CN103864683B - Medicine eutectic of ciprofloxacin and salicylic acid and preparation process thereof - Google Patents
Medicine eutectic of ciprofloxacin and salicylic acid and preparation process thereof Download PDFInfo
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- CN103864683B CN103864683B CN201410051017.XA CN201410051017A CN103864683B CN 103864683 B CN103864683 B CN 103864683B CN 201410051017 A CN201410051017 A CN 201410051017A CN 103864683 B CN103864683 B CN 103864683B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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Abstract
The invention discloses a medicine eutectic of ciprofloxacin and salicylic acid and a preparation process thereof. The preparation method of the eutectic comprises the steps: adding ciprofloxacin and salicylic acid in an alcohol water solution or methane water solution, stirring, standing, filtering, naturally volatilizing filtrate at a room temperature, obtaining a solid-liquid mixture containing a colorless blocky crystal after 1-3 weeks, collecting the colorless blocky crystal after filtering, and drying to obtain the medicine eutectic of ciprofloxacin and salicylic acid. The invention further provides an industrialized rapid preparation method of the eutectic. The preparation method comprises the steps: adding ciprofloxacin and salicylic acid in the alcohol water solution, mixing, stirring, heating to 70-80 DEG C, reflowing for 2 hours, and stopping reaction after a reaction solution is clarified, filtering at a temperature of 70-80 DEG C, loading filtrate in a closed container, and standing for 6-24 hours at a room temperature to obtain the medicine eutectic of ciprofloxacin and salicylic acid. The method for synthesizing the medicine eutectic of ciprofloxacin and salicylic acid, disclosed by the invention, is low in equipment requirement, good in eutectic heat stability, and high in yield; and the industrialized production is easily realized.
Description
Technical field
The present invention relates to technical field of pharmaceutical co-crystal, relate in particular to Ciprofloxacin and salicylic pharmaceutical co-crystals body and preparation method thereof.
Technical background
Due to the importance of hydrogen bond action in crystal engineering, in order to understand the structure of hydrogen bond system and want to develop it, people have paid great effort (G. R. Desiraju at Materials science, molecular recognition and biological entities and pharmaceutical industry, Crystal Engineering:The Design of Organic Solids. Elsevier:New York, 1989; Shen man piebald horse, Sun Junqi. Research Development of Supramolacular Science. Bulletin of Chinese Academy of Sciences, 2004,19,420 424.).In the past in Two decades years, the crystal formation of active medicine component is more and more subject to people's attention.People generally believe that the crystal formation of medicine comprises polymorphic, hydrate, solvate, salt and eutectic.(this material is solid to active medicine component (APIs) at normal temperatures with another kind of material, as being then considered as solvate for liquid state) molecule just can produce a kind of solid form with different physicochemical property by the connection of non covalent bond, this is pharmaceutical co-crystals (C. B. Aakero y, M. E. Fasulo, J. Desper
mol. Pharmaceutics2007,
4, 317 322).
Meanwhile, supramolecule synthon (supramolecular synthon) (G. R. Desiraju,
angew. Chem., Int. Ed. Engl.1995,
34, 2,311 2327) and become a kind of design medicine solid-state form newly and the effective means generating novel structure.Supramolecule synthon refers to a kind of supramolecular structure unit generated by the known or possible synthetic method relating to intermolecular interaction.The difference that a large amount of documents describes drug crystal forms can change the physicochemical property of medicine activity component.When active medicine component (APIs) appears in pharmaceutical co-crystals time, from the angle that covalent linkage is formed, APIs itself does not change, therefore original drug effect can also be kept, and the aspects such as the solubleness of eutectic medicine, bioavailability, stability have great improvement, this has obtained the checking of many achievements in research.Therefore pharmaceutical co-crystals is as a kind of novel medical solid form, has advantage more more than conventional medicament formulation, has very large potentiality.
Ciprofloxacin is a kind of fluoroquinolone zwitter-ion extensive pedigree antibiotic of synthetic, is widely used in clinically treating various bacterial infection.Due to its indissoluble (0.08 mg/ml) in water, have a strong impact on the design (D. L. Ross, C. M. Riley. Int. J. Pharm. 1990,63,237 – 250.) of regular dosage form and liquid dosage form (as tablet, injection and eye drop).Therefore the solvability that the solid-state form by changing medicine improves Ciprofloxacin is very necessary.Ciprofloxacin has fluorine atom and piperazine ring, and it may form eutectic with acidic-group.And prototropy between hydroxy-acid group and piperazine group, can be there is, this is recently confirmed in the crystalline structure of flouroquinolone drugs (J. S. Reddy, S. V. Ganesh, R. Nagalapalli, R. Dandela, K. A. Solomon, K. A. Kumar, N. R. Goud, A. Nangia
j. Pharm. Sci.2011,
100, 3160 – 3176.).The solvability of the eutectic that Ciprofloxacin and phenylformic acid are formed can improve 100 times in water neutralising phosphoric acid damping fluid.This shows, the solubleness of aromatic acid ciprofloxacin pharmaceutical also can obtain sizable improvement, and higher solubleness also will bring higher bioavailability.Chinese patent 02139499.7 proposes ciprofloxacin mandelate, ofloxacin mandelate and preparation technology thereof, illustrate that the ciprofloxacin mandelate of two kinds of drug effects can be released to two kinds of one-components under suitable ph, but amygdalic acid range of application is narrower, be combined the object not having dual synergy, broad-spectrum antimicrobial with Ciprofloxacin.
Meanwhile, Whitfield's ointment (usually with sodium salicylate or acetylsalicylic acid form administration) is one of clinical the most frequently used medicine.At present not only at pain relieving, anti-inflammatory, bringing down a fever and treat in gout etc. has critical role, owing to there being anticoagulation, is preventing also may have certain effect in phlebothrombosis, coronary artery thrombus and pulmonary infarction etc.In view of this, inventor spy proposes pharmaceutical co-crystals body and the preparation technology thereof of Ciprofloxacin and Whitfield's ointment formation, both remained the pharmacological properties of two kinds of medicines itself, and the physicochemical property such as the stability of medicine, solubleness can have been improved again, improve drug effect and bioavailability.
Described pharmaceutical co-crystals has good effect except to the solvability, stability etc. that improve Ciprofloxacin, there has also been obvious change relative to two kinds of bulk drugs in broad-spectrum antimicrobial, anti-inflammatory analgesic etc.
Summary of the invention
The object of the invention is the novel Ciprofloxacin of open one and salicylate agent eutectic.Bulk drug Ciprofloxacin selected by the present invention, as medicine activity component (API), take Whitfield's ointment as precursor (cocrystal former), thus obtains a kind of organic pharmaceutical co-crystal of novel texture.This pharmaceutical co-crystals body adopts nontoxic ethanol or first alcohol and water to carry out crystallization, and good stability, making method is simple, and molar yield is high, and reproducibility is good, is conducive to suitability for industrialized production.
For achieving the above object, the technical solution adopted in the present invention is:
A kind of pharmaceutical co-crystals body, comprise Ciprofloxacin and Whitfield's ointment, the structural formula of pharmaceutical co-crystals body is:
。
Described Ciprofloxacin molecular formula is C
17h
18fN
3o
3, structural formula is:
; Described Whitfield's ointment molecular formula is C
7h
6o
3, structural formula is:
; Described Ciprofloxacin and salicylic mol ratio are 1:1 ~ 1:4.
Its Ciprofloxacin and salicylic pharmaceutical co-crystals body structure simplified summary as follows: the unsymmetrical structure unit of new crystal by a Ciprofloxacin positively charged ion be protonated (hereinafter referred to as HCf
+ ) and salicylate negatively charged ion composition, this is because the prototropy on carboxyl on Whitfield's ointment causes to the nitrogen-atoms on the piperazine group of Ciprofloxacin.For each HCf
+ positively charged ion, its hydroxy-acid group and part fluoroquinolone in same plane, and form intramolecular hydrogen bond with the Sauerstoffatom of ketone group in fluoroquinolone molecule.Because Ciprofloxacin there is the existence of fluorine atom, allly defines reactive force in multiple more weak molecule Ciprofloxacin molecule is extended.Meanwhile, the hydrogen atom in a Whitfield's ointment molecule on carboxyl, as giving body, forms hydrogen bond with the Sauerstoffatom on carboxyl in another Whitfield's ointment molecule as acceptor.And the hydrogen atom of hydroxy-acid group is as giving body in Whitfield's ointment molecule, the nitrogen-atoms in Ciprofloxacin molecule on piperazine ring forms as hydrogen bond receptor the one dimension supramolecular structure that is similar to catfish skeleton.Piperazine ring has chair conformation, and its protonated nitrogen-atoms facilitates the interaction of hydrogen bond between carboxylate salt.
The ciprofloxacin pharmaceutical new crystal spacer that the present invention prepares is triclinic(crystalline)system, its axial length a=9.194 (3), b=12.720 (4), c=14.712 (5), shaft angle α=82.783 (9) °, β=77.177 (9) °, γ=76.989 (9) °.
Present invention also offers the preparation method of a kind of Ciprofloxacin and salicylic pharmaceutical co-crystals body, described preparation method comprises 1:1 ~ 1:4 in molar ratio and gets Ciprofloxacin and Whitfield's ointment joins in aqueous ethanolic solution or methanol aqueous solution, obtain containing Ciprofloxacin and salicylic ethanol or methanol aqueous solution, leave standstill after 30 minutes after stirring, filter, naturally volatilize filtering under the settled solution obtained is placed in room temperature, the solidliquid mixture containing colourless bulk crystals is obtained after 1-3 week, by the colourless bulk crystals of solidliquid mixture collecting by filtration of gained, and dry 12 hours in 60 ~ 70 DEG C, obtain Ciprofloxacin and salicylic pharmaceutical co-crystals body.
Further, in described ethanol or methanol aqueous solution, the volume ratio of ethanol or first alcohol and water is 2:1 ~ 1:2;
Again further, in described Ciprofloxacin and methyl alcohol or aqueous ethanolic solution, the mass ratio of water is 1:90 ~ 1:182.
Further, described oven dry standard is dry colourless bulk crystals to constant weight.
Present invention also offers the fast preparation method of a kind of Ciprofloxacin and salicylic pharmaceutical co-crystals body, comprise following technique: 1:1 ~ 1:4 gets Ciprofloxacin and Whitfield's ointment joins in aqueous ethanolic solution in molar ratio, to mix, stir, be heated to 70 ~ 80 DEG C containing Ciprofloxacin and salicylic aqueous ethanolic solution, reflux 2 hours, stopped reaction after the clarification of question response liquid, filter at the temperature of 70 ~ 80 DEG C, filtrate loads in encloses container, room temperature leaves standstill 6-24 hour, obtains Ciprofloxacin and salicylic pharmaceutical co-crystals body.
In described aqueous ethanolic solution, the volume ratio of second alcohol and water is 2:1 ~ 1:2;
In described Ciprofloxacin and aqueous ethanolic solution, the mass ratio of water is 1:90 ~ 1:182.
The invention has the beneficial effects as follows:
The present invention adopts normal temperature volatilization method to synthesize Ciprofloxacin and salicylic pharmaceutical co-crystals body, preparation process adopts second alcohol and water as solvent, nontoxic, required conversion unit is simple, operation is simple, productive rate is high, reproducibility is good, and the eutectic prepared both had remained the pharmacological properties of medicine itself, be again that the physicochemical property of modified medicaments, raising drug effect and bioavailability provide possibility, in broad-spectrum antimicrobial, anti-inflammatory analgesic, had remarkable improvement, and there is Heat stability is good, molar yield advantages of higher, easily realizes suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the eutectiferous structural unit schematic diagram of Ciprofloxacin Whitfield's ointment;
Fig. 2 is the eutectiferous hydrogen bond network figure of Ciprofloxacin Whitfield's ointment;
Fig. 3 is the eutectiferous powder diagram of Ciprofloxacin Whitfield's ointment;
Fig. 4 is Ciprofloxacin and Ciprofloxacin Whitfield's ointment eutectic mean blood plasma concentration one time plot.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.
The preparation of embodiment 1 Ciprofloxacin and salicylic pharmaceutical co-crystals body
0.1mmol Ciprofloxacin (33.1mg), 0.1mmol Whitfield's ointment (13.8mg) are joined in the methanol aqueous solution be made up of 6ml methyl alcohol and 3mL water.Stir 15 minutes after mixing, leave standstill 30 minutes, filter, filtrate is loaded 25ml test tube, prick hole with preservative film sealing, obtain settled solution and naturally volatilize under being placed in room temperature, obtain the solidliquid mixture containing colourless bulk crystals after 1 week, by the colourless bulk crystals of solidliquid mixture collecting by filtration of gained, and dry 12 hours in 60 ~ 70 DEG C, obtain Ciprofloxacin and salicylic pharmaceutical co-crystals body 33.84mg, molar yield is 72%.
The preparation of embodiment 2 Ciprofloxacin and salicylic pharmaceutical co-crystals body
0.1mmol Ciprofloxacin (33.1mg), 0.1mmol Whitfield's ointment (13.8mg) are joined in the methanol aqueous solution be made up of 6ml methyl alcohol and 3mL water.Stir 15 minutes after mixing, leave standstill 30 minutes, filter, filtrate is loaded 25ml test tube, prick hole with preservative film sealing, obtain settled solution and naturally volatilize under being placed in room temperature, obtain the solidliquid mixture containing colourless bulk crystals after 2 weeks, by the colourless bulk crystals of solidliquid mixture collecting by filtration of gained, and dry 12 hours in 60 ~ 70 DEG C, obtain Ciprofloxacin and salicylic pharmaceutical co-crystals body 35.25mg, molar yield is 75%.
The preparation of embodiment 3 Ciprofloxacin and salicylic pharmaceutical co-crystals body
0.1mmol Ciprofloxacin (33.1mg), 0.1mmol Whitfield's ointment (13.8mg) are joined in the methanol aqueous solution be made up of 6ml methyl alcohol and 3mL water.Stir 15 minutes after mixing, leave standstill 30 minutes, filter, filtrate is loaded 25ml test tube, prick hole with preservative film sealing, obtain settled solution and naturally volatilize under being placed in room temperature, obtain the solidliquid mixture containing colourless bulk crystals after 3 weeks, by the colourless bulk crystals of solidliquid mixture collecting by filtration of gained, and dry 12 hours in 60 ~ 70 DEG C, obtain Ciprofloxacin and salicylic pharmaceutical co-crystals body 37.13mg, molar yield is 79%.
The preparation of embodiment 4 Ciprofloxacin and salicylic pharmaceutical co-crystals body
0.1mmol Ciprofloxacin (33.1mg), 0.1mmol Whitfield's ointment (13.8mg) join in the methanol aqueous solution be made up of 3ml methyl alcohol and 3mL water.Stir 15 minutes after mixing, leave standstill 30 minutes, filter, filtrate is loaded 25ml test tube, hole is pricked with preservative film sealing, obtain settled solution and naturally volatilize under being placed in room temperature, obtaining the solidliquid mixture containing colourless bulk crystals after 3 weeks, by the colourless bulk crystals of solidliquid mixture collecting by filtration of gained, and dry 12 hours in 60 ~ 70 DEG C, obtain Ciprofloxacin and salicylic pharmaceutical co-crystals body 41.36mg, molar yield is 88%.
The preparation of embodiment 5 Ciprofloxacin and salicylic pharmaceutical co-crystals body
0.1mmol Ciprofloxacin (33.1mg), 0.1mmol Whitfield's ointment (13.8mg) join in the methanol aqueous solution be made up of 3ml methyl alcohol and 6ml water.Stir 15 minutes after mixing, leave standstill 30 minutes, filter, filtrate is loaded 25ml test tube, prick hole with preservative film sealing, obtain settled solution and naturally volatilize under being placed in room temperature, obtain the solidliquid mixture containing colourless bulk crystals after 3 weeks, by the colourless bulk crystals of solidliquid mixture collecting by filtration of gained, and dry 12 hours in 60 ~ 70 DEG C, obtain Ciprofloxacin and salicylic pharmaceutical co-crystals body 39.95mg, molar yield is 85%.
The preparation of embodiment 6 Ciprofloxacin and salicylic pharmaceutical co-crystals body
0.1mmol Ciprofloxacin (33.1mg), 0.2mmol Whitfield's ointment (27.6mg) join in the methanol aqueous solution be made up of 6ml methyl alcohol and 3ml water.Stir 15 minutes after mixing, leave standstill 30 minutes, filter, filtrate is loaded 25ml test tube, prick hole with preservative film sealing, obtain settled solution and naturally volatilize under being placed in room temperature, obtain the solidliquid mixture containing colourless bulk crystals after 3 weeks, by the colourless bulk crystals of solidliquid mixture collecting by filtration of gained, and dry 12 hours in 60 ~ 70 DEG C, obtain Ciprofloxacin and salicylic pharmaceutical co-crystals body 38.54mg, molar yield is 82%.
The preparation of embodiment 7 Ciprofloxacin and salicylic pharmaceutical co-crystals body
0.1mmol Ciprofloxacin (33.1mg), 0.2mmol Whitfield's ointment (27.6mg) join the methanol aqueous solution be made up of 3ml methyl alcohol and 3ml water.Stir 15 minutes after mixing, leave standstill 30 minutes, filter, filtrate is loaded 25ml test tube, prick hole with preservative film sealing, obtain settled solution and naturally volatilize under being placed in room temperature, obtain the solidliquid mixture containing colourless bulk crystals after 2 weeks, by the colourless bulk crystals of solidliquid mixture collecting by filtration of gained, and dry 12 hours in 60 ~ 70 DEG C, obtain Ciprofloxacin and salicylic pharmaceutical co-crystals body 38.54mg, molar yield is 82%.
The preparation of embodiment 8 Ciprofloxacin and salicylic pharmaceutical co-crystals body
0.1mmol Ciprofloxacin (33.1mg), 0.4mmol Whitfield's ointment (55.2mg) join the methanol aqueous solution be made up of 3ml methyl alcohol and 6ml water.Stir 15 minutes after mixing, leave standstill 30 minutes, filter, filtrate is loaded 25ml test tube, hole is pricked with preservative film sealing, obtain settled solution and naturally volatilize under being placed in room temperature, obtaining the solidliquid mixture containing colourless bulk crystals after 1 week, by the colourless bulk crystals of solidliquid mixture collecting by filtration of gained, and dry 12 hours in 60 ~ 70 DEG C, obtain Ciprofloxacin and salicylic pharmaceutical co-crystals body 37.60mg, molar yield is 80%.
The preparation of industrialization of embodiment 9 Ciprofloxacin and salicylic pharmaceutical co-crystals body
1mol Ciprofloxacin (33.1g), 1mol Whitfield's ointment (13.8g) joins in the aqueous ethanolic solution be made up of 390ml ethanol and 625ml water, will containing Ciprofloxacin and the mixing of salicylic aqueous ethanolic solution, stir, be heated to 70 ~ 80 DEG C, reflux 2 hours, stopped reaction after the clarification of question response liquid, filter at the temperature of 70 ~ 80 DEG C, filtrate loads the Erlenmeyer flask of 1L, with the airtight bundle hole of preservative film, room temperature leaves standstill 6-24 hour, obtain the solidliquid mixture containing clear crystal, by the solidliquid mixture collecting by filtration clear crystal of gained, and dry 12 hours in 60 ~ 70 DEG C, obtain Ciprofloxacin and salicylic pharmaceutical co-crystals body 44.5g, molar yield is 94.7%.
The preparation of industrialization of embodiment 10 Ciprofloxacin and salicylic pharmaceutical co-crystals body
1mol Ciprofloxacin (33.1g), 4mol Whitfield's ointment (55.2g) joins in the aqueous ethanolic solution be made up of 390ml ethanol and 625ml water, will containing Ciprofloxacin and the mixing of salicylic aqueous ethanolic solution, stir, be heated to 70 ~ 80 DEG C, reflux 2 hours, stopped reaction after the clarification of question response liquid, filter at the temperature of 70 ~ 80 DEG C, filtrate loads the Erlenmeyer flask of 1L, with the airtight bundle hole of preservative film, room temperature leaves standstill 6-24 hour, obtain the solidliquid mixture containing clear crystal, by the solidliquid mixture collecting by filtration clear crystal of gained, and dry 12 hours in 60 ~ 70 DEG C, obtain Ciprofloxacin and salicylic pharmaceutical co-crystals body 43.9g, molar yield is 93.4%.
The preparation of industrialization of embodiment 11 Ciprofloxacin and salicylic pharmaceutical co-crystals body
1mol Ciprofloxacin (33.1g), 2mol Whitfield's ointment (27.6g) joins in the aqueous ethanolic solution be made up of 390ml ethanol and 625ml water, will containing Ciprofloxacin and the mixing of salicylic aqueous ethanolic solution, stir, be heated to 70 ~ 80 DEG C, reflux 2 hours, stopped reaction after the clarification of question response liquid, filter at the temperature of 70 ~ 80 DEG C, filtrate loads the Erlenmeyer flask of 1L, with the airtight bundle hole of preservative film, room temperature leaves standstill 6-24 hour, obtain the solidliquid mixture containing clear crystal, by the solidliquid mixture collecting by filtration clear crystal of gained, and dry 12 hours in 60 ~ 70 DEG C, obtain Ciprofloxacin and salicylic pharmaceutical co-crystals body 44.1g, molar yield is 93.8%.
The eutectic structure that embodiment 12 is total to Ciprofloxacin and salicylic pharmaceutical co-crystals body characterizes
Crystal structure determination adopts Bruker Apex II CCD diffractometer, under 296 (2) K, with through graphite monochromatised
mo K αray (
λ=0.71073) with
ωscan mode collects point diffraction, and the data of collection also carry out semiempirical absorption correction by SADABS method by SAINT programe reduction.Structure elucidation and refine adopt SHELXS and SHELXL of SHELXTL program to complete respectively, by complete matrix least square method pair
f 2carry out revising the coordinate and anisotropic parameters that obtain whole non-hydrogen atom.All hydrogen atoms are fixed on parent atom by theory in structure refinement process, give the isotropy displacement parameter of slightly larger than parent atom displacement parameter (C – H, 1.2 or O/N – H, 1.5 times).Detailed axonometry data are in table 1, and structural unit schematic diagram is as Fig. 1, and the eutectiferous hydrogen bond network figure of Ciprofloxacin Whitfield's ointment is as Fig. 2, and the eutectiferous powder diagram of Ciprofloxacin Whitfield's ointment is as Fig. 3.
The mensuration of embodiment 13 Ciprofloxacin and salicylic pharmaceutical co-crystals body bioavailability
Get healthy male SD rat 15, weight 200 ~ 220 g, ad lib and drinking-water.After 3 days adaptability is raised, be divided into 3 groups at random by weight, I group is blank group, and II group is Ciprofloxacin control group, and III group is Ciprofloxacin Whitfield's ointment eutectic group.Before administration, fasting 12 h, can't help water.I group limbs venous blood sampling 0.5 mL, leaves standstill centrifugal 10 min of 30 min, 3 000 r/min, pipettes upper serum, and sealing is stored in-80 ° of C.II group, III group give gavage calglucon and the L mono-aspartic acid chelating calcium aqueous solution respectively by 20 mg/kg dosage, 10min, 20min, 30min after administration, 45min, 60min, 120min, 240min be limbs venous blood sampling 0.5 mL respectively, leave standstill 30 min, centrifugal 10 min of 3 000 r/rain, pipette upper serum, and sealing is stored in-80 ° of C.
For each sample, get 200ul sample, the internal standard substance (paraxin/methyl alcohol) (100ng/ml) of 200ul and 400ul methyl alcohol are in 2 milliliters of centrifuge tubes, with 13, centrifugal 10 minutes of 000 rpm, removes supernatant liquid, and is evaporated to dry in nitrogen gas stream gentle under 37 ° of C.Then dried resistates is dissolved in again the methyl alcohol of 200ul, and transfers in 2 milliliters of vials, get 5 μ L aliquots containig inject UPLC-MS/MS analyze. detailed data in table 2,
ciprofloxacin and Ciprofloxacin Whitfield's ointment eutectic mean blood plasma concentration one time plot are shown in Fig. 4.
Above example is only for illustration of content of the present invention, and in addition, the present invention also has other embodiment.But all employings are equal to replacement or the technical scheme that formed of equivalent deformation mode all drops in protection scope of the present invention.
Claims (7)
1. Ciprofloxacin and a salicylic pharmaceutical co-crystals body, comprise Ciprofloxacin and Whitfield's ointment, and the structural formula of its pharmaceutical co-crystals body is:
.
2. the preparation method of Ciprofloxacin according to claim 1 and salicylic pharmaceutical co-crystals body, it is characterized in that: described preparation method comprises 1:1 ~ 1:4 in molar ratio and gets Ciprofloxacin and Whitfield's ointment joins in aqueous ethanolic solution or methanol aqueous solution, obtain containing Ciprofloxacin and salicylic ethanol or methanol aqueous solution, leave standstill after 30 minutes after stirring, filter, naturally volatilize filtering under the settled solution obtained is placed in room temperature, the solidliquid mixture containing colourless bulk crystals is obtained after 1-3 week, by the colourless bulk crystals of solidliquid mixture collecting by filtration of gained, and dry 12 hours in 60 ~ 70 DEG C, obtain Ciprofloxacin and salicylic pharmaceutical co-crystals body.
3. the preparation method of Ciprofloxacin according to claim 2 and salicylic pharmaceutical co-crystals body, is characterized in that: in described ethanol or methanol aqueous solution, the volume ratio of ethanol or first alcohol and water is 2:1 ~ 1:2.
4. the preparation method of Ciprofloxacin according to claim 2 and salicylic pharmaceutical co-crystals body, is characterized in that: in described Ciprofloxacin and methyl alcohol or aqueous ethanolic solution, the mass ratio of water is 1:90 ~ 1:182.
5. the preparation method of Ciprofloxacin according to claim 2 and salicylic pharmaceutical co-crystals body, is characterized in that: described oven dry is for drying colourless bulk crystals to constant weight.
6. the preparation method of Ciprofloxacin according to claim 1 and salicylic pharmaceutical co-crystals body, it is characterized in that: 1:1 ~ 1:4 gets Ciprofloxacin and Whitfield's ointment joins in aqueous ethanolic solution in molar ratio, to mix, stir, be heated to 70 ~ 80 DEG C containing Ciprofloxacin and salicylic aqueous ethanolic solution, reflux 2 hours, stopped reaction after the clarification of question response liquid, filter at the temperature of 70 ~ 80 DEG C, filtrate loads in encloses container, room temperature leaves standstill 6-24 hour, obtains Ciprofloxacin and salicylic pharmaceutical co-crystals body.
7. the preparation method of Ciprofloxacin according to claim 6 and salicylic pharmaceutical co-crystals body, is characterized in that: in described aqueous ethanolic solution, the volume ratio of second alcohol and water is 2:1 ~ 1:2; In described Ciprofloxacin and aqueous ethanolic solution, the mass ratio of water is 1:90 ~ 1:182.
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| CN105777711B (en) * | 2016-04-07 | 2018-08-14 | 常州大学 | A kind of pharmaceutical co-crystals body and preparation method thereof of Lomefloxacin and 5-F- M-phthalic acids |
| CN106995409A (en) * | 2017-03-31 | 2017-08-01 | 常州大学 | Improve the preparation method and structure of the phthalic acid pharmaceutical co-crystals body of Ciprofloxacin solubility |
| CN107098858A (en) * | 2017-03-31 | 2017-08-29 | 常州大学 | A kind of Ciprofloxacin and the eutectiferous structure of tetrachloro-p-phenylene's dioctyl phthalate and its solvothermal preparation method |
| RU2706351C1 (en) * | 2019-05-14 | 2019-11-18 | Федеральное государственное бюджетное учреждение науки институт химии растворов им. Г.А. Крестова Российской академии наук | Hydrate of ciprofloxacin salt with 4-aminobenzoic acid |
| CN114656445B (en) * | 2022-03-31 | 2023-08-01 | 佳木斯大学 | Gatifloxacin-sulfosalicylic acid pharmaceutical co-crystal single crystal and preparation method thereof |
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| Basavoju S.等.Pharmaceutical Cocrystal and Salts of Norfloxacin.《Crystal Growth & * |
| Design》.2006,第6卷(第12期),第2699-2708页. * |
| Fluoroquinolone Salts with Carboxylic Acids;Reddy J. S.等;《J. Pharm. Sci.》;20110831;第100卷(第8期);第3160-3176页 * |
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