CN103288851A - Preparation method of flucloxacillin sodium crystal form III - Google Patents

Preparation method of flucloxacillin sodium crystal form III Download PDF

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CN103288851A
CN103288851A CN2013101683646A CN201310168364A CN103288851A CN 103288851 A CN103288851 A CN 103288851A CN 2013101683646 A CN2013101683646 A CN 2013101683646A CN 201310168364 A CN201310168364 A CN 201310168364A CN 103288851 A CN103288851 A CN 103288851A
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crystal
flucloxacillin
sodium
peak
crystal form
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CN103288851B (en
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刘峥
周肖寅
王苗苗
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Guilin University of Technology
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Guilin University of Technology
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Abstract

The invention discloses a preparation method of a flucloxacillin sodium crystal form III. The preparation method comprises the following steps of: dissolving 1.0g of flucloxacillin sodium raw material medicines in 13mL of acetone; magnetically stirring; heating for 0.5 h in a boiling condition, and then filtering while hot; performing cooling crystallization at 5-15 DEG C; collecting crystals after the crystallization, and drying at a constant temperature of 50 DEG C; and drying for 12 hours, and air-tightly storing in a drier at a normal temperature. The flucloxacillin sodium crystal form III prepared by the preparation method disclosed by the invention is high in solubility in a neutral environment (with a pH of 6.8), thus showing high bioavailability.

Description

The preparation method of Sodium flucloxacillin crystal form II I
This case application is June 17 2011 applying date, application number 2011101650164, and invention and created name is: the preparation method of the amorphous and three kinds of polymorphic forms of Sodium flucloxacillin divides an application.
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)-and 6-[[3-(2-chloro-6-fluorophenyl)-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 salt] be known as a kind of semi-synthetic penicillins antimicrobial drug.Medicine of the same race adopts different solvents, and the crystallization processes crystallization makes the crystal of generation have different space structures, and we are referred to as the medicine heteromorphism.The medicine polycrystalline it is generally acknowledged four types: conformation polymorphic, configuration polymorphic, look polymorphic, pseudo-polymorphic.Molecule is called the conformation polymorphic at the different crystal that form of the arrangement of lattice vacancy in the crystal, and the crystal formation of most medicines all belongs to this type of.The different crystal that form in the position of atom in the crystal in molecule are called the configuration polymorphic.Medicine during crystallization, forms the crystal of different colours in different solvents, this is because the crystal formation difference, and optical property is also different, thereby has produced distinct colors, and this crystal is called the look polymorphic.Medicine is when crystallization, and solvent molecule is combined in the lattice with stoichiometric ratio and constitutes molecular complex, claims also to be called the solvent affixture by pseudo-polymorphic.Known many organic compound generally have polymorphic form, and this depends on the kind of recrystallization solvent, recrystallization temperature, the difference of factors such as pressure.
The Sodium flucloxacillin bulk drug is the mixture that amorphous and unknown crystal formation are arranged by analysis, the dissolving properties instability.
Summary of the invention
The preparation method who the purpose of this invention is to provide 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 the 10-20mL organic solvent, magnetic agitation, filtered while hot behind heating 0.5h under the 50-55 ℃ of condition, collect filtrate, the room temperature cooling crystallization, treat to collect crystal and 50 ℃ of freeze-day with constant temperature after crystal is separated out, the normal temperature sealing is kept in the moisture eliminator after dry 12 hours;
Described organic solvent is a kind of in Virahol, ethyl acetate, ethanol, acetone, methyl alcohol and the tetrahydrofuran (THF).
Two, Flucloxacillin sodium crystal I-III and unbodied being characterized as:
1, the feature of Flucloxacillin sodium crystal I:
In the differential scanning calorimetric analysis curve, there is endotherm(ic)peak in 60 ° of C; At about 65 ° of C exothermic peak is arranged;
165 ° of C have crystal conversion and melting hump; At 210 ° of C the decomposition peak is arranged; In the X-ray powder diffraction, the strongest diffraction peak (I/I ° is arranged in 2 θ=19.3375 0=100), in 2 θ=6.799; 15.0499; 21.1936 ° locate also to have strong diffraction peak; In infrared spectra about 783; 901; 1250; 1340; 1500; 1600; 1770; 2980; 3370; 3520cm -1Characteristic absorbance is arranged.
2, the feature of Sodium flucloxacillin crystal form II:
In the differential scanning calorimetric analysis curve, there are endotherm(ic)peak in 40 ° of C and 100 ° of C; Put at about 65 ° of C
Thermal spike; At 145 ° of C and 165 ° of C crystal conversion and melting hump are arranged; At 210 ° of C the decomposition peak is arranged; In the X-ray powder diffraction, the strongest diffraction peak (I/I ° is arranged in 2 θ=8.9858 0=100); In infrared spectra about 785; 899; 1330; 1400; 1510; 1600; 1670; 1770; 3370cm -1Characteristic absorbance is arranged.
3, the feature of Sodium flucloxacillin crystal form II I:
In the differential scanning calorimetric analysis curve, there is endotherm(ic)peak in 65 ° of C; At about 150 ° of C exothermic peak is arranged;
170 ° of C and 190 ° of C have crystal conversion and melting hump; At 230 ° of C the decomposition peak is arranged; In the X-ray powder diffraction, the strongest diffraction peak (I/I ° is arranged in 2 θ=6.4951 0=100); In infrared spectra about 781; 899; 1250; 1330; 1410; 1500; 1610; 1660; 1770; 3370; 3510cm -1Characteristic absorbance is arranged.
4, the unbodied feature of Sodium flucloxacillin:
In the differential scanning calorimetric analysis curve, there is endotherm(ic)peak in 25 ° of C; At about 150 ° of C exothermic peak is arranged;
180 ° of C have melting hump; At 220 ° of C the decomposition peak is arranged; In the X-ray powder diffraction, do not have the crystalline diffraction peak, locate to exist amorphous feature steamed bun peak at 2 θ=10-30 °; In infrared spectra about 787; 899; 1250; 1400; 1450; 1510; 1600; 1660; 1740; 3400cm -1Characteristic absorbance is arranged.
Amorphous and three kinds of polymorphic Sodium flucloxacillins equal tool in neutral environment (pH=6.8) of the present invention's preparation
Higher solubleness is arranged, thereby show high bioavailability.
Description of drawings
Fig. 1 is differential scanning calorimetric analysis (DSC) curve of Flucloxacillin sodium crystal I of the present invention.
Among the figure: show that in the DSC curve there is endotherm(ic)peak in 60 ° of C, exothermic peak is arranged and at 165 ° of C crystal conversion and melting hump are arranged at about 65 ° of C at 210 ° of C the decomposition peak is arranged.In the X-ray powder diffraction, the strongest diffraction peak (I/I ° is arranged in 2 θ=19.3375 0=100), in 2 θ=6.799; 15.0499; 21.1936 ° locate also to have strong diffraction peak, this obviously is 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.
Among the figure: show that in the DSC curve there is endotherm(ic)peak in 40,100 ° of C, exothermic peak is arranged and at 145,165 ° of C crystal conversion and melting hump are arranged at about 65 ° of C at 210 ° of C the decomposition peak is arranged.In the X-ray powder diffraction, the strongest diffraction peak (I/I ° is arranged in 2 θ=8.9858 0=100), this obviously is 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.
Among the figure: show that in the DSC curve 65 ° of C exist endotherm(ic)peak to have exothermic peak to reach 170 at about 150 ° of C
° C and 190 ° of C have crystal conversion and melting hump, at 230 ° of C the decomposition peak are arranged.In the X-ray powder diffraction, the strongest diffraction peak (I/I ° is arranged in 2 θ=6.4951 0=100), this obviously is 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.
Among the figure: show that in the DSC curve there is endotherm(ic)peak in 25 ° of C, have exothermic peak to reach 180 at about 150 ° of C
° C has melting hump, at 220 ° of C the decomposition peak is arranged.In the X-ray powder diffraction, locate to exist amorphous feature steamed bun peak at 2 θ=10-30 °, this obviously is 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.
Among the figure: infrared spectra shows, 3090, cm -11460,1500,1600 cm are arranged on the phenyl ring=the C-H stretching vibration -1There is the phenyl ring skeletal vibration, 984 cm -1Be C-H in-plane bending vibration on the trisubstituted benzene ring, 783,847cm -1There are three adjacent=C-H out-of-plane deformation vibrations on the phenyl ring, 3520cm in the place -1Intramolecularly, intermolecular hydrogen bonding O-H stretching vibration, 3370 cm -The 1N-H stretching vibration, 2980cm -1The place is CH 3The C-H asymmetrical stretching vibration, 1770 cm -1Be carbonyl C=O stretching vibration on the beta-lactam ring, 1660 cm -1The stretching vibration that is absorbed as conjugation C=O by force and and C=C stretching vibration mixing peak, 1600 cm -1Be that phenyl ring skeletal vibration and C=N stretching vibration lotus root are closed the peak lotus root and close the peak, 1410cm -1On the hydrogenation thiazole ring-and CH3, asymmetric bending vibration, 1340 cm -1Strong the absorption be on C-C skeletal vibration and the thiophene oxime ring ring-the C-H asymmetric bending vibronic coupling peak of CH3 1250cm -1Be thiophene oxime ring C-O stretching vibration, 901cm -1Be N-O stretching vibration on the thiophene oxime ring.
Fig. 6 is the X-ray powder diffraction pattern of Sodium flucloxacillin crystal form II of the present invention.
Among the figure: infrared spectra shows, 1450,1510,1600 cm -1There is the phenyl ring skeletal vibration, 987 cm -1Be C-H in-plane bending vibration on the trisubstituted benzene ring, 785,841cm -1There are three adjacent=C-H out-of-plane deformation vibrations on the phenyl ring, 3370 cm in the place -The 1N-H stretching vibration, 2970cm -1The place is CH 3The C-H asymmetrical stretching vibration, 1770 cm -1Be carbonyl C=O stretching vibration on the beta-lactam ring, 1670 cm -1The stretching vibration that is absorbed as conjugation C=O by force and and C=C stretching vibration mixing peak, 1600 cm -1Be that phenyl ring skeletal vibration and C=N stretching vibration lotus root are closed the peak, 1400cm -1On the hydrogenation thiazole ring-and the CH asymmetric bending of CH3 vibration, 1330 cm -1Strong the absorption be on C-C skeletal vibration and the thiophene oxime ring ring-the C-H asymmetric bending vibronic coupling peak of CH3 899cm -1Be N-O stretching vibration on the thiophene oxime ring.
Fig. 7 is the X-ray powder diffraction pattern of Sodium flucloxacillin crystal form II I of the present invention.
Among the figure: infrared spectra shows, 1450,1500,1610 cm -1There is the phenyl ring skeletal vibration, 995 cm -1For C-H in-plane bending vibration on the trisubstituted benzene ring, at 781cm -1There are three adjacent=C-H out-of-plane deformation vibrations on the phenyl ring, 3510cm in the place -1Intramolecularly, intermolecular hydrogen bonding O-H stretching vibration, 3370 cm -1N-H becomes stretching vibration, 2970cm -1The place is CH 3The C-H stretching vibration, 1770 cm -1Be carbonyl C=O stretching vibration on the beta-lactam ring, 1660 cm -1The stretching vibration that is absorbed as conjugation C=O by force and and C=C stretching vibration mixing peak, 1610 cm -1Be that phenyl ring skeletal vibration and C=N stretching vibration lotus root are closed the peak, 1410cm -1On the hydrogenation thiazole ring-and the CH asymmetric bending of CH3 vibration, 1330 cm -1Strong the absorption be on C-C skeletal vibration and the thiophene oxime ring ring-the C-H asymmetric bending vibronic coupling peak of CH3 1250cm -1For being thiophene oxime ring C-O stretching vibration; 899cm -1Be N-O stretching vibration on the thiophene oxime ring.
Fig. 8 is the unbodied X-ray powder diffraction pattern of Sodium flucloxacillin of the present invention.
Among the figure: infrared spectra shows, 1450,1510,1600 cm -1There is the phenyl ring skeletal vibration, 978 cm -1For C-H in-plane bending vibration on the trisubstituted benzene ring, at 787cm -1There are three adjacent=C-H out-of-plane deformation vibrations on the phenyl ring, 3400cm in the place -1N-H becomes stretching vibration, 1770 cm -1Be carbonyl C=O stretching vibration on the beta-lactam ring, 1660 cm -1The stretching vibration that is absorbed as conjugation C=O by force and and C=C stretching vibration mixing peak, 1600 cm -1Be that phenyl ring skeletal vibration and C=N stretching vibration lotus root are closed the peak, 1450cm -1Be the phenyl ring skeletal vibration and-CH3 symmetric curvature vibronic coupling peak, 1250cm -1For being thiophene oxime ring C-O stretching vibration; 899cm -1Be N-O stretching vibration on the thiophene oxime ring.
Fig. 9 is the infrared absorption spectrum of Flucloxacillin sodium crystal I of the present invention.
Among the figure: calculate according to the TG curve diagram data, Flucloxacillin sodium crystal I of the present invention contain 1 molecule in conjunction with water, planar water and crystallization moisture account for respectively about 0.53% and 3.34%, 210 ° of C of total mass and decompose
Figure 10 is the infrared absorption spectrum of Sodium flucloxacillin crystal form II of the present invention.
Among the figure: calculate according to the TG curve diagram data, Sodium flucloxacillin crystal form II of the present invention contain 1 molecule in conjunction with water, planar water and crystallization moisture account for respectively about 1.21% and 3.31%, 230 ° of C of total mass and decompose.
Figure 11 is the infrared absorption spectrum of Sodium flucloxacillin crystal form II I of the present invention.
Among the figure: calculate according to the TG curve diagram data, Sodium flucloxacillin crystal form II I of the present invention contain 1 molecule in conjunction with water, planar water and crystallization moisture account for respectively about 0.51% and 3.14%, 220 ° of C of total mass and decompose.
Figure 12 is the unbodied infrared absorption spectrum of Sodium flucloxacillin of the present invention.
Among the figure: calculate according to the TG curve diagram data, Sodium flucloxacillin of the present invention is amorphous not to be contained in conjunction with water, and planar water accounts for about 3.89%, 220 ° of C of total mass decomposes.
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.
Among the figure: shown in TG curve and data computation, Flucloxacillin sodium crystal I-III contains an one's share of expenses for a joint undertaking in conjunction with water, does not amorphously contain in conjunction with water.In pure water, amorphous and crystal form II I has higher solubleness.The solubleness of each crystal formation is respectively (g/kg water): crystal formation I 542.824 during 35 ° of C; Crystal form II 462.406; Crystal form II I 934.864; Amorphous 965.021.Amorphous and crystal form II I almost is 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, preparation Flucloxacillin sodium crystal I:
In the 50mL there-necked flask, add 1.0g Sodium flucloxacillin bulk drug and 17mL Virahol, magnetic agitation, stirring velocity 20r/min.Filtered while hot behind heating 0.5h under the 50-55 ℃ of condition is collected filtrate, and the room temperature cooling crystallization is treated to collect crystal and 50 ℃ of freeze-day with constant temperature after crystal is separated out, and the normal temperature sealing is kept in the moisture eliminator after dry 12 hours.
Two, the affirmation 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 is made blank reagent.
Operational condition:
Detector: UV-2450 ultraviolet spectrophotometer
As a result, as the Flucloxacillin sodium crystal I of acquisition as described in the embodiment 1 and standard substance to go out the peak position consistent.
2. infrared spectroscopy:
Adopt the KBr compressing tablet to handle specimen, agate grinds ware and grinds, 12kPa compressing tablet pressure.
Operational condition:
Detector: ShimadzuFTIR-8400 type infrared spectrometer
Result: with 2009 editions European Pharmacopoeia contrasts, 2000-400cm -1It is little mainly to go out the peak position difference in the scope, and the intensity at part peak is variant, and this is relevant with used instrument with crystal formation.
The instrumental analysis of Flucloxacillin sodium crystal I (DSC curve, X-ray powder diffraction and infrared spectra)
Flucloxacillin sodium crystal I with DSC curve (NETZSCH, DSC204 type), X-ray powder diffraction (Shimadzu, Xpert PRO type) and infrared spectra (Shimadzu, FTIR-8400 type) analysis.The results are shown among Fig. 1,5,9.
Three, Flucloxacillin sodium crystal I moisture determination:
(NETZSCH STA-449) has tested the crystal water content of Flucloxacillin sodium crystal I to adopt thermogravimetric analyzer.
The result records in conjunction with water-content 3.34% with this instrument, planar water content 0.53%.With the relative molecular mass 475.87 of Sodium flucloxacillin, the relative molecular mass 18 of water is the basis, finds that Flucloxacillin sodium crystal I contains a part in conjunction with water.
Four, the solubility test of Flucloxacillin sodium crystal I:
Adopt the solubleness of stationary method test Flucloxacillin sodium crystal I in pure water, institute adopts standard substance drawing standard curve earlier, obtain typical curve equation y=6.1301x-0.8546, r=0.9989, dispose the saturated solution of sodium crystal I in Flucloxacillin under the differing temps again, measure absorbancy at the 286nm place, substitution typical curve equation is tried to achieve the solubleness of Flucloxacillin sodium crystal I under differing temps.
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 seen Figure 17.
 
Embodiment 2:
One, preparation Sodium flucloxacillin crystal form II:
In the 50mL there-necked flask, add 2.0g Sodium flucloxacillin bulk drug and 20mL ethanol, magnetic agitation, stirring velocity 20r/min.Behind heating 0.5h under the boiling condition, filtered while hot, slowly cooling crystallization is treated to collect crystal and 50 ℃ of freeze-day with constant temperature after crystal is separated out, and the normal temperature sealing is kept in the moisture eliminator after dry 12 hours.
Two, the affirmation 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 is made blank reagent.
Operational condition:
Detector: UV-2450 ultraviolet spectrophotometer
As a result, as the Sodium flucloxacillin crystal form II of acquisition as described in the embodiment 6 and standard substance to go out the peak position consistent.
2. infrared spectroscopy
Adopt the KBr compressing tablet to handle specimen, agate grinds ware and grinds, 12kPa compressing tablet pressure.
Operational condition:
Detector: ShimadzuFTIR-8400 type infrared spectrometer
Result: with 2009 editions European Pharmacopoeia contrasts, 2000-400cm -1It is little mainly to go out the peak position difference in the scope, and the intensity at part peak is variant, and this is relevant with used instrument with crystal formation.
The instrumental analysis of Sodium flucloxacillin crystal form II (DSC curve, X-ray powder diffraction and infrared spectra)
With DSC curve (NETZSCH, DSC204 type), X-ray powder diffraction (Shimadzu, Xpert PRO type) and the Sodium flucloxacillin crystal form II of infrared spectra (Shimadzu, FTIR-8400 type) analysis shown in embodiment 6.The results are shown among Fig. 2,6,10.
Three, Sodium flucloxacillin crystal form II moisture determination:
(NETZSCH STA-449) has tested the crystal water content of Sodium flucloxacillin crystal form II to adopt thermogravimetric analyzer.
The result records in conjunction with water-content 3.31% with this instrument, planar water content 1.21%.With the relative molecular mass 475.87 of Sodium flucloxacillin, the relative molecular mass 18 of water is the basis, finds that the Sodium flucloxacillin crystal form II contains a part in conjunction with water.
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, institute adopts standard substance drawing standard curve earlier, obtain typical curve equation y=6.1301x-0.8546, r=0.9989, dispose the saturated solution of Sodium flucloxacillin crystal form II under the differing temps again, measure absorbancy at the 286nm place, substitution typical curve equation is tried to achieve the solubleness of Sodium flucloxacillin crystal form II under differing temps.
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 seen Figure 17.
 
Embodiment 3:
One, preparation Sodium flucloxacillin crystal form II I:
In the 50mL there-necked flask, add 1.0g Sodium flucloxacillin bulk drug and 13mL acetone, magnetic agitation, stirring velocity 20r/min.Behind heating 0.5h under the boiling condition, filtered while hot, lesser temps cooling crystallization (5-15 ℃) is treated to collect crystal and 50 ℃ of freeze-day with constant temperature after crystal is separated out, and the normal temperature sealing is kept in the moisture eliminator after dry 12 hours.
Two, the affirmation 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 is made blank reagent.
Operational condition:
Detector: UV-2450 ultraviolet spectrophotometer
As a result, as the Sodium flucloxacillin crystal form II I of acquisition as described in the embodiment 11 and standard substance to go out the peak position consistent.
2. infrared spectroscopy:
Adopt the KBr compressing tablet to handle specimen, agate grinds ware and grinds, 12kPa compressing tablet pressure.
Operational condition:
Detector: ShimadzuFTIR-8400 type infrared spectrometer
Result: with 2009 editions European Pharmacopoeia contrasts, 2000-400cm -1It is little mainly to go out the peak position difference in the scope, and the intensity at part peak is variant, and this is relevant with used instrument with crystal formation.
The instrumental analysis of Sodium flucloxacillin crystal form II I (DSC curve, X-ray powder diffraction and infrared spectra)
Analyze Flucloxacillin sodium crystal III with DSC curve (NETZSCH, DSC204 type), X-ray powder diffraction (Shimadzu, Xpert PRO type) and infrared spectra (Shimadzu, FTIR-8400 type).The results are shown among Fig. 3,7,11.
Three, Sodium flucloxacillin crystal form II I moisture determination:
(NETZSCH STA-449) has tested the crystal water content of Sodium flucloxacillin crystal form II I to adopt thermogravimetric analyzer.
The result records in conjunction with water-content 3.14% with this instrument, planar water content 0.51%.With the relative molecular mass 475.87 of Sodium flucloxacillin, the relative molecular mass 18 of water is the basis, finds that Sodium flucloxacillin crystal form II I contains a part in conjunction with water.
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, institute adopts standard substance drawing standard curve earlier, obtain typical curve equation y=6.1301x-0.8546, r=0.9989, dispose the saturated solution of Sodium flucloxacillin crystal form II I under the differing temps again, measure absorbancy at the 286nm place, substitution typical curve equation is tried to achieve the solubleness of Sodium flucloxacillin crystal form II I under differing temps.
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 seen Figure 17.
 
Embodiment 4:
One, the preparation Sodium flucloxacillin is amorphous:
In the 50mL there-necked flask, add 1.0g Sodium flucloxacillin bulk drug and 17mL methyl alcohol (or 6mL tetrahydrofuran (THF)), magnetic agitation, stirring velocity 20r/min.Filtered while hot behind heating 0.5h under the boiling condition, room temperature cooling crystallization or use Rotary Evaporators evaporating solvent are treated to collect crystal and 50 ℃ of freeze-day with constant temperature after crystal is separated out, and normal temperature seals and is kept in the moisture eliminator after dry 12 hours.
Two, the unbodied affirmation 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 is made blank reagent.
Operational condition:
Detector: UV-2450 ultraviolet spectrophotometer
As a result, Sodium flucloxacillin amorphous with standard substance to go out the peak position consistent.
2. infrared spectroscopy:
Adopt the KBr compressing tablet to handle specimen, agate grinds ware and grinds, 12kPa compressing tablet pressure.
Operational condition:
Detector: ShimadzuFTIR-8400 type infrared spectrometer
Result: with 2009 editions European Pharmacopoeia contrasts, 2000-400cm -1It is little mainly to go out the peak position difference in the scope, and the intensity at part peak is variant, and this is relevant with used instrument with crystal formation.
The unbodied instrumental analysis of Sodium flucloxacillin (DSC curve, X-ray powder diffraction and infrared spectra)
It is amorphous to analyze Sodium flucloxacillin with DSC curve (NETZSCH, DSC204 type), X-ray powder diffraction (Shimadzu, Xpert PRO type) and infrared spectra (Shimadzu, FTIR-8400 type).The results are shown among Fig. 4,8,12.
Three, the amorphous moisture determination of Sodium flucloxacillin:
(NETZSCH STA-449) has tested the unbodied crystal water content of Sodium flucloxacillin shown in embodiment 11 to adopt thermogravimetric analyzer.
The result records in conjunction with water-content 0% with this instrument, planar water content 3.89%.With the relative molecular mass 475.87 of Sodium flucloxacillin, the relative molecular mass 18 of water is the basis, finds that Sodium flucloxacillin is amorphous not contain in conjunction with water.
Four, the unbodied solubility test of Sodium flucloxacillin:
Adopt the amorphous solubleness in pure water of stationary method test Sodium flucloxacillin, institute adopts standard substance drawing standard curve earlier, obtain typical curve equation y=6.1301x-0.8546, r=0.9989, dispose the unbodied saturated solution of Sodium flucloxacillin under the differing temps again, measure absorbancy at the 286nm place, substitution typical curve equation is tried to achieve the amorphous solubleness under differing temps 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 seen Figure 17.
Each crystal formation solubleness contrast finds that crystalline form III solubleness is the highest, following closely amorphous when 37 ° of C, and the solubleness of the two is far superior to crystal formation I and II, has bioavailability preferably.Can adopt amorphous and crystal form II I to produce medical injection.

Claims (1)

1. the preparation method of a Sodium flucloxacillin crystal form II I is characterized in that step is:
Sodium flucloxacillin bulk drug 1.0g is dissolved in the 13mL acetone, and magnetic agitation is behind heating 0.5h under the boiling condition, filtered while hot, 5-15 ℃ of cooling crystallization treated to collect crystal and 50 ℃ of freeze-day with constant temperature after crystal is separated out, and the normal temperature sealing is kept in the moisture eliminator after dry 12 hours;
Described Sodium flucloxacillin crystal form II I is characterized as: in the differential scanning calorimetric analysis curve, there is endotherm(ic)peak in 65 ° of C; At 150 ° of C exothermic peak is arranged; At 170 ° of C and 190 ° of C crystal conversion and melting hump are arranged; At 230 ° of C the decomposition peak is arranged; In the X-ray powder diffraction, ° the strongest diffraction peak being arranged in 2 θ=6.4951 is I/I 0=100; In infrared spectra about 781; 899; 1250; 1330; 1410; 1500; 1610; 1660; 1770; 3370; 3510cm -1Characteristic absorbance is arranged.
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