CN106749174B - A kind of sitafloxacin dihydrate crystal form, preparation method and combinations thereof tablet - Google Patents
A kind of sitafloxacin dihydrate crystal form, preparation method and combinations thereof tablet Download PDFInfo
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention belongs to pharmaceutical technology fields.Specifically, the present invention relates to sitafloxacin dihydrate crystal form, preparation method and combinations thereof tablets.Sitafloxacin dihydrate crystal form provided by the present invention, preparation method include the steps that dissolution, crystallization.The present invention also provides the compositions containing the crystallization, include the component of following weight ratio: sitafloxacin dihydrate 32-33%, mannitol 38-39%, starch 19-20%, hydroxypropyl cellulose 6-7%, hydroxypropyl methyl cellulose 1.3-1.4%, magnesium stearate 0.9-1% by sitafloxacin dihydrate crystallization effective component；The method for making above-mentioned Sitafloxacin hydrate tablet, including pulverize and sieve, pelletize, drying, whole grain, total mix, tabletting.Compared with prior art, dissolution rate and bioavilability improve obtained Sitafloxacin hydrate tablet according to the present invention.
Description
Technical field
The invention belongs to pharmaceutical technology fields, specifically, being related to a kind of sitafloxacin dihydrate crystal form, preparation method
And combinations thereof tablet.
Background technique
Sitafloxacin (sitafloxacin), entitled 7- [(7S)-amino -5- azaspiro [2.4] hept- 5- the yl] -8- of chemistry
The chloro- fluoro- 1- of 6- [(1R, 2S)-cis-2- fluorine cyclopropyl]-Isosorbide-5-Nitrae-dihydro -4- oxo -3- quinoline carboxylic acid is Japanese first pharmacy
The Development of Fluoroquinolone Antibacterials of company's research and development, its clinical 3/2 hydrate.Sitafloxacin be a kind of new oral, have it is wide
The N-1- fluorine cyclopropyl novel carbostyril antimicrobial for composing antibacterial activity, to aerobism or anaerobic gram positive bacteria and Ge Lanyin
Property bacterium, Mycoplasma and chlamydiaceae etc. there is broad-spectrum antibacterial action.Sitafloxacin compound has there are three asymmetric carbon atom,
With 1 enantiomter and 6 diastereoisomers, determine the absolute configuration of its medicinal compound for guaranteeing medication peace
It is of great significance entirely.
Document report five kinds of different crystal forms [Int.J.Pharm., 2010,402,110-116] of sitafloxacin at present,
Including anhydride α, β type, 1/2 hydrate, 1 hydrate and 3/2 hydrate, medicinal crystal form is 3/2 hydrate, i.e. 7-
[7- (S)-amino -5- azaspiro [2.4] heptane -5- base] the fluoro- 1- of the chloro- 6- of -8- [the fluoro- 1- cyclopropyl of (1R, 2S) -2-] -1,4-
3/2 hydrate of dihydro -4- Oxoquinoline-3-carboxylic acid.But it is dissolved in water since sitafloxacin is extremely difficult, it is made using existing crystal form
Tablet, dissolution slowly, and is difficult to reach and be completely dissolved in vivo after taking orally, and causes the bioavilability of drug to reduce, no
Ideal antibacterial effect can be obtained.Those skilled in the art have been surprisingly found that, using novel crystal forms made from sitafloxacin dihydrate,
Tablet is made in the suitable auxiliary material of addition, surprisingly finds tablet produced by the present invention, and dissolution rate and bioavilability improve, thus
Complete the present invention.
Summary of the invention
The first object of the present invention is to provide a kind of sitafloxacin dihydrate crystal form.
Second object of the present invention is to provide a kind of preparation method of sitafloxacin dihydrate crystal form, this method work
Skill is simple, easy to operate, and the sitafloxacin dihydrate crystalline stability prepared using this method is good.
Another object of the present invention is to provide one kind containing sitafloxacin dihydrate crystal form of the present invention or adopt
Tablet composition and preparation method thereof, the present inventor is made in the sitafloxacin dihydrate crystal form made from the method for the invention
It was found that improving drug dissolution using tablet made from sitafloxacin dihydrate crystal form, improving bioavilability.
To achieve the purpose of the present invention, the present invention adopts the following technical scheme:
A kind of compound of sitafloxacin dihydrate crystal form shown in formula (I), wherein
Preferably, the X-ray powder that sitafloxacin dihydrate crystal form provided by the invention is indicated with the 2 θ ± 0.2 ° angles of diffraction
Last diffracting spectrum 3.7 °, 5.3 °, 10.3 °, 11.5 °, 15.3 °, 16.8 °, 17.7 °, 19.8 °, 21.7 °, 24.8 °, 27.6 °,
Characteristic diffraction peak is shown at 30.6 °, 34.1 ° and 39.8 °.
Preferably, the X-ray that sitafloxacin dihydrate crystal form provided by the invention is obtained using Cu-K alpha ray measurement
Powder diagram is as shown in Figure 1.
Second object of the present invention is achieved through the following technical solutions:
A kind of preparation method of sitafloxacin dihydrate crystal form described in claim 1, includes the following steps:
1) sitafloxacin crude product is dissolved in dehydrated alcohol, anhydrous propanone and deionized water, is heated to reflux, obtain solution A；
2) 40 DEG C~50 DEG C are cooled to, active carbon is added, stirs 30min, filtering obtains solution B, is cooled to 20~25 DEG C
Crystallization 1h, growing the grain 3~12 hours；
3) it is eluted with dehydrated alcohol, obtains white solid；
4) the resulting solid of step 3) is placed in vacuum oven, system vacuumizes, and drying is to constant weight to get sitafloxacin
Dihydrate crystal form.
Preferably, by weight, sitafloxacin in step 1): dehydrated alcohol: anhydrous propanone 1:3-8:2-5:5-20, into
One step preferably, sitafloxacin: dehydrated alcohol: anhydrous propanone 1:3-5:2-3:8-10.
Preferably, drying described in step 4) carries out under the conditions of 30-50 DEG C.
The present invention also provides a kind of composition tablets containing sitafloxacin dihydrate, wherein the composition tablet contains
There is sitafloxacin dihydrate crystal form produced by the present invention.
Composition label effective component includes following weight ratio: sitafloxacin dihydrate 32-33%, mannitol 38-
39%, starch 19-20%, hydroxypropyl cellulose 6-7%, hydroxypropyl methyl cellulose 1.3-1.4%, magnesium stearate 0.9-1%.
The present inventor has prepared a kind of sitafloxacin dihydrate crystal form in the research process of sitafloxacin bulk pharmaceutical chemicals,
Stability of crystal form is good, and with sitafloxacin dihydrate of the invention crystallize made of tablet, effective ingredient can with compared with
Fast speed is released from drug, improves the dissolution rate and bioavilability of drug.
Composition tablet provided by the present invention can be used that well known to a person skilled in the art methods to be prepared, and preferably adopt
It prepares with the following method:
(1) it pulverizes and sieves: sitafloxacin is smashed it through into 80 meshes, other auxiliary materials cross 80 meshes.
(2) sitafloxacin dihydrate crystal form is mixed with the supplementary material through pulverizing and sieving, is pelletized, dry, whole grain,
Tabletting to get.
Compared with prior art, the present invention has the advantage that
(1) sitafloxacin dihydrate crystal form provided by the present invention, stability are good.
(2) Dissolution of Tablet made of sitafloxacin dihydrate crystal form prepared by the present invention and bioavilability are high.(3)
The preparation method simple process of sitafloxacin dihydrate crystal form provided by the present invention, it is easy to operate.
Detailed description of the invention
Fig. 1 is the X-ray diffracting spectrum of sitafloxacin dihydrate crystal form of the invention；
Fig. 2 is the TG map of sitafloxacin dihydrate crystal form of the invention；
Fig. 3 is Xi Tasha after 24 male volunteers multi-dose oral 50mg sitafloxacin test preparations and reference preparation
Star mean blood plasma concentration-time graph.
Specific embodiment
The present invention can be further described by the following examples, however invention of the invention is not limited to
The following examples, these embodiments do not limit the scope of the invention in any way.Those skilled in the art wants in right
Made certain changes and adjustment also are regarded as belonging to the scope of the present invention in the range of asking.
Embodiment 1: the preparation of sitafloxacin dihydrate crystal form
1) sitafloxacin crude product 1kg is dissolved in 3kg dehydrated alcohol, 2kg anhydrous propanone and deionized water 5kg, is heated back
Stream, obtains solution A；
2) 40 DEG C~50 DEG C are cooled to, active carbon 25g is added, 30min is stirred, obtains solution B, be cooled to 20~25 DEG C of crystallizations
1h, growing the grain 3 hours；
3) it is eluted with 2kg dehydrated alcohol, obtains white solid；
4) the resulting solid of step 3) being placed in vacuum oven, system vacuumizes, it is dried under the conditions of 30 DEG C to constant weight,
Up to sitafloxacin dihydrate crystal form.
Prepared sitafloxacin dihydrate crystal form is composed using the X-ray powder diffraction that Cu-K alpha ray measurement obtains
Scheme (see Fig. 1) in characteristic peak 2 θ be 3.7 °, 5.3 °, 10.3 °, 11.5 °, 15.3 °, 16.8 °, 17.7 °, 19.8 °, 21.7 °,
24.8 °, 27.6 °, 30.6 °, 34.1 ° and 39.8 ° displays.
Elemental analysis:
Measured value: C51.21%, H4.98%, Cl7.97%, F8.51%, N9.45%, O17.95%.
Theoretical value: C51.18%, H4.97%, Cl7.95%, F8.52%, N9.42%, O17.94%.
Elemental analysis result and theoretical value are almost the same, molecular formula C19H18ClF2N3O3·2H2O
Using Perkin-Elmer company, U.S. PEPyrisDiamondTG thermal analyzer, thermogravimetric analysis experiment show (see
Fig. 2): the moisture content 8.079% that contains in the sitafloxacin dihydrate crystallization of embodiment preparation, this with it is (theoretical containing 2 crystallizations water
It is worth for result 8.084%) within the error range.
Embodiment 2: the preparation of sitafloxacin dihydrate crystal form
1) sitafloxacin crude product 1kg is dissolved in 8kg dehydrated alcohol, 5kg anhydrous propanone and deionized water 10kg, is heated back
Stream, obtains solution A；
2) 40 DEG C~50 DEG C are cooled to, active carbon 25g is added, stirs 30min, filtering obtains solution B, is cooled to 20~25
DEG C crystallization 1h, growing the grain 6 hours；
3) it is eluted with 3kg dehydrated alcohol, obtains white solid；
4) the resulting solid of step 3) being placed in vacuum oven, system vacuumizes, it is dried under the conditions of 40 DEG C to constant weight,
Up to sitafloxacin dihydrate crystal form.
According to XPRD data, gained crystal form is consistent with crystal form in embodiment 1.Using Perkin-Elmer company, the U.S.
The thermogravimetric analysis map and embodiment 1 that PEPyrisDiamondTG thermogravimetric analyzer obtains are consistent.
Embodiment 3: the preparation of sitafloxacin dihydrate crystal form
1) sitafloxacin crude product 1kg is dissolved in 5kg dehydrated alcohol, 3kg anhydrous propanone and deionized water 20kg, is heated back
Stream, obtains solution A；
2) 40 DEG C~50 DEG C are cooled to, active carbon 25g is added, stirs 30min, filtering obtains solution B, is cooled to 20~25
DEG C crystallization 1h, growing the grain 12 hours；
3) it is eluted with 5kg dehydrated alcohol, obtains white solid；
4) the resulting solid of step 3) being placed in vacuum oven, system vacuumizes, it is dried under the conditions of 50 DEG C to constant weight,
Up to sitafloxacin dihydrate crystal form.
According to XPRD data, gained crystal form is consistent with crystal form in embodiment 1.Using Perkin-Elmer company, the U.S.
The thermogravimetric analysis map and embodiment 1 that PEPyrisDiamondTG thermogravimetric analyzer obtains are consistent.
Embodiment 4: the preparation of sitafloxacin dihydrate crystal form
1) sitafloxacin crude product 1kg is dissolved in 3kg dehydrated alcohol, 2kg anhydrous propanone and deionized water 8kg, is heated back
Stream, obtains solution A；
2) 40 DEG C~50 DEG C are cooled to, active carbon 25g is added, stirs 30min, filtering obtains solution B, is cooled to 20~25
DEG C crystallization 1h, growing the grain 9 hours；
3) it is eluted with 3kg dehydrated alcohol, obtains white solid；
4) the resulting solid of step 3) being placed in vacuum oven, system vacuumizes, it is dried under the conditions of 30 DEG C to constant weight,
Up to sitafloxacin dihydrate crystal form.
According to XPRD data, gained crystal form is consistent with crystal form in embodiment 1.Using Perkin-Elmer company, the U.S.
The thermogravimetric analysis map and embodiment 1 that PEPyrisDiamondTG thermogravimetric analyzer obtains are consistent.
The preparation of [example of formulations] sitafloxacin composition tablet
Embodiment 1
The present embodiment provides a kind of sitafloxacin tablet composition, effective ingredient includes the component of following weight ratio:
Label:
Sitafloxacin dihydrate crystal form 54.39g (is equivalent to 50gC19H18ClF2N3O3)；
Mannitol 64.59g；
Starch 33.99g；
Hydroxypropyl cellulose 11.39g；
Hydroxypropyl methyl cellulose 2.38g；
Magnesium stearate 1.52g.
Coating: Opadry (OPADRYXYWHITE) 4.13g, pure water 30.29g.
The preparation method of the present embodiment sitafloxacin dihydrate tablet composition the following steps are included:
A, it pulverizes and sieves: sitafloxacin dihydrate crystal form is smashed it through into 80 meshes, other label auxiliary materials cross 80 mesh
Sieve.
B, it pelletizes: sitafloxacin, mannitol, starch, hydroxypropyl cellulose is placed in high speed wet mixing pelletizer, mix
It closes uniformly, hydroxypropyl methyl cellulose is configured to 5% hydroxypropyl methyl cellulose aqueous solution as adhesive, by adhesive
1000 wet granulars are mixed and made into the supplementary material in granulator.
C, drying: wet granular aeration-drying at 55-65 DEG C becomes dry particl.
D, whole grain: dry particl is through 30 mesh sieves.
E, total mix: weighing magnesium stearate and surplus hydroxypropyl cellulose, is placed in mixing machine and is mixed with dry particl one
It is even.
Intermediate product detecting step: the parameters such as angle of repose of intermediate product that detection total mix step obtains, if complying with standard, into
Row is in next step.
F, tabletting: mixed particle carries out tabletting.
G, it is coated: being made into coating solution with pure water and Opadry, be coated in coat tablets and drying, obtain 1000 finished products, often
Piece contains pure sitafloxacin 50mg.
Embodiment 2
The present embodiment provides a kind of sitafloxacin tablet composition, effective ingredient includes the component of following weight ratio:
Label:
Sitafloxacin dihydrate crystal form 54.42g (is equivalent to 50gC19H18ClF2N3O3)；
Mannitol 64.31g；
Starch 31.33g；
Hydroxypropyl cellulose 11.05g；
Hydroxypropyl methyl cellulose 2.14g；
Magnesium stearate 1.65g
Coating: Opadry (OPADRYXYWHITE) 4.13g, pure water 30.29g.
The preparation method of the present embodiment sitafloxacin dihydrate tablet composition the following steps are included:
A, it pulverizes and sieves: sitafloxacin dihydrate crystal form is smashed it through into 80 meshes, other label auxiliary materials cross 80 mesh
Sieve.
B, it pelletizes: sitafloxacin, mannitol, starch, hydroxypropyl cellulose is placed in high speed wet mixing pelletizer, mix
It closes uniformly, hydroxypropyl methyl cellulose is configured to 5% hydroxypropyl methyl cellulose aqueous solution as adhesive, by adhesive
1000 wet granulars are mixed and made into the supplementary material in granulator.
C, drying: wet granular aeration-drying at 55-65 DEG C becomes dry particl.
D, whole grain: dry particl is through 30 mesh sieves.
E, total mix: weighing magnesium stearate and surplus hydroxypropyl cellulose, is placed in mixing machine and is mixed with dry particl one
It is even.
Intermediate product detecting step: the parameters such as angle of repose of intermediate product that detection total mix step obtains, if complying with standard, into
Row is in next step.
F, tabletting: mixed particle carries out tabletting.
G, it is coated: being made into coating solution with pure water and Opadry, be coated in coat tablets and drying, obtain 1000 finished products, often
Piece contains pure sitafloxacin 50mg.
Test example 1: accelerated stability is investigated
By 1.5 crystallizations water of commercially available sitafloxacin, 1 sitafloxacin dihydrate crystal form of embodiment in climatic chamber into
Row 6 months accelerated stability tests.Experimental condition was: 40 DEG C/75% relative humidity (RH), respectively at 0,1,2,3,6 month
Sampling carries out purity and foreign impurity matters test (high performance liquid chromatography), as a result see the table below 1.
1 Acceleration study result of table
By upper table result it is found that the stability of sitafloxacin dihydrate crystal form is better than sitafloxacin 1.5 in the prior art
A crystallization water.
Aforementioned stable test has also been carried out to sitafloxacin dihydrate crystal form prepared by the embodiment of the present invention 2~4,
The result that it is obtained is similar.
Test example 2: dissolution in vitro compares
Contrast solution preparation method: taking the dry sitafloxacin reference substance to constant weight appropriate, accurately weighed, uses dissolution medium
It is diluted to the solution of about 5 μ g in every 1ml.
Take commercially available first pharmacy Sankyo Co., Ltd (trade name: Gracevit) sitafloxacin tablet and preparation real respectively
Apply sitafloxacin dihydrate tablet made from example 1, every batch of 6, using water as dissolution medium, according to above-mentioned dissolution and measurement side
Method is tested.Take solution appropriate and fluid infusion respectively at 5min, 10min, 15min, 30min, 45min, 60min, filtration is accurate
Measurement subsequent filtrate is appropriate, and solubilization goes out the solution that medium water is diluted to about 5 μ g in every 1ml, and absorbance is measured at 288nm, calculates
Dissolution rate, the results are shown in Table 2.
2 dissolution rate comparing result of table
| Compare item | 5min | 10min | 15min | 30min | 45min | 60min |
| Commercial product | 25.1 | 46.2 | 62.4 | 74.2 | 83.4 | 91.2 |
| 1 product of embodiment | 60.2 | 81.9 | 90.5 | 95.6 | 97.8 | 98.3 |
The tablet dissolution rate prepared by the present invention it can be seen from upper table result is greater than commercial product dissolution rate.
Test example 3: bioavilability compares
It compares by test preparation (the sitafloxacin dihydrate tablet composition of invention formulation embodiment 1) and reference system
Agent (is made, except that sitafloxacin used is commercially available original using the prescription and preparation process of invention formulation embodiment 1
Material) pharmacokinetics.
After 24 male volunteers multi-dose oral 50mg sitafloxacin test preparations and reference preparation, sitafloxacin is average
Blood concentration-time curve is shown in Fig. 3.
It can be seen that from mean blood plasma concentration-time graph of sitafloxacin and be better than reference reagent by the Cmax of test preparation,
Identical test is also carried out to sitafloxacin tablet prepared by invention formulation embodiment 2, the result obtained is similar.
Claims (7)
1. a kind of sitafloxacin dihydrate crystal form, which is characterized in that its X-ray powder indicated with the 2 θ ± 0.2 ° angles of diffraction
Diffracting spectrum 3.7 °, 5.3 °, 10.3 °, 11.5 °, 15.3 °, 16.8 °, 17.7 °, 19.8 °, 21.7 °, 24.8 °, 27.6 °,
Characteristic diffraction peak is shown at 30.6 °, 34.1 ° and 39.8 °；The structural formula of the sitafloxacin dihydrate is as follows:
。
2. sitafloxacin dihydrate crystal form as described in claim 1, which is characterized in that obtained using Cu-K alpha ray measurement
X-ray powder diffraction figure it is as shown in Figure 1.
3. a kind of preparation method of sitafloxacin dihydrate crystal form described in claim 1, which is characterized in that the preparation
Method includes the following steps:
1) sitafloxacin crude product is dissolved in dehydrated alcohol, anhydrous propanone and deionized water, is heated to reflux, obtain solution A；
2) 40 DEG C~50 DEG C are cooled to, active carbon is added, stirs 30min, filtering obtains solution B, is cooled to 20~25 DEG C of crystallizations
1h, growing the grain 3~12 hours；
3) it is eluted with dehydrated alcohol, obtains white solid；
4) the resulting solid of step 3) is placed in vacuum oven, system vacuumizes, and drying is to constant weight to get two water of sitafloxacin
Close object crystal form.
4. the preparation method of sitafloxacin dihydrate crystal form as claimed in claim 3, which is characterized in that by weight, step
It is rapid 1) described in sitafloxacin: dehydrated alcohol: anhydrous propanone: deionized water 1:3-8:2-5:5-20.
5. the preparation method of sitafloxacin dihydrate crystal form according to claim 3, which is characterized in that by weight,
Sitafloxacin described in step 1): dehydrated alcohol: anhydrous propanone: deionized water 1:3-5:2-3:8-10.
6. the preparation method of sitafloxacin dihydrate crystal form as claimed in claim 3, it is characterised in that: described in step 4)
Drying carried out under the conditions of 30~50 DEG C.
7. a kind of composition tablet containing sitafloxacin dihydrate crystal form described in claim 1, which is characterized in that label
Effective component includes following weight ratio: sitafloxacin dihydrate crystal form 32-33%, mannitol 38-39%, starch 19-20%,
Hydroxypropyl cellulose 6-7%, hydroxypropyl methyl cellulose 1.3-1.4%, magnesium stearate 0.9-1%.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1106006A (en) * | 1993-09-10 | 1995-08-02 | 第一制药株式会社 | Crystals of antimicrobial compound |
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2016
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1106006A (en) * | 1993-09-10 | 1995-08-02 | 第一制药株式会社 | Crystals of antimicrobial compound |
Non-Patent Citations (2)
| Title |
|---|
| Elucidation of the crystal structure–physicochemical property relationship among polymorphs and hydrates of sitafloxacin, a novel fluoroquinolone antibiotic;Tetsuya Suzuki et al.;《International Journal of Pharmaceutics》;20111006;第422卷;第1-8页 |
| Studies on mechanism of thermal crystal transformation of sitafloxacin hydrates through melting and recrystallization, yielding different anhydrates depending on initial crystalline forms;Tetsuya Suzuki et al.;《International Journal of Pharmaceutics》;20101007;第402卷;第110-116页 |
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