate grinds ware grinding, 12kPa tableting pressure.
Operational condition:
Detector: ShimadzuFTIR-8400 type infrared spectrometer
Result: contrast with 2009 editions European Pharmacopoeias, 2000-400cm
-1mainly go out peak position difference in scope little, the intensity at part peak is variant, and this is relevant with crystal formation and instrument.
The unbodied instrumental analysis of Sodium flucloxacillin (DSC curve, X-ray powder diffraction and infrared spectra)
Sodium flucloxacillin is analyzed amorphous with DSC curve (NETZSCH, DSC204 type), X-ray powder diffraction (Shimadzu, XpertPRO type) and infrared spectra (Shimadzu, FTIR-8400 type).Result is shown in Fig. 4,8,12.
Three, the amorphous moisture determination of Sodium flucloxacillin:
Employing thermogravimetric analyzer (NETZSCH, STA-449) tests the unbodied crystal water content of Sodium flucloxacillin as described in Example 11.
This instrument of result records Bound moisture content 0%, planar water content 3.89%.With the relative molecular mass 475.87 of Sodium flucloxacillin, based on the relative molecular mass 18 of water, find that Sodium flucloxacillin is amorphous not containing Bound moisture.
Four, the unbodied solubility test of Sodium flucloxacillin:
Adopt the amorphous solubleness in pure water of stationary method test Sodium flucloxacillin, first adopt standard substance drawing standard curve, obtain typical curve equation y=6.1301x-0.8546, r=0.9989, configure the unbodied saturated solution of Sodium flucloxacillin under differing temps again, measure absorbancy at 286nm place, substitute into typical curve Solving Equations and obtain the amorphous solubleness at different temperatures of Sodium flucloxacillin.
Operational condition:
Water: second distillation
Detector: UV-2450 ultraviolet spectrophotometer
Solution temperature 20,25,30,35,40 ° of C
As a result, the amorphous solubleness in pure water of Sodium flucloxacillin increases along with the rising of temperature, and detailed content is shown in Figure 17.
Each crystal formation solubleness contrast finds, when 37 ° of C, crystalline form III solubleness is the highest, following closely amorphous, and the solubleness of the two is far superior to crystal formation I and II, has good bioavailability.Amorphous and crystal form II I can be adopted to produce medical injection.
Claims (1)
1. a preparation method of Sodium flucloxacillin crystal form II I, is characterized in that step is:
Sodium flucloxacillin bulk drug 1.0g is dissolved in 13mL acetone, magnetic agitation, heat 0.5h under boiling condition after, filtered while hot, 5-15 DEG C of cooling crystallization, collects crystal and 50 DEG C of freeze-day with constant temperature after crystal is separated out, and after dry 12 hours, normal temperature sealing is kept in moisture eliminator;
The feature of described Sodium flucloxacillin crystal form II I is: in differential scanning calorimetric analysis curve, and 65 ° of C exist endotherm(ic)peak; Exothermic peak is had at 150 ° of C; Crystal conversion and melting hump is had at 170 ° of C and 190 ° C; Decomposition peak is had at 230 ° of C; In X-ray powder diffraction, there are the strongest diffraction peak and I/I in 2 θ=6.4951 °
0=100; In infrared spectra about 781; 899; 1250; 1330; 1410; 1500; 1610; 1660; 1770; 3370; 3510cm
-1there is characteristic absorbance.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310168364.6A CN103288851B (en) | 2011-06-17 | 2011-06-17 | The preparation method of Sodium flucloxacillin crystal form II I |
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| CN201310168364.6A CN103288851B (en) | 2011-06-17 | 2011-06-17 | The preparation method of Sodium flucloxacillin crystal form II I |
| CN 201110165016 CN102285998B (en) | 2011-06-17 | 2011-06-17 | Preparation method of amorphous and three polymorphic substances of flucloxacillin sodium |
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| CN 201110165016 Division CN102285998B (en) | 2011-06-17 | 2011-06-17 | Preparation method of amorphous and three polymorphic substances of flucloxacillin sodium |
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| EP0273156A2 (en) * | 1986-12-23 | 1988-07-06 | Giovanni Bonfanti | Method for producing pure crystalline products |
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| EP0273156A2 (en) * | 1986-12-23 | 1988-07-06 | Giovanni Bonfanti | Method for producing pure crystalline products |
| CN101475578A (en) * | 2009-02-12 | 2009-07-08 | 海南本创医药科技有限公司 | Flucloxacillin sodium compound and preparation thereof |
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| A Multifaceted Approach to the Study of the Side-Chain Conformation in 6-Lactamase-Resistant Penicillins;Patrick C. Blanpain，等;《J. Med. Chem.》;19801231;第23卷;第1283-1292页 * |
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