CN105566351A - New crystal form cefamandole nafate compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation - Google Patents
New crystal form cefamandole nafate compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
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Abstract
The invention discloses a new crystal form cefamandole nafate compound and a crystallization preparation method thereof. The new crystal form cefamandole nafate compound is prepared by adopting the particle process crystal product molecular assembling and morphology optimizing technology. The compound has the advantages of being high in purity, low in impurity content and good in fluidity and stability. The invention also discloses a preparation which is prepared from cefamandole nafate, namely cefamandole nafate for injection.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of particle process crystal product molecule that adopts and assemble and the Sodium O-formylcefamole crystal compound of form optimisation technique and preparation.
Background technology
Sodium O-formylcefamole (Cefamandolenafate) chemistry 7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5 base) thiomethyl]-3-cephem-4-carboxylic acid sodium salt by name, molecular weight 512.5, structural formula is:
Sodium O-formylcefamole is the prodrug of Cefamandole, is hydrolyzed to rapidly effective constituent Cefamandole in vivo after vein or intramuscular injection.This medicine is the semisynthetic cynnematin of the s-generation of Lilly Co., Eli.'s development in 1972, and be applied to clinical in 1978, commodity are called Mandol.At present, American Pharmacopeia, British Pharmacopoeia, European Pharmacopoeia, Chinese Pharmacopoeia all record this product.
Sodium O-formylcefamole is applicable to pulmonary infection caused by sensitive organism, urinary tract infections, biliary tract infection, skin soft-tissue infection, bone and the infection of joint and septicemia, abdominal cavity infection etc.
The synthetic method of Sodium O-formylcefamole has a lot of document and patent report, most employing 7-amino-3-[[(1-methyl isophthalic acid-H-tetrazole-5-base) sulfo-] methyl]-3-cephalo-4-carboxylic acid (7-ATCA) and D-(-)-2-methanoyl-phenylacetyl chlorine are precursor intermediate, are synthesized by the method for active ester or chloride method.But all there is the defects such as purity difference, colour-difference, content is low in the product that existing method and above-mentioned patent obtain, have impact on the mass effect of its preparation.Particularly Sodium O-formylcefamole is commonly used for injection in clinical, the low untoward reaction that even can cause predicting of purity, thus limits the use of medicine.Address this problem and must research and develop novel crystallization production technology, to optimize the process parameters such as solvent, temperature, reaction times, additive, crystallization is carried out under the suitable conditions, thus obtain a kind of quality Mandokef sodium novel crystal form more reliably.
The assembling of particle process crystal product molecule and form optimisation technique, be intended to the requirement optimized for specific functional product form, carries out molecular assembly assembling with regularly arranged.
The above problem that the present invention exists mainly for Cefamandole nafate compounds, to solvent in crystal formation process, temperature, external force, on the basis that the factors such as additive are fully investigated, the assembling of particle process crystal product molecule and form optimisation technique is adopted to obtain a kind of purity high, look level is good, good fluidity, the Sodium O-formylcefamole crystal compound of good stability, this synthesis step preparation process more in the past more focuses on the control of reagent in building-up process and parameter, step is simple, the raw material etc. used is low price, nontoxic or low-toxicity product, be suitable for commercial scale production.
Summary of the invention
The first object of the present invention is to provide a kind of Sodium O-formylcefamole crystal compound, and this compound adopts the assembling of particle process crystal product molecule to prepare with form optimisation technique, has that purity is high, look level is good, the feature of good stability.
The X-ray powder diffraction pattern that Sodium O-formylcefamole crystal compound of the present invention represents with 2 θ diffraction angle is at 6.67 ° ± 0.2 °, 12.27 ° ± 0.2 °, 13.36 ° ± 0.2 °, 16.03 ° ± 0.2 °, 18.92 ° ± 0.2 °, 19.98 ° ± 0.2 °, 20.39 ° ± 0.2 °, 26.19 ° ± 0.2 ° place's indicating characteristic diffraction peak.
Sodium O-formylcefamole crystal compound preparation of the present invention comprises the following steps:
(1) be dissolved in methylene dichloride by 7-ATCA, under whipped state, in above-mentioned solution, add N, the two trimethylsilyl ethanamide (BSA) of O-, stirring reaction, cools to-5-10 DEG C; The ethyl acetate solution of slow dropping formyl mandelic acid chloride, reacts complete, in above-mentioned reactor, add deionized water and sodium-acetate, stirs, stratification; Get organic layer and add saturated nacl aqueous solution, merge organic layer.Reagent 1 is added in organic layer; Add activated carbon decolorizing again, filter, dry, obtain the solidliquid mixture of Cefamandole acid.
(2) in above-mentioned solidliquid mixture, add Sodium isooctanoate and Virahol, stirred crystallization, filter, with acetone/ethanol mixing solutions washing leaching cake, vacuum-drying, obtains Sodium O-formylcefamole.
(3) add in ethyl lactate by the Sodium O-formylcefamole of above-mentioned preparation, stirring and dissolving, hold over night, suction filtration, filter cake cold ethyl lactate and ether wash for several times successively respectively, remove unnecessary ethyl lactate, dry; Add in ethanol by dry thing, stirring at room temperature, suction filtration, vacuum-drying obtains preparation of fine cefamandole nafate.
Preferably, in above-mentioned preparation method, the weight ratio of described 7-ATCA and formyl mandelic acid chloride is 1:0.5 ~ 1:2.More preferably, weight ratio is 1:1.
Preferably, in above-mentioned preparation method, described reagent 1 is the one in magnesium sulfate, sodium sulfate or sodium-chlor.
More preferably, reagent 1 is magnesium sulfate.
Preferably, in above-mentioned preparation method, the ratio of described acetone/ethanol is 1:1 ~ 3:1.More preferably, the ratio of acetone/ethanol is 2:1.
Preferably, in above-mentioned preparation method, the drying temperature in described step (2) is for being no more than 40 DEG C.More preferably, temperature is no more than 35 DEG C.
Preferably, in above-mentioned preparation method, described step is dried to moisture < 2.0% in (2).More preferably, moisture < 1.0%.
Preferably, in above-mentioned preparation method, in described step (3), hold over night temperature is 0 ~ 15 DEG C.More preferably, temperature is 5 ~ 10 DEG C.。
Preferably, in above-mentioned preparation method, in described step (3), dry thing adds churning time after in ethanol is 20 ~ 60min.More preferably, churning time is 30min.。
The second object of the present invention is to provide a kind of preparation comprising Sodium O-formylcefamole crystal compound of the present invention, and said preparation has better stability compared with product in the past and side effect is little.
The preparation of Mandokef preparation of sodium of the present invention is mainly carried out aseptic subpackaged to above-mentioned prepared Sodium O-formylcefamole crystal compound.
Accompanying drawing explanation
Fig. 1: the X-ray powder diffraction pattern of Sodium O-formylcefamole crystal compound, the 2 θ values that in figure, diffraction peak numbering is corresponding are see table 1.
Embodiment
Below will the present invention will be further described by embodiment; but therefore do not limit the present invention in described scope of embodiments, one skilled in the art will understand that the equivalent replacement that content of the present invention is done; or improve accordingly, still belong within protection scope of the present invention.
Embodiment 1: the preparation of Sodium O-formylcefamole crystal compound
(1) add 7-ATCA10.5g and methylene dichloride 100ml in reactor successively, stir 10min; Continue progressively to add BSA15ml in above-mentioned solution; At 25 ~ 30 DEG C of reaction 3h, cool to-5 ~-10 DEG C; Slow dropping 8.1g formyl mandelic acid chloride (being dissolved in 25ml ethyl acetate), after dropwising, is warmed up to 0 ~ 5 DEG C of reaction 3h.The deionized water 100ml of about 15 DEG C, sodium-acetate 100g is added in above-mentioned reactor; Stir 30min, leave standstill 30min layering; Water layer is separated, and adds 50ml saturated nacl aqueous solution again in organic layer, stirs 15min, merges organic layer.In organic layer, add 15g anhydrous magnesium sulfate, stir dehydration 60min; Add 2g gac again, stir decolouring 30min; Filter, filtrate puts vacuum-drying under 28 DEG C of conditions, obtains the solidliquid mixture of Cefamandole acid.。
(2) in above-mentioned solidliquid mixture, add Sodium isooctanoate 25g, Virahol 100ml, control temperature 15 ~ 20 DEG C, stirred crystallization 1h, filter, with acetone/ethanol (2:1) the solution washing filter cake of 50ml, vacuum-drying temperature is no more than 35 DEG C.Be dried to sampling survey moisture and be less than < 1.0%, obtain Sodium O-formylcefamole crude product.
(3) in reactor, add the Sodium O-formylcefamole 10.1g of ethyl lactate 80ml and above-mentioned preparation, stir and be warming up to 30 DEG C.Entirely molten after 2h, hold over night under mixture 5 ~ 10 DEG C of conditions, there is a large amount of crystal to separate out, continue under 5 ~ 10 DEG C of conditions to stir 3h, stir 1h again under-5 DEG C of conditions, suction filtration, the cold ethyl lactate 20ml of filter cake washes 2 times, wash 4 times with ether 30ml, remove unnecessary ethyl lactate, dry.Added in ethanol 80ml by dry thing, room temperature stirs 30min slowly, suction filtration, and 40 DEG C of vacuum-dryings obtain preparation of fine cefamandole nafate 9.29g.
X-ray powder diffraction (XRPD) is adopted to study and characterize the new crystallized form of Cefuroxime sodium.
Plant and instrument: EMPYREAN (sharp shadow) X-ray diffractometer (Dutch Panalytical company).
The X-ray powder diffraction pattern of embodiment 1 product, at 6.67 °, 12.27 °, 13.36 °, 16.03 °, 18.92 °, 19.98 °, 20.39 °, locates indicating characteristic diffraction peaks for 26.19 °.Specifically see Figure of description 1.
The concrete data of described XRPD diffraction are as shown in the table:
Table 1 Mandokef sodium crystal
| Numbering | D value | 2θ(°) | I/I 0％ |
| 1 | 13.25 | 6.67 | 59.77 |
| 2 | 7.21 | 12.27 | 55.03 |
| 3 | 6.63 | 13.36 | 11.47 |
| 4 | 5.53 | 16.03 | 53.97 |
| 5 | 4.69 | 18.92 | 23.07 |
| 6 | 4.44 | 19.98 | 100.00 |
| 7 | 4.35 | 20.39 | 42.30 |
| 8 | 3.40 | 26.19 | 20.61 |
Embodiment 2: the preparation of Sodium O-formylcefamole crystal compound
(1) add 7-ATCA11.4g and methylene dichloride 100ml in reactor successively, stir 10min; Continue progressively to add BSA15ml in above-mentioned solution; At 25 ~ 30 DEG C of reaction 3h, cool to-5 ~-10 DEG C; Slow dropping 11.4g formyl mandelic acid chloride (being dissolved in 35ml ethyl acetate), after dropwising, is warmed up to 0 ~ 5 DEG C of reaction 3h.The deionized water 100ml of about 15 DEG C, sodium-acetate 100g is added in above-mentioned reactor; Stir 30min, leave standstill 30min layering; Water layer is separated, and adds 50ml saturated nacl aqueous solution again in organic layer, stirs 15min, merges organic layer.In organic layer, add 13.8g anhydrous magnesium sulfate, stir dehydration 60min; Add 2g gac again, stir decolouring 30min; Filter, filtrate puts vacuum-drying under 30 DEG C of conditions, obtains the solidliquid mixture of Cefamandole acid.。
(2) in above-mentioned solidliquid mixture, Sodium isooctanoate 25g, Virahol 100ml is added, control temperature 15 ~ 20 DEG C, stirred crystallization 1h, filter, with acetone/ethanol (1:1) the solution washing filter cake of 50ml, vacuum-drying temperature 33 DEG C, is dried to sampling survey moisture and is less than < 1.0%, obtain Sodium O-formylcefamole crude product.
(3) in reactor, add the Sodium O-formylcefamole 10.5g of ethyl lactate 80ml and above-mentioned preparation, stir and be warming up to 30 DEG C.Entirely molten after 2h, hold over night under mixture 0-5 DEG C condition, there is a large amount of crystal to separate out, continue under 0-5 DEG C of condition to stir 3h, stir 1h again under-5 DEG C of conditions, suction filtration, the cold ethyl lactate 20ml of filter cake washes 2 times, wash 4 times with ether 30ml, remove unnecessary ethyl lactate, dry.Added in ethanol 80ml by dry thing, room temperature stirs 40min slowly, suction filtration, and 40 DEG C of vacuum-dryings obtain preparation of fine cefamandole nafate 9.45g.
The X-ray powder diffraction pattern of embodiment 2 product, at 6.67 °, 12.27 °, 13.36 °, 16.03 °, 18.92 °, 19.98 °, 20.39 °, locates indicating characteristic diffraction peaks for 26.19 °.
Embodiment 3: the preparation of Sodium O-formylcefamole crystal compound
(1) add 7-ATCA11.4g and methylene dichloride 100ml in reactor successively, stir 10min; Continue progressively to add BSA15ml in above-mentioned solution; At 25 ~ 30 DEG C of reaction 3h, cool to-5 ~-10 DEG C; Slow dropping 20.5g formyl mandelic acid chloride (being dissolved in 60ml ethyl acetate), after dropwising, is warmed up to 0 ~ 5 DEG C of reaction 3h.The deionized water 200ml of about 15 DEG C, sodium-acetate 200g is added in above-mentioned reactor; Stir 30min, leave standstill 30min layering; Water layer is separated, and adds 50ml saturated nacl aqueous solution again in organic layer, stirs 15min, merges organic layer.In organic layer, add 20.4g anhydrous magnesium sulfate, stir dehydration 60min; Add 2g gac again, stir decolouring 30min; Filter, filtrate puts vacuum-drying under 30 DEG C of conditions, obtains the solidliquid mixture of Cefamandole acid.。
(2) in above-mentioned solidliquid mixture, Sodium isooctanoate 25g, Virahol 100ml is added, control temperature 15 ~ 20 DEG C, stirred crystallization 1h, filter, with acetone/ethanol (1:1) the solution washing filter cake of 50ml, vacuum-drying temperature 33 DEG C, is dried to sampling survey moisture and is less than < 1.0%, obtain Sodium O-formylcefamole crude product.
(3) in reactor, add the Sodium O-formylcefamole 11.2g of ethyl lactate 80ml and above-mentioned preparation, stir and be warming up to 30 DEG C.Entirely molten after 2h, hold over night under mixture 10 ~ 15 DEG C of conditions, there is a large amount of crystal to separate out, continue under 10 ~ 15 DEG C of conditions to stir 3h, stir 1h again under-5 DEG C of conditions, suction filtration, the cold ethyl lactate 20ml of filter cake washes 2 times, wash 4 times with ether 30ml, remove unnecessary ethyl lactate, dry.Added in ethanol 80ml by dry thing, room temperature stirs 60min slowly, suction filtration, and 40 DEG C of vacuum-dryings obtain preparation of fine cefamandole nafate 9.97g.
The X-ray powder diffraction pattern of embodiment 3 product, at 6.67 °, 12.27 °, 13.36 °, 16.03 °, 18.92 °, 19.98 °, 20.39 °, locates indicating characteristic diffraction peaks for 26.19 °.
Embodiment 4: the preparation of cefamandole nafate for inj
Prepare Sodium O-formylcefamole crystal compound according to the step of embodiment 1, adopt this raw material to prepare cefamandole nafate for inj, specification 0.5g.
Prescription:
Preparation process:
(1) get the raw materials ready: after bulk drug content and moisture conversion, take Sodium O-formylcefamole by recipe quantity;
(2) packing: be sub-packed in the cillin bottle cleaning also dry sterilization under the protection of filling nitrogen, tamponade;
(3) lid is rolled;
Comparative example 1: the preparation of Cefamandole nafate compounds
According to the process for purification described in Chinese patent CN101279979, purifying is carried out to the Sodium O-formylcefamole of the purity 92% obtained according to US4351947.100g Sodium O-formylcefamole crude product high speed adverse current chromatogram is carried out three separation and purification, high speed adverse current chromatogram adopts the solvent system being formed stationary phase, moving phase with trichloromethane, ethyl acetate, first alcohol and water, upper is stationary phase mutually, and lower is moving phase mutually, obtains Sodium O-formylcefamole highly finished product 87g.
Comparative example 2: the preparation of cefamandole nafate for inj
Get comparative example 1 and prepare Cefamandole nafate compounds, adopt this raw material to prepare cefamandole nafate for inj, specification 0.5g.
Prescription:
Preparation process:
(1) get the raw materials ready: after bulk drug content and moisture conversion, take Sodium O-formylcefamole by recipe quantity;
(2) packing: be sub-packed in the cillin bottle cleaning also dry sterilization under the protection of filling nitrogen, tamponade;
(3) lid is rolled;
Test example 1:
The present inventor has carried out purity detecting to Cefamandole nafate compounds prepared by the embodiment of the present invention 1 and comparative example 1.
Purity detecting result:
Result: the Cefamandole nafate compounds that Sodium O-formylcefamole crystal compound purity prepared by the present invention is prepared apparently higher than prior art.
Test example 2:
The present inventor is studied the mobility of Cefamandole nafate compounds prepared by the embodiment of the present invention 1 and comparative example 1.Slope of repose detection method is that particle is placed in fixing funnel, makes it freely drop down onto on horizontal plane, forms the disc accumulation body that a bottom radius is r, and the height measuring accumulation body is H, calculates according to formula tan θ=H/r.
Slope of repose detected result:
| Embodiment | Height H | Radius r | Slope of repose θ |
| Embodiment 1 | 30mm | 58.2mm | 27.3° |
| Comparative example 1 | 30mm | 43.6mm | 34.5° |
Result: the mobility of Sodium O-formylcefamole crystal compound prepared by the present invention, apparently higher than the Cefamandole nafate compounds of prior art, in the preparation process of preparation, can meet the needs of preparation method.
Test example 3:
The present inventor has carried out accelerated stability to cefamandole nafate for inj prepared by the embodiment of the present invention 4 and comparative example 2 and has investigated test.Investigation condition is temperature 40 DEG C ± 2 DEG C, relative humidity 75% ± 5%.Place 6 months, respectively at sampling at 0,1,2,3,6 the end of month.Inspection target is proterties, solution colour, visible foreign matters, acidity, content and related substance.
Accelerated test investigates result:
Result: embodiment and comparative example product place 6 months at the conditions of the experiments described above, content and related substance and other indices all conform with the regulations, and quality is more stable.Embodiment content and related substance are all little compared with comparative example change.
Sodium O-formylcefamole crystal compound of the present invention and preparation thereof are investigated through indices inspection and accelerated test and are shown good stability, reliable in quality.
Claims (10)
1. a Sodium O-formylcefamole crystal compound, it is characterized in that, the X-ray powder diffraction pattern represented with 2 θ diffraction angle is at 6.67 ° ± 0.2 °, 12.27 ° ± 0.2 °, 13.36 ° ± 0.2 °, 16.03 ° ± 0.2 °, 18.92 ° ± 0.2 °, 19.98 ° ± 0.2 °, 20.39 ° ± 0.2 °, 26.19 ° ± 0.2 ° place's indicating characteristic diffraction peak.
2. a kind of Sodium O-formylcefamole crystal compound as claimed in claim 1, it is characterized in that, preparation method's concrete steps are:
(1) be dissolved in methylene dichloride by 7-ATCA, under whipped state, in above-mentioned solution, add N, the two trimethylsilyl ethanamide (BSA) of O-, stirring reaction, cools to-5-10 DEG C; The ethyl acetate solution of slow dropping formyl mandelic acid chloride, reacts complete, in above-mentioned reactor, add deionized water and sodium-acetate, stirs, stratification; Get organic layer and add saturated nacl aqueous solution, merge organic layer; Reagent 1 is added in organic layer; Add activated carbon decolorizing again, filter, dry, obtain the solidliquid mixture of Cefamandole acid;
(2) in above-mentioned solidliquid mixture, add Sodium isooctanoate and Virahol, stirred crystallization, filter, with acetone/ethanol mixing solutions washing leaching cake, vacuum-drying, obtains Sodium O-formylcefamole;
(3) add in ethyl lactate by the Sodium O-formylcefamole of above-mentioned preparation, stirring and dissolving, hold over night, suction filtration, filter cake cold ethyl lactate and ether wash for several times successively respectively, remove unnecessary ethyl lactate, dry; Add in ethanol by dry thing, stirring at room temperature, suction filtration, vacuum-drying obtains preparation of fine cefamandole nafate.
3. a kind of method preparing Sodium O-formylcefamole crystal compound as claimed in claim 2, is characterized in that the weight ratio of described 7-ATCA and formyl mandelic acid chloride is 1:0.5 ~ 1:2.
4. a kind of method preparing Sodium O-formylcefamole crystal compound as claimed in claim 2, is characterized in that described reagent 1 is the one in magnesium sulfate, sodium sulfate or sodium-chlor.
5. a kind of method preparing Sodium O-formylcefamole crystal compound as claimed in claim 2, is characterized in that the ratio of described acetone/ethanol is 1:1 ~ 3:1.
6. a kind of method preparing Sodium O-formylcefamole crystal compound as claimed in claim 2, is characterized in that drying temperature in described step (2) is for being no more than 40 DEG C.
7. a kind of method preparing Sodium O-formylcefamole crystal compound as claimed in claim 2, is characterized in that being dried to moisture < 2.0% in described step (2).。
8. a kind of method preparing Sodium O-formylcefamole crystal compound as claimed in claim 2, is characterized in that in described step (3), hold over night temperature is 0 ~ 15 DEG C.
9. a kind of method preparing Sodium O-formylcefamole crystal compound as claimed in claim 2, it is characterized in that in described step (3) that dry thing adds churning time after in ethanol is 20 ~ 60min.
10. a cefamandole nafate for inj, is characterized in that its Sodium O-formylcefamole crystal compound containing Sodium O-formylcefamole crystal compound according to claim 1 or the preparation method described in claim 2 ~ 9 any one and obtain.
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