CN102924449B - Moxifloxacin hydrochloride H crystal form and preparation method thereof and pharmaceutical composition - Google Patents
Moxifloxacin hydrochloride H crystal form and preparation method thereof and pharmaceutical composition Download PDFInfo
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- CN102924449B CN102924449B CN201210424822.3A CN201210424822A CN102924449B CN 102924449 B CN102924449 B CN 102924449B CN 201210424822 A CN201210424822 A CN 201210424822A CN 102924449 B CN102924449 B CN 102924449B
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Abstract
The invention discloses a kind of new crystal of Moxifloxacin hydrochloride, i.e. H crystal form, and the preparation method of this crystal formation.In addition, the invention also discloses pharmaceutical composition and the purposes of Moxifloxacin hydrochloride H crystal form.New crystal disclosed by the invention, compared with existing crystal formation, has notable difference, and its quality is more stable, and preparation technology is simple, is easy to realize suitability for industrialized production.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, particularly a kind of Moxifloxacin hydrochloride H crystal form, and preparation method thereof and pharmaceutical composition.
Background technology
Moxifloxacin hydrochloride, is developed by Beyer Co., Ltd, the clinical treatment for respiratory system infection, genital system infection, skin soft-tissue infection etc.The formulation of current listing comprises injection, eye drop and oral tablet, its chemical name is 1-cyclopropyl-7-([S, S]-2,8-diazabicyclo [4.3.0]-nonanal-8-group)-6-fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinolone carboxylic acid, structural formula is as follows:
Current, the crystal formation report relevant to Moxifloxacin hydrochloride is more.Such as: the Chinese patent ZL96123220.X of Beyer Co., Ltd discloses the new crystal of Moxifloxacin hydrochloride monohydrate.
Quimica Sintetica company discloses a kind of new crystal of Moxifloxacin hydrochloride in international application for patent WO2008028959, the crystal formation of this Moxifloxacin hydrochloride is characterised in that: the characteristic peak positions of 2 θ shown in powder X-ray diffractogram is: 8.1,9.8,15.2,17.7,22.6.The preparation method of this crystal formation is: be scattered in the mixed solvent of methanol/water by Moxifloxacin hydrochloride crude product, be heated to backflow, in mixed solution, add acetone and holding temperature at 40-45 DEG C; After be cooled to 15-25 DEG C of crystallization, filter, be dried to constant weight and get final product.
Chemo iberica, S, A company discloses α 1 crystal formation and α 2 crystal formation of Moxifloxacin hydrochloride hydrate in international application for patent WO2009087151.The feature of this Moxifloxacin hydrochloride hydrate (α 1 crystal formation) is: the characteristic peak positions of 2 θ shown in powder X-ray diffractogram is: 5.6,7.0,8.3,9.9,14.3,15.4,17.2,20.2,23.4,26.4,27.3,29.0; The feature of α 2 crystal formation is: the characteristic peak positions of 2 θ shown in powder X-ray diffractogram is 5.7,7.1,8.4,10.2,14.4,16.9,19.1,21.5,26.3,27.2.
In addition, the A crystal formation that international application for patent WO2004091619 discloses Moxifloxacin hydrochloride III crystal formation, WO2005054240 discloses Moxifloxacin hydrochloride and B crystal form, WO2007010555 disclose X crystal formation and the Y crystal formation of Moxifloxacin hydrochloride.
Summary of the invention
Studied by the stability to above crystal formation, water absorbability, mobility, the present inventor has been surprised to find a kind of new crystal of Moxifloxacin hydrochloride, by its called after H crystal form, the X-ray powder diffraction pattern of this crystal formation is compared with existing crystal formation, there is notable difference, and its quality is more stable, preparation technology is simple, is easy to realize suitability for industrialized production.
The object of the present invention is to provide a kind of new crystal of Moxifloxacin hydrochloride, i.e. H crystal form.
Second object of the present invention is the preparation method providing a kind of Moxifloxacin hydrochloride H crystal form.
3rd object of the present invention is to provide a kind of pharmaceutical composition containing Moxifloxacin hydrochloride H crystal form.
4th object of the present invention is the purposes providing Moxifloxacin hydrochloride H crystal form.
Specifically, the invention provides a kind of new crystal of Moxifloxacin hydrochloride, i.e. H crystal form, it is characterized in that, characterize with x-ray diffractogram of powder, use has the anticathode diffractometer of copper and measures, and represents with θ angle, Prague 2 and relative intensity, described relative intensity represents with the percentage ratio of the strongest ray, and this diffractogram comprises the diffraction peak that following relative intensity is greater than 20: 5.89,10.15,17.47 and 29.25.
In a kind of preferred embodiment of the present invention, the invention provides a kind of H crystal form of Moxifloxacin hydrochloride, it is characterized in that, characterize with x-ray diffractogram of powder, use has the anticathode diffractometer of copper and measures, represent with θ angle, Prague 2 and relative intensity, described relative intensity represents with the percentage ratio of the strongest ray, and this diffractogram comprises the diffraction peak that following relative intensity is greater than 20:
2 θ are 5.89, and relative intensity is 41; 2 θ are 10.15, and relative intensity is 22; 2 θ are 17.47, and relative intensity is 100; Be 29.25 with 2 θ, relative intensity is 25.
In a kind of preferred embodiment of the present invention, the invention provides a kind of H crystal form of Moxifloxacin hydrochloride, it is characterized in that, characterize with following x-ray diffractogram of powder, use has the anticathode diffractometer of copper and measures, represent with spacing d, θ angle, Prague 2 and relative intensity, described relative intensity represents with the percentage ratio of the strongest ray:
In a kind of particularly preferred embodiment, the invention provides a kind of H crystal form of Moxifloxacin hydrochloride, it is characterized in that, characterize with following x-ray diffractogram of powder, as shown in Figure 1.
In embodiments of the invention, θ angle, Prague 2 numerical value in described x-ray diffractogram of powder is ± 0.1 °.
In embodiments of the invention, the invention provides a kind of H crystal form of Moxifloxacin hydrochloride, it is characterized in that, the infrared spectra that its KBr pressed disc method records, be about 3527cm in peak position
-1, 3469cm
-1, 2964cm
-1, 2925cm
-1, 2890cm
-1, 1707cm
-1, 1623cm
-1, 1431cm
-1, 1351cm
-1, 1318cm
-1, 1105cm
-1, 1045cm
-1, 874cm
-1there is specific infrared absorption band at place.
In embodiments of the invention, the invention provides a kind of H crystal form of Moxifloxacin hydrochloride, it is characterized in that, be maximum heat melting temperatur (DTG-60H determinator near 243.89 DEG C in differential thermal analysis (DSC) collection of illustrative plates, test condition: 30 ~ 400 DEG C, heat-up rate 10.00 DEG C/min, under nitrogen environment).
In embodiments of the invention, Moxifloxacin hydrochloride H crystal form provided by the invention, is characterized in that, water content is 2.5 ~ 4.5 % by weight, preferably, is 3.0 ~ 4.0 % by weight (Karl_Fischer method mensuration).
Another aspect, the invention provides the preparation method of above-mentioned Moxifloxacin hydrochloride H crystal form, comprises the steps:
(1) Moxifloxacin free alkali is joined in the aqueous solution of 2 ~ 15 times of (V/W adds quality in Moxifloxacin free alkali) lower alcohols;
(2) be heated to 50 ~ 100 DEG C of dissolvings, insulation, drip the concentrated hydrochloric acid of 1 ~ 5 equivalent;
(3) maintain 50 ~ 100 DEG C to stir 0.5 ~ 3 hour, have solid to separate out, drip the acetone of 3 ~ 10 times (V/W adds quality in Moxifloxacin free alkali);
(4) be cooled to 0 ~ 30 DEG C of abundant crystallization, filter, filter cake is with the washing with acetone of 0.5-1.5 times (V/W adds quality in Moxifloxacin free alkali);
(5) get filter cake drying under reduced pressure at 30 ~ 80 DEG C and be no more than 8 hours, vacuum tightness-0.08MPa ~ 0.095MPa, obtain Moxifloxacin hydrochloride H crystal form.
In embodiments of the invention, Moxifloxacin hydrochloride H crystal form preparation method provided by the invention, preferably, the lower alcohol described in step (1) is selected from one or more (namely two or more) in methyl alcohol, ethanol, Virahol, the trimethyl carbinol and ethylene glycol; The aqueous solution content of described lower alcohol is 30 ~ 95 volume %, and most preferably, the content of described aqueous lower alcoholic solutions is 40 ~ 65 volume %; The add-on of the aqueous solution of described lower alcohol is 4 ~ 8 times (V/W adds quality in Moxifloxacin free alkali) of Moxifloxacin free alkali.
In embodiments of the invention, Moxifloxacin hydrochloride H crystal form preparation method provided by the invention, preferably, the Heating temperature described in step (2) is 55 ~ 75 DEG C; Described concentrated hydrochloric acid add-on is 2 ~ 3.5 equivalents.
In embodiments of the invention, Moxifloxacin hydrochloride H crystal form preparation method provided by the invention, preferably, the churning time described in step (3) is 1 ~ 2 hour.
In embodiments of the invention, Moxifloxacin hydrochloride H crystal form preparation method provided by the invention, preferably, the acetone add-on described in step (3) is 4 ~ 6 times (V/W adds quality in Moxifloxacin free alkali).
In embodiments of the invention, Moxifloxacin hydrochloride H crystal form preparation method provided by the invention, preferably, the cooling temperature described in step (4) is 5 ~ 15 DEG C; Described acetone add-on is 1.0 ~ 1.2 times.
In embodiments of the invention, Moxifloxacin hydrochloride H crystal form preparation method provided by the invention, preferably, the drying temperature described in step (5) is 50 ~ 60 DEG C; The time of described drying under reduced pressure is 3 ~ 8 hours.
In embodiments of the invention, described W/V is weightmeasurement ratio, and described V/W is envelope-bulk to weight ratio, and W/W is weight ratio.
The third aspect, the invention provides the pharmaceutical composition containing Moxifloxacin hydrochloride H crystal form.Those skilled in the art under the teachings of the present invention, can any suitable route of administration be supplied to patient's effective dose by H crystal form Moxifloxacin hydrochloride of the present invention, such as: can be used as oral, injection or topical ophthalmic use, therefore, the formulation of pharmaceutical composition of the present invention includes but not limited to capsule, tablet, injection, granule, gelifying agent etc.Such as, those skilled in the art can with reference to the listing formulation-tablet of Moxifloxacin hydrochloride, sodium chloride injection and eye drop, Moxifloxacin hydrochloride H crystal form pharmaceutical composition of the present invention is made tablet, specification is 400mg, and auxiliary material can adopt Microcrystalline Cellulose, Zeparox, croscarmellose sodium, Magnesium Stearate, hypromellose, polyoxyethylene glycol, titanium dioxide and ferric oxide; Sodium chloride injection, specification is 250ml:400mg, and auxiliary material is sodium-chlor, water for injection, also may contain hydrochloric acid or sodium hydroxide adjust ph, and every bottle of injection liquid comprises sodium-chlor and the 400mg Moxifloxacin of 0.8%, and pH value range is 4.1 ~ 4.6; Eye drop, specification is 3ml:15mg, and auxiliary material is boric acid, sodium-chlor and purified water, may also containing about hydrochloric acid or sodium hydrate regulator solution pH value to 6.8.Or with reference to following documents: Chinese patent CN99813214.5, CN200910212686.X, CN200410026561.5, CN200510021739.1, CN00811427.7, or the development Moxifloxacin hydrochloride eye drop etc. such as volume o. 11th Dong's root November the 25th in 2006 mountain, medical Leader.
Fourth aspect, the invention provides Moxifloxacin hydrochloride H crystal form can effectively for the treatment of respiratory system infection, genital system infection, skin soft-tissue infection etc., comprise the grownup for suffering from upper respiratory tract infection, as acute sinusitis, acute episode of chronic bronchitis, community acquired pneumonia, and the treatment of Skin and soft tissue infection etc.
Compared with prior art, Moxifloxacin hydrochloride H crystal form provided by the invention has that preparation technology is simple, purity is high, product stability is excellent, is easy to realize the advantages such as suitability for industrialized production.
Accompanying drawing explanation
The X-ray powder diffraction pattern of the Moxifloxacin hydrochloride H crystal form that what Fig. 1 represented is prepares by the embodiment of the present invention 1.
The X-ray powder diffraction pattern of the Moxifloxacin hydrochloride H crystal form that what Fig. 2 represented is prepares by the embodiment of the present invention 4.
The infared spectrum (IR) of the H crystal form Moxifloxacin hydrochloride that what Fig. 3 represented is prepares by the embodiment of the present invention 1.
Thermal analyses (DSC) collection of illustrative plates of the H crystal form Moxifloxacin hydrochloride that what Fig. 4 represented is prepares by the embodiment of the present invention 1.
Embodiment
X-ray powder diffraction condition determination:
INSTRUMENT MODEL XRD-6000 powder diffractometer
Test condition: pipe pressure: 40kv; Guan Liu: 30mA; Scan mode: continuous sweep; Retouch speed: 4.0deg/min.
Infrared (IR) detecting instrument and condition: instrument: Shimadzu FTIR-8400S type, KBr compressing tablet.
DSC detecting instrument and testing conditions thereof: DTG-60H determinator; Test condition: 30 ~ 400 DEG C, heat-up rate 10.00 DEG C/min, under nitrogen environment.
Specifically describe embodiment of the present invention by following examples, but the present invention is not limited by the following examples:
Embodiment 1
360g Moxifloxacin (obtaining Moxifloxacin with reference to patent ZL93121757.1, lower same) is suspended in the aqueous ethanolic solution of 2160ml 45 volume %, is heated to 70 DEG C of dissolvings, be incubated 70 DEG C and drip 218g concentrated hydrochloric acid, drip and finish, stir 1 hour, have solid to separate out.2160ml acetone is dripped at 70 DEG C.Drip and finish, cool to 5 ~ 10 DEG C of abundant stirring and crystallizing 2 hours, filter, filter cake is with 360ml washing with acetone.After in dry 6 hours of 50 ~ 60 DEG C of decompressions (vacuum tightness :-0.08MPa ~ 0.095MPa), obtain H crystal form Moxifloxacin hydrochloride 320g, HPLC purity 99.8%, water content is 3.82%.The X-ray powder diffraction data of gained Moxifloxacin hydrochloride as shown in Figure 1
The condition of Moxifloxacin hydrochloride purity detecting and method (lower same):
Chromatographic condition: chromatographic column: 250*4.6mm, 5um, end-blocking phenyl post, with methyl alcohol-phosphate buffered saline buffer (0.5g 4-butyl ammonium hydrogen sulfate, 1.0g potassium primary phosphate, 3.4g phosphoric acid, be diluted with water to 1000ml) (30:70) be moving phase, column temperature 35 DEG C, determined wavelength is 293nm, and flow velocity is 1.0ml/min.
Detection method: get this product in right amount, adds thinner and dissolves and dilute the solution made about containing 0.5mg in every 1ml, as need testing solution; Precision measures need testing solution 10 μ l again, injection liquid chromatography, record color atlas.Main peak purity is calculated by area normalization method.
Moxifloxacin hydrochloride H crystal form determination of moisture method (Chinese Pharmacopoeia, 2,010 two annex VIII M first methods, lower same):
Instrument: electronic balance, moisture content tester
Test operation process
Demarcate: add anhydrous methanol in reaction cup, to flood electrode exposed end.Start magnetic stirrer, with the moisture content in karl Fischer reagent titration methyl alcohol, be titrated to terminal (not recording the volume of karl Fischer reagent).Get suitable quantity of water (0.01 ~ 0.02g), accurately weighed, be placed in reaction cup, terminal is titrated to karl Fischer reagent, then the water equivalent T (g/ml) of karl Fischer reagent is calculated as follows, parallel test three times, using the mean value of continuous three times as final titre (titre of demarcating for three times should in ± 1.0%).
In formula:
M---add the weight g of water;
V---titration consumes the volume of karl Fischer reagent, ml;
F-----every 1ml Ka Erfeixiushi liquid is equivalent to the quality of water, mg.
Sample determination: continue to add anhydrous methanol in reaction cup, to flood electrode exposed end.Be titrated to terminal with karl Fischer reagent, sample thief is about 1.0g, accurately weighed, rapidly by sample impouring reaction cup, is titrated to terminal with karl Fischer reagent.Sample parallel measures three times, and moisture content is calculated as follows:
In formula:
In formula: V----trial-product consume the volume of Ka Erfeixiushi liquid, ml
F----every 1ml Ka Erfeixiushi liquid is equivalent to the quality of water, mg
M---trial-product weight; g
Embodiment 2
360g Moxifloxacin is suspended in the methanol aqueous solution of 2160ml 65 volume %, is heated to 60 ~ 65 DEG C of dissolvings, maintain 60 ~ 65 DEG C and drip 202g concentrated hydrochloric acid, drip and finish, stir 1 hour, have solid to separate out.2160ml acetone is dripped at 60 ~ 65 DEG C.Drip and finish, cool to 10 DEG C of abundant stirring and crystallizing 2 hours, filter, filter cake is with 360ml washing with acetone.Collect solid, 50 ~ 60 DEG C of decompressions (vacuum tightness :-0.08MPa ~ 0.095MPa) drying 6 hours, obtains H crystal form Moxifloxacin hydrochloride 318g, HPLC purity 99.6%, moisture content 3.95%.Gained Moxifloxacin hydrochloride H crystal form, use has the anticathode diffractometer of copper and measures, represent with θ angle, Prague 2 and relative intensity, described relative intensity represents with the percentage ratio of the strongest ray, this diffractogram comprises the diffraction peak that following relative intensity is greater than 20: 2 θ are 5.89, and relative intensity is 41; 2 θ are 10.16, and relative intensity is 22; 2 θ are 17.49, and relative intensity is 100; Be 29.27 with 2 θ, relative intensity is 25.
Embodiment 3
360g Moxifloxacin is suspended in the isopropanol water solution of 2160ml 50 volume %, is heated to 50 ~ 55 DEG C of dissolvings, maintain 50 ~ 55 DEG C and drip 202g concentrated hydrochloric acid, drip and finish, stir 1 hour, have solid to separate out.2160ml acetone is dripped at 50 ~ 55 DEG C.Drip and finish, cool to 10 DEG C of abundant stirring and crystallizing 2 hours, filter, filter cake is with 360ml washing with acetone.Collect solid, 50 ~ 60 DEG C of decompressions (vacuum tightness :-0.08MPa ~ 0.095MPa) drying 6 hours, obtains H crystal form Moxifloxacin hydrochloride 318g, HPLC purity 99.6%, moisture content 3.94%.Use has the anticathode diffractometer of copper and measures, represent with θ angle, Prague 2 and relative intensity, described relative intensity represents with the percentage ratio of the strongest ray, and this diffractogram comprises the diffraction peak that following relative intensity is greater than 20: 2 θ are 5.90, and relative intensity is 40; 2 θ are 10.15, and relative intensity is 22; 2 θ are 17.49, and relative intensity is 100; Be 29.28 with 2 θ, relative intensity is 25.
Embodiment 4
360g Moxifloxacin is suspended in the tertiary butanol aqueous solution of 2160ml 50 volume %, is heated to 50 ~ 55 DEG C of dissolvings, maintain 50 ~ 55 DEG C and drip 205g concentrated hydrochloric acid, drip and finish, stir 1 hour, have solid to separate out.2160ml acetone is dripped at 50 ~ 55 DEG C.Drip and finish, cool to 10 DEG C of abundant stirring and crystallizing 2 hours, filter, filter cake is with 360ml washing with acetone.Collect solid, 50 ~ 60 DEG C of decompressions (vacuum tightness :-0.08MPa ~ 0.095MPa) drying 6 hours, obtain H crystal form Moxifloxacin hydrochloride 318g, HPLC purity is greater than 99.7%, moisture content 3.98%.The powdery diffractometry figure of gained Moxifloxacin hydrochloride H crystal form as shown in Figure 2.
Embodiment 5 Moxifloxacin hydrochloride tablet (for 1000)
Preparation technology:
Take recipe quantity Moxifloxacin hydrochloride, Microcrystalline Cellulose, pre-paying starch and partial cross-linked Xylo-Mucine, sieve, mix;
Add 0.6% appropriate hypromellose cellulose solution wet method softwood, softwood sieves granulation, dries, whole grain;
Add croscarmellose sodium and the Magnesium Stearate of residual content, mix;
Compressing tablet, sheet is 700mg heavily about, and tablet weight variation controls in the scope of ± 5%, sheet about hardness 12Kg;
With Opadry coating liquid dressing, coating weight gain about 3%.
Embodiment 6 Moxifloxacin hydrochloride capsule (for 1000)
Preparation technology:
Take recipe quantity Moxifloxacin hydrochloride, Microcrystalline Cellulose, pre-paying starch and partial cross-linked Xylo-Mucine, sieve, mix;
Add 1% appropriate hypromellose cellulose solution wet method softwood, softwood sieves granulation, dries, whole grain;
Add croscarmellose sodium and the Magnesium Stearate of residual content, mix;
Capsule-filling, grain is 700mg heavily about, and the grain method of double differences is different to be controlled in the scope of ± 5%.
Embodiment 7 moxifloxacin hydrochloride injection (for 1000 bottles)
Moxifloxacin hydrochloride (embodiment 3 obtains H crystal form product) 436.8g
Sodium-chlor 2000.0g
Water for injection adds to 250.0L
Preparation technology:
Take recipe quantity Moxifloxacin hydrochloride and sodium-chlor, add the water for injection of 90% recipe quantity, stirring makes supplementary material dissolve completely, about the pH value to 4.4 with 0.1M hydrochloric acid soln or 0.1M sodium hydroxide solution regulator solution, add the needle-use activated carbon of 0.1% (W/V), stir 20min ~ 30min, filter with the titanium rod circulation decarburization of 4 μm;
Benefit adds to the full amount of water for injection, and stirs evenly;
Liquid is again through 0.45 μm and the filter of 0.22 μm of core strainer essence;
Filling, every bottle of filling 250ml;
121 DEG C of moist heat sterilizations 20 minutes.
Embodiment 8 Moxifloxacin hydrochloride eye drop (for 10000 bottles)
Preparation technology:
Take recipe quantity Moxifloxacin hydrochloride, sodium-chlor and hydroxypropyl ethyl ester, add the water for injection of 90% recipe quantity, stirring makes supplementary material dissolve completely, about the pH value to 6.8 with 0.1M hydrochloric acid soln or 0.1M sodium hydroxide solution regulator solution, add the needle-use activated carbon of 0.1% (W/V), stir 20min ~ 30min, with the titanium rod circulation decarburization of 4 μm;
Benefit adds to the full amount of water for injection, and stirs evenly;
Liquid is again through 0.45 μm and the filter of 0.22 μm of core strainer essence;
100 DEG C of flowing steam sterilization 30min;
Sterile filling, every bottle of filling 3ml.
Embodiment 9 study on the stability
Water absorbability is investigated
In order to investigate Moxifloxacin hydrochloride H crystal form stability of the present invention, we prepare II crystal formation by patent CN1160052A, prepare III crystal formation by patent WO2004091619, prepare A and B crystal form by patent WO2005054240 respectively, prepare X and Y crystal formation respectively by patent WO2007010555, separately get the H crystal form of the embodiment of the present invention 2 gained, this several crystal formation is exposed to 25 DEG C and 50% relative humidity conditions under, investigate its water absorbability.Experimental result is as follows:
Experimental data as can be seen from table, moisture absorption is very fast under test conditions for III crystal formation, A crystal formation, B crystal form and X crystal formation, II crystal formation and Y crystal formation also slightly water absorbability, the crystal formation of the embodiment of the present invention 2 gained, i.e. H crystal form moisture absorption 0.04% in 32 hours, be starkly lower than other crystal formations, so crystal formation of the present invention makes moderate progress compared with other crystal formations in water absorbability.
Fluid loss property is investigated
In order to investigate the stability of the H crystal form Moxifloxacin hydrochloride of gained of the present invention further, under seven kinds of crystal formations (crystal formation source is the same) sealing is kept at the environment of 40 DEG C by us, measured its water content respectively at 0 month, 1 month, 2 months, 3 months, 6 months, result is as follows:
It is substantially constant that gained Moxifloxacin hydrochloride H crystal form of the present invention tests 6 months water-contents; II crystal formation and Y crystal formation test slightly dehydration in 6 months; III crystal formation, A crystal formation, B crystal form and X crystal formation have certain water-absorbent.Therefore, Moxifloxacin hydrochloride crystal formation of the present invention has obvious advantage compared with other crystal formations in fluid loss property.
Light stability is investigated
In order to investigate gained Moxifloxacin hydrochloride H crystal form of the present invention to the stability of light, we distinguish Example 2 gained H crystal form, II crystal formation and Y crystal formation (crystal formation source is the same) and have carried out illumination experiment, and result is as follows:
Experimental result shows, H crystal form Moxifloxacin hydrochloride becomes oyster in the little color constantly of illumination 48, purity slightly reduction by 0.08%.II crystal formation illumination 48 hours, color becomes yellow-green colour, purity drop 0.27%.Y crystal formation is after 48 h light, and color becomes orange, purity drop 0.53%.Therefore, H crystal form is obviously better than II crystal formation and Y crystal formation to the stability of light.
Acid, alkali, strong oxidizer and thermostability are investigated
In order to investigate the stability of H crystal form Moxifloxacin hydrochloride of the present invention to acid, alkali, strong oxidizer and hot conditions, we by H crystal form, II crystal formation and Y crystal formation 0.1mol/L hydrochloric acid soln place 3 hours, 0.1mol/L sodium hydroxide solution place 3 hours, to place in hydrogen peroxide at 3 hours, 105 DEG C dry 5 hours, experimental result is as follows:
| Treatment process | H crystal form | II crystal formation | Y crystal formation |
| Before process | 99.93％ | 99.92％ | 99.89％ |
| 0.1mol/L hydrochloric acid soln places 3 hours | 99.94％ | 99.92％ | 99.90％ |
| 0.1mol/L sodium hydroxide solution places 3 hours | 99.92％ | 99.84％ | 99.60％ |
| Place 3 hours in hydrogen peroxide | 99.87％ | 99.70％ | 99.62％ |
| Drying 5 hours at 105 DEG C | 99.85％ | 99.63％ | 99.65％ |
Result shows, the stability of H crystal form under acidity, alkalescence, strong oxidizer and hot conditions is obviously better than II crystal formation and Y crystal formation.
Embodiment 10
Mobility is investigated
In order to investigate the mobility of Moxifloxacin hydrochloride H crystal form product of the present invention, we get Moxifloxacin hydrochloride H crystal form, II crystal formation and Y crystal formation (crystal formation source is the same) respectively, and survey its bulk density and slope of repose, result is as follows:
| Crystal formation | Bulk density | Slope of repose |
| H crystal form | 0.6913g/ml | 50.2° |
| II crystal formation | 0.7089g/ml | 49.8° |
| Y crystal formation | 0.6748g/ml | 52.4° |
Test-results shows, the bulk density of H crystal form and slope of repose and II crystal formation basically identical, the two is all better than Y crystal formation, also namely the mobility of H crystal form and II crystal formation basically identical, be better than Y crystal formation.
Claims (9)
1. Moxifloxacin hydrochloride H crystal form, it is characterized in that, characterize with following x-ray diffractogram of powder, use has the anticathode diffractometer of copper and measures, represent with spacing d, θ angle, Prague 2 and relative intensity, described relative intensity represents with the percentage ratio of the strongest ray:
2. Moxifloxacin hydrochloride H crystal form according to claim 1, it is characterized in that, characterize with following x-ray diffractogram of powder, use has the anticathode diffractometer of copper and measures, represent with spacing d, θ angle, Prague 2 and relative intensity, described relative intensity represents with the percentage ratio of the strongest ray, and its x-ray diffractogram of powder as shown in Figure 1.
3. the Moxifloxacin hydrochloride H crystal form described in claim 1 or 2, is characterized in that, the infrared spectra that its KBr pressed disc method records, and is about 3527cm in peak position
-1, 3469cm
-1, 2964cm
-1, 2925cm
-1, 2890cm
-1, 1707cm
-1, 1623cm
-1, 1431cm
-1, 1351cm
-1, 1318cm
-1, 1105cm
-1, 1045cm
-1, 874cm
-1there is specific infrared absorption band at place.
4. the Moxifloxacin hydrochloride H crystal form described in claim 1 or 2, is characterized in that, is maximum heat melting temperatur in differential thermal analysis collection of illustrative plates near 243.89 DEG C.
5. the Moxifloxacin hydrochloride H crystal form described in claim 1 or 2, is characterized in that, water content is 2.5 ~ 4.5 % by weight.
6. Moxifloxacin hydrochloride H crystal form according to claim 5, is characterized in that, water content is 3.0 ~ 4.0 % by weight.
7. the preparation method of Moxifloxacin hydrochloride H crystal form described in arbitrary claim in claim 1 to 6, comprises the steps:
(1) joined by Moxifloxacin free alkali in the aqueous solution of 2 ~ 15 times of lower alcohols, here, described 2 ~ 15 times is the aqueous solution of lower alcohol and the envelope-bulk to weight ratio of Moxifloxacin free alkali; Described lower alcohol be selected from methyl alcohol, ethanol, Virahol, the trimethyl carbinol and ethylene glycol one or more;
(2) be heated to 50 ~ 100 DEG C of dissolvings, insulation, drip the concentrated hydrochloric acid of 1 ~ 5 equivalent;
(3) maintain 50 ~ 100 DEG C to stir 0.5 ~ 3 hour, have solid to separate out, drip the acetone of 3 ~ 10 times, here, described 3 ~ 10 times is the envelope-bulk to weight ratio of acetone and Moxifloxacin free alkali;
(4) be cooled to 0 ~ 30 DEG C of abundant crystallization, filter, filter cake is with 0.5-1.5 washing with acetone doubly, and here, described 0.5-1.5 is doubly the envelope-bulk to weight ratio of acetone and Moxifloxacin free alkali;
(5) get filter cake drying under reduced pressure at 30 ~ 80 DEG C and be no more than 8 hours, vacuum tightness-0.08MPa ~ 0.095MPa, obtain Moxifloxacin hydrochloride H crystal form.
8. the pharmaceutical composition containing Moxifloxacin hydrochloride H crystal form described in arbitrary claim in claim 1 to 6.
9. in claim 1 to 6, Moxifloxacin hydrochloride H crystal form described in arbitrary claim is preparing the application in anti-infectives.
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| CN201210424822.3A CN102924449B (en) | 2012-10-30 | 2012-10-30 | Moxifloxacin hydrochloride H crystal form and preparation method thereof and pharmaceutical composition |
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| CN103965189B (en) * | 2013-12-30 | 2015-09-09 | 西安万隆制药股份有限公司 | A kind of new moxifloxacin hydrochloride compound |
| CN109342470A (en) * | 2018-11-02 | 2019-02-15 | 福州大学 | The test method of beta crystal content in a kind of non-planar polypropylene material |
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Address after: 401254 No. 1 Hua Nan Road, chemical industrial park, Changshou District, Chongqing Co-patentee after: Fu'an Pharmaceutical (Group) Limited by Share Ltd Patentee after: Fu'an Pharmaceutical Group Pharmaceutical Co., Ltd. Chongqing Bosheng Address before: No. 2, Huang Yang Road, Yubei District, Chongqing Co-patentee before: Fu'an Pharmaceutical Group Pharmaceutical Co., Ltd. Chongqing Bosheng Patentee before: Fu'an Pharmaceutical (Group) Limited by Share Ltd |