CN116813614A - Prafloxacin hydrochloride dihydrate crystal and preparation method thereof - Google Patents
Prafloxacin hydrochloride dihydrate crystal and preparation method thereof Download PDFInfo
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- CN116813614A CN116813614A CN202310634032.6A CN202310634032A CN116813614A CN 116813614 A CN116813614 A CN 116813614A CN 202310634032 A CN202310634032 A CN 202310634032A CN 116813614 A CN116813614 A CN 116813614A
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- 239000013078 crystal Substances 0.000 title claims abstract description 46
- NSNHWTBQMQIDCF-UHFFFAOYSA-N dihydrate;hydrochloride Chemical compound O.O.Cl NSNHWTBQMQIDCF-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000007787 solid Substances 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 abstract description 13
- 238000000634 powder X-ray diffraction Methods 0.000 abstract description 10
- 238000001914 filtration Methods 0.000 abstract description 7
- 238000003860 storage Methods 0.000 abstract description 3
- 150000004683 dihydrates Chemical class 0.000 abstract description 2
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 230000007774 longterm Effects 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 229960002652 pramipexole dihydrochloride Drugs 0.000 abstract 1
- VQMNWIMYFHHFMC-UHFFFAOYSA-N tert-butyl 4-hydroxyindole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC(C)(C)C)C=CC2=C1O VQMNWIMYFHHFMC-UHFFFAOYSA-N 0.000 abstract 1
- 239000000047 product Substances 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000004807 desolvation Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000003828 vacuum filtration Methods 0.000 description 5
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- WUPBAVNMWVWXBI-VFZPIINCSA-N 7-[(4as,7as)-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl]-8-cyano-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid;hydrochloride Chemical compound Cl.C12=C(C#N)C(N3C[C@H]4NCCC[C@H]4C3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 WUPBAVNMWVWXBI-VFZPIINCSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229940124307 fluoroquinolone Drugs 0.000 description 2
- 238000000879 optical micrograph Methods 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 1
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 229940072132 quinolone antibacterials Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Abstract
The invention relates to a pramipexole dihydrochloride crystal form dihydrate, which is characterized in that the crystal X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2θ=6.9+/-0.2 degrees, 7.6+/-0.2 degrees, 9.7+/-0.2 degrees, 12.4+/-0.2 degrees, 14.0+/-0.2 degrees, 15.6+/-0.2 degrees, 21.9+/-0.2 degrees and 29.0+/-0.2 degrees, and the crystal X-ray powder diffraction pattern has a powdery appearance. The preparation method comprises dissolving a certain amount of prafloxacin solid in water at room temperature, adding a certain amount of hydrochloric acid, magnetically stirring, keeping the temperature of the solution to 25 ℃, and keeping the temperature for 2-4 hours under the condition until crystals are separated out; filtering the product, and placing the obtained crystal in a drying oven at 40 ℃ for drying; and drying to obtain the final prafloxacin hydrochloride dihydrate product. The invention has stable process, simple operation, less energy consumption, more than 90 percent of crystal form product yield and more than 99 percent of product purity, and is suitable for manufacturing and long-term storage of pharmaceutical preparations.
Description
Technical Field
The invention belongs to the technical field of medicine separation, and particularly relates to a prafloxacin hydrochloride dihydrate crystal form and a crystallization preparation method thereof.
Background
Prafloxacin hydrochloride (Pradofloxacin hydrochloride) with chemical formula of C 21 H 22 FClN 4 O 3 The relative molecular weight is 432.88, the chemical name is 8-cyano-1-cyclopropyl-7- (1S, 6S-2, 8-diazabicyclo [ 4.3.0)]Nonan-8-yl) -6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride having a structure shown in the following figure. The commercial product is light yellow powder, is easy to dissolve in water, has small solubility in most organic solvents, is not yet popularized in China, and belongs to a new medicine development stage.
Prafloxacin hydrochloride (pradofloxacin hydrochloride) is a new third-generation fluoroquinolone antibacterial agent special for animals, developed by German Bayer company, with the trade name Veraflox hydrochloride, and is used for treating bacterial infection of dogs and cats, the quinolone antibacterial agent mainly inhibits the A subunit of DNA rotary chemical book enzyme (also called topoisomerase II), and only a few medicines also act on the B subunit, so that the activity of the antibacterial agent is destroyed, the synthesis of deoxyribonucleic acid, ribonucleic acid and protein is interfered, and bacteria can not split any more, thereby playing a role in sterilization. Compared with the existing fluoroquinolone antibacterial agents, the prafloxacin hydrochloride has enhanced antibacterial activity on gram-positive bacteria and anaerobic pathogenic bacteria and has wider antibacterial effect.
Polymorphism is a common phenomenon of drug molecules, and different crystal forms can show different physicochemical properties so as to influence the curative effect of the drug. The prafloxacin hydrochloride solid sold in the market at present only has the prafloxacin hydrochloride and the prafloxacin hemihydrochloride, and has the problems of complex process, poor stability and the like, so that the prafloxacin hydrochloride is necessary to be subjected to polymorphic research and the dominant crystal form is screened.
Disclosure of Invention
The invention provides prafloxacin hydrochloride dihydrate and a crystal preparation method of the dihydrate.
The X-ray powder diffraction pattern of the prafloxacin hydrochloride dihydrate crystal provided by the invention has characteristic peaks at diffraction angles 2θ=6.9+/-0.2°, 7.6+/-0.2 °, 9.7+/-0.2 °, 12.4+/-0.2 °, 14.0+/-0.2 °, 15.6+/-0.2 °, 21.9+/-0.2 ° and 29.0+/-0.2 ° as shown in fig. 1.
Preferably, the prafloxacin hydrochloride dihydrate crystal has a molecular formula of C 21 H 26 FClN 4 O 5 。
Any of the above is preferred, wherein the prafloxacin hydrochloride dihydrate crystals are desolvated at 60 ℃. As shown in figure 2, a DSC profile of the prafloxacin hydrochloride dihydrate crystals showing desolvation at 60 ℃.
The invention also provides a preparation method of the prafloxacin hydrochloride dihydrate crystal, which comprises the following steps:
step 1: dissolving prafloxacin solids in water and/or ethanol until clear;
step 2: keeping the temperature of the solution obtained in the step 1 constant, and adding hydrochloric acid into the solution obtained in the step 1;
step 3: growing crystal at constant temperature;
step 4: and (3) drying the product obtained in the step (3) to obtain the final prafloxacin hydrochloride dihydrate product.
Preferably, the concentration of the prafloxacin solution after dissolution in the step 1 is 0.05-0.15 g/ml.
In step 2, the hydrochloric acid is preferably added at a rate of 1ml/min to 4ml/min.
In any of the above steps, the constant temperature in step 2 is preferably 25 to 30 ℃.
In step 3, the crystal growth time is preferably 2 to 4 hours
In any of the above steps, the crystal growth temperature is preferably 25 to 30 ℃.
In any one of the above preferred steps, in step 4, the product obtained in step 3 is filtered, and the obtained crystals are dried in a drying oven; and drying to obtain the final prafloxacin hydrochloride dihydrate product.
In any of the above steps, it is preferable that the drying temperature is 40 to 45℃and the drying time is 2 to 4 hours in step 4.
Any one of the above is preferable, and the specific steps are as follows:
(1) Dissolving a certain amount of prafloxacin solid in water or ethanol and methanol at room temperature, and magnetically stirring to clarify the prafloxacin solid; preferably, the concentration of the prafloxacin aqueous solution or the ethanol solution is 0.05-0.15 g/ml;
(2) Keeping the temperature of the solution to 25 ℃ and keeping the temperature, and adding a certain amount of hydrochloric acid into the solution at a feeding rate of 1 ml/min-4 ml/min;
(3) Stirring for 2-4 h at constant temperature under the condition until crystals are separated out;
(4) Filtering the product, and carrying out vacuum suction filtration;
(5) Placing the obtained crystal in a drying oven at 40 ℃ for drying;
(6) And drying to obtain the final prafloxacin hydrochloride dihydrate.
In the method, the crystallization mode is reaction crystallization.
The invention examines the chemical stability of the prepared prafloxacin hydrochloride dihydrate crystal, and the color, purity and morphology of the crystal form are not changed in the period of 30 days of storage under the conditions of 30 ℃ +/-5 ℃ and 40+/-5% RH, thus indicating that the crystal form has good chemical stability. The examination results are shown in Table 1.
Table 1 table of examination of chemical stability of prafloxacin hydrochloride dihydrate
The prafloxacin hydrochloride dihydrate of the invention has simple operation, stable process, less energy consumption, high economy, high product yield up to more than 90 percent, high product purity up to more than 99 percent, stable preparation process and high reproducibility, and the process has short production period, improves the production efficiency, and is suitable for manufacturing and long-term storage of pharmaceutical preparations.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of crystalline prafloxacin hydrochloride dihydrate of examples 1-5 of the present invention.
FIG. 2 is a DSC-TG analysis of prafloxacin hydrochloride dihydrate of examples 1-5 of the present invention.
Fig. 3 is a polarized light microscope image of prafloxacin hydrochloride dihydrate in examples 1-5 of the present invention.
Fig. 4 is a diagram showing the structure of single crystal of prafloxacin hydrochloride dihydrate in examples 1 to 5 of the present invention.
Detailed Description
The invention is described in further detail below with reference to the drawings and the detailed description. Wherein FIG. 1 is an X-ray powder diffraction pattern of the crystalline prafloxacin hydrochloride dihydrate obtained in examples 1 to 5 of the present invention; FIG. 2 is a DSC-TG analysis of prafloxacin hydrochloride dihydrate obtained in examples 1 to 5 of the present invention; FIG. 3 is a polarized light microscope image of prafloxacin hydrochloride dihydrate of examples 1-5 of the present invention; fig. 4 is a diagram showing the structure of single crystal of prafloxacin hydrochloride dihydrate in examples 1 to 5 of the present invention. The Cell number in fig. 4 is shown in the following table.
| a＝6.5285 | b＝12.9915 | c＝25.6615 |
| α＝90 | β＝90 | γ＝90 |
The foregoing examples are provided for clarity of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.
Example 1
(1) Dissolving 1.5g of prafloxacin in 10ml of deionized water at 25 ℃, magnetically stirring, and keeping the temperature for 15 minutes to completely dissolve and uniformly disperse the solid in the solvent; (2) 1ml of hydrochloric acid was added thereto at a feed rate of 1ml/min; (3) Continuously stirring, and culturing the crystal for 2 hours at constant temperature; (4) filtering the product, and carrying out vacuum filtration; (5) placing the obtained crystal in a drying oven at 40 ℃ for drying; (6) And drying to obtain the final prafloxacin hydrochloride dihydrate.
The X-ray powder diffraction pattern of the product has characteristic peaks at diffraction angles 2θ=6.9±0.2°,7.6±0.2°,9.7±0.2°,12.4±0.2°,14.0±0.2°,15.6±0.2°,21.9±0.2°, and 29.0±0.2°. DSC showed a desolvation temperature of 60 ℃. The product appearance is light yellow powder, the purity of the product is 99.8%, and the process yield is 90.5%.
Example 2
(1) Dissolving 1.0g of prafloxacin solid in 15ml of ethanol at 28 ℃, magnetically stirring, and keeping the temperature for 15min to completely dissolve and uniformly disperse the solid in a solvent; (2) 0.5ml of hydrochloric acid was added thereto at a feed rate of 2ml/min; (3) Continuously stirring, and carrying out crystal growth at constant temperature for 3h; (4) filtering the product, and carrying out vacuum filtration; (5) placing the obtained crystal in a drying oven at 40 ℃ for drying; (6) And drying to obtain the final prafloxacin hydrochloride dihydrate.
The X-ray powder diffraction pattern of the product has characteristic peaks at diffraction angles 2θ=6.9±0.2°,7.6±0.2°,9.7±0.2°,12.4±0.2°,14.0±0.2°,15.6±0.2°,21.9±0.2°, and 29.0±0.2°. DSC showed a desolvation temperature of 60 ℃. The product appearance is light yellow powder, the purity of the product is 99.5%, and the process yield is 90.2%.
Example 3
(1) Dissolving 1.5g of prafloxacin solid in 8ml of methanol at 30 ℃, magnetically stirring, and keeping the temperature for 20 minutes to ensure that the solid is completely dissolved and uniformly dispersed in a solvent; (2) 1.5ml of hydrochloric acid was added thereto at a feed rate of 3ml/min; (3) Continuously stirring, and culturing the crystal for 2 hours at constant temperature; (4) filtering the product, and carrying out vacuum filtration; (5) placing the obtained crystal in a drying oven at 35 ℃ for drying; (6) And drying to obtain the final prafloxacin hydrochloride dihydrate. The X-ray powder diffraction pattern of the product has characteristic peaks at diffraction angles 2θ=6.9±0.2°,7.6±0.2°,9.7±0.2°,12.4±0.2°,14.0±0.2°,15.6±0.2°,21.9±0.2°, and 29.0±0.2°. DSC showed a desolvation temperature of 60 ℃. The product appearance is light yellow powder, the purity of the product is 99.4%, and the process yield is 90.4%.
Example 4
(1) Dissolving 1.2g of prafloxacin solid in 10ml of methanol at 40 ℃, magnetically stirring, and keeping the temperature for 15 minutes to ensure that the solid is completely dissolved and uniformly dispersed in the solvent; (2) 0.8ml of hydrochloric acid was added thereto at a feed rate of 4ml/min;
(3) Continuously stirring, and culturing the crystal for 4 hours at constant temperature; (4) filtering the product, and carrying out vacuum filtration; (5) placing the obtained crystal in a drying oven at 40 ℃ for drying; (6) And drying to obtain the final prafloxacin hydrochloride dihydrate.
The X-ray powder diffraction pattern of the product was measured at diffraction angles 2θ=6.9±0.2°,7.6±0.2°,9.7±0.2°,
the characteristic peak is at 12.4+/-0.2 degrees, 14.0+/-0.2 degrees, 15.6+/-0.2 degrees, 21.9+/-0.2 degrees and 29.0+/-0.2 degrees. DSC showed a desolvation temperature of 60 ℃. The product appearance is light yellow powder, the purity of the product is 99.2%, and the process yield is 91.5%.
Example 5
(1) Dissolving 1.1g of prafloxacin solid in 5ml of deionized water at 30 ℃, magnetically stirring, and keeping the temperature for 15 minutes to completely dissolve and uniformly disperse the solid in a solvent; (2) 2ml of hydrochloric acid was added thereto at a feed rate of 4ml/min; (3) Continuously stirring, and culturing the crystal for 2 hours at constant temperature; (4) filtering the product, and carrying out vacuum filtration; (5) placing the obtained crystal in a drying oven at 40 ℃ for drying; (6) And drying to obtain the final prafloxacin hydrochloride dihydrate.
The X-ray powder diffraction pattern of the product has characteristic peaks at diffraction angles 2θ=6.9±0.2°,7.6±0.2°,9.7±0.2°,12.4±0.2°,14.0±0.2°,15.6±0.2°,21.9±0.2°, and 29.0±0.2°. DSC showed a desolvation temperature of 60 ℃. The product appearance is light yellow powder, the purity of the product is 99.6%, and the process yield is 91.2%.
The invention discloses and proposes a crystal form of prafloxacin hydrochloride dihydrate and a preparation method thereof, and a person skilled in the art can properly change links such as raw materials, technological parameters and the like by referring to the content of the invention. While the methods and products of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and modifications can be applied to the methods and products described herein to practice the techniques of this invention without departing from the spirit or scope of the invention. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be included within the spirit, scope and content of the invention.
Claims (10)
1. A crystalline prafloxacin hydrochloride dihydrate, characterized in that the crystalline prafloxacin hydrochloride dihydrate has a characteristic peak in a diffraction angle 2θ=6.9±0.2°,7.6±0.2°,9.7±0.2°,12.4±0.2°,14.0±0.2°,15.6±0.2°,21.9±0.2°,29.0±0.2°.
2. The crystalline prafloxacin hydrochloride dihydrate of claim 1 having a molecular formula of C 21 H 26 FClN 4 O 5 。
3. Crystals of prafloxacin hydrochloride dihydrate according to claim 1 or 2, characterized in that the crystals are desolvated at 60 ℃.
4. A process for preparing crystals of prafloxacin hydrochloride dihydrate, for preparing the crystals of any one of claims 1-3, comprising the steps of:
step 1: dissolving prafloxacin solids in water and/or ethanol until clear;
step 2: keeping the temperature of the solution obtained in the step 1 constant, and adding hydrochloric acid into the solution obtained in the step 1;
step 3: growing crystal at constant temperature;
step 4: and (3) drying the product obtained in the step (3) to obtain the final prafloxacin hydrochloride dihydrate product.
5. The process of claim 4, wherein the concentration of the prafloxacin solution after dissolution in step 1 is 0.05 to 0.15g/ml.
6. The method according to claim 4, wherein the hydrochloric acid is fed at a rate of 1ml/min to 4ml/min in step 2.
7. The method according to claim 4, wherein in the step 2, the constant temperature is 25 to 30 ℃.
8. The method according to claim 4, wherein in the step 3, the crystal growth time is 2 to 4 hours and the temperature is 25 to 30 ℃.
9. The method according to claim 4, wherein in step 4, the product obtained in step 3 is filtered, and the obtained crystals are dried in a drying oven; and drying to obtain the final prafloxacin hydrochloride dihydrate product.
10. The method according to claim 9, wherein in step 4, the drying temperature is 40 to 45 ℃ and the drying time is 2 to 4 hours.
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