CN105646534A - Novel-crystal-form cefathiamidine compound adopting crystal product molecular assembly and form optimization technology in particle process and preparation - Google Patents
Novel-crystal-form cefathiamidine compound adopting crystal product molecular assembly and form optimization technology in particle process and preparation Download PDFInfo
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- CN105646534A CN105646534A CN201610091167.2A CN201610091167A CN105646534A CN 105646534 A CN105646534 A CN 105646534A CN 201610091167 A CN201610091167 A CN 201610091167A CN 105646534 A CN105646534 A CN 105646534A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—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, cefaclor, or cephalexine
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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
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/28—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by an aliphatic carboxylic acid, which is substituted by hetero atoms
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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
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- C—CHEMISTRY; METALLURGY
- 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
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention discloses a novel-crystal-form cefathiamidine compound and a crystallization preparation method thereof. The novel-crystal-form cefathiamidine compound is prepared with a crystal product molecular assembly and form optimization technology in a particle process. The novel-crystal-form cefathiamidine compound has the characteristics of high purity, low impurity content, good flowability and good stability. Meanwhile, the invention further discloses cefathiamidine for a preparation, namely, cefathiamidine for injection, prepared from the cefathiamidine.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to a kind of cefathiamidine crystal compound adopting the assembling of particle process crystal product molecule and form optimisation technique and preparation.
Background technology
Cefathiamidine (Cefathiamidine) has another name called C-18, chemistry (6R by name, 7R)-3 [(acetoxyl group) methyl]-7-[��-(N, N'-diisopropylamidinateand sulfenyl)-acetylamino] 8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-formic acid betaine, molecular formula is C19H28N4O6S2, molecular weight is 472.59, and its chemical structural formula is:
Cefathiamidine is by the beta-lactam antibiotic of the common independent research of Shanghai Institute of Pharmaceutical Industry and Baiyunshan Pharmaceutics Stock-sharing Co., Ltd., Guangzhou City, gram positive bacteria is had stronger antibacterial action, particularly enterococcus there is is unique curative effect, use extensively clinically.
Cefathiamidine has the unique molecular structure of amphion inner salt, heat, chance light, chance moist lability, easily decomposes variable color. Cefathiamidine uses bromoacetyl bromide in building-up process, if dealt with improperly, easily remains bromide ion in the product. In addition in the condensation reaction, solvent system selects bad, not easily removes impurity, causes content in crude product low. Cefathiamidine compound on domestic market, its purity is poor, and color level is bad, poor stability, thus have impact on its quality of the pharmaceutical preparations.
The less stable of cefathiamidine routine crystal formation, heat, meta-acid environment, meta-alkali environment is all unstable, show that outward appearance is easy to change, content reduces, the problems such as catabolite occurs. Solving this problem and must research and develop novel crystallization production technology, to optimize the process parameters such as solvent, temperature, response time, additive, making crystallization carry out under the suitable conditions, thus obtaining the cefathiamidine crystal formation that a kind of quality is relatively reliable.
Particle process crystal product molecule assembles and form optimisation technique, it is intended to for the requirement that specific functional product form optimizes, and carries out molecular assembly and assembles with regularly arranged.
Present invention is generally directed to the problem above that cefathiamidine compound exists, to solvent in crystal formation process, temperature, external force, on the basis that the factors such as additive are fully investigated, adopt particle process crystal product molecule to assemble and obtain a kind of purity height with form optimisation technique, color level is good, good fluidity, the cefathiamidine crystal compound of good stability, the more conventional preparation process of this synthesis step more focuses on the control of the 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 to industrial-scale production. utilizing the preparation that heretofore described compound is made, more conventional preparation has better stability.
Summary of the invention
The first object of the present invention is in that to provide a kind of cefathiamidine crystal compound, and this compound adopts particle process crystal product molecule to assemble and the preparation of form optimisation technique, has that purity height, color level be good, the feature of good stability.
Cefathiamidine crystal compound X-ray powder diffraction of the present invention measures, the X-ray powder diffraction pattern represented with the 2 �� angles of diffraction is at 8.82 �� �� 0.2 ��, 11.39 �� �� 0.2 ��, 16.94 �� �� 0.2 ��, 17.72 �� �� 0.2 ��, 18.79 �� �� 0.2 ��, 21.09 �� �� 0.2 ��, 21.64 �� �� 0.2 ��, 24.65 �� �� 0.2 �� place's display characteristic diffraction peak. As shown in Figure 1.
Cefathiamidine crystal compound of the present invention preparation comprises the following steps:
(1) N, N '-diisopropyl sulfur adds in dichloromethane, and stirring and dissolving is added thereto to bromacetamido Cephalosporanic acid and enters triethylamine, insulation reaction, is down to reaction temperature to 0 DEG C of insulation crystallize, forms crystal solution, sucking filtration, washing with acetone, vacuum drying obtains cefathiamidine crude product;
(2) being dissolved in water for injection by cefathiamidine crude product, medicinal charcoal decolours, and adopts sterilizing filter to be filtered destaining solution, regulate filtrate pH value with reagent 1, in filtrate, add isopropanol, crystallization, with washing with acetone, with ethanol for solvent, recrystallization must refine cefathiamidine.
Preferably, in above-mentioned preparation method, described N, N ' weight ratio of-diisopropyl sulfur and bromacetamido Cephalosporanic acid is 1:1��1:3; It is highly preferred that weight ratio is 1:2.
Preferably, in above-mentioned preparation method, the insulation reaction temperature in described step (1) is 30��50 DEG C. It is highly preferred that reaction temperature is 45 DEG C.
Preferably, in above-mentioned preparation method, in described step (1), recrystallization temperature is 0��10 DEG C. It is highly preferred that temperature is 5 DEG C.
Preferably, in above-mentioned preparation method, the reagent 1 in described step (2) is the one in hydrochloric acid, formic acid, glacial acetic acid. It is highly preferred that reagent 1 is hydrochloric acid.
Preferably, in above-mentioned preparation method, described step (2) adjust pH to be 3��5 with reagent 1. It is highly preferred that pH is 4��4.5.
The second object of the present invention is in that to provide a kind of preparation comprising cefathiamidine compound of the present invention, and said preparation has better stability compared with conventional product and side effect is little.
Above-mentioned prepared cefathiamidine crystal compound is mainly carried out aseptic subpackaged by the preparation of cefathiamidine preparation of the present invention.
Accompanying drawing explanation
Fig. 1: the X-ray powder diffraction pattern of cefathiamidine crystal compound, the 2 �� values that in figure, diffraction maximum numbering is corresponding are referring to table 1.
Detailed description of the invention
Following by detailed description of the invention, the present invention will be further described; but therefore do not limit the present invention in described scope of embodiments, it should be understood by those skilled in the art that the equivalent replacement that present invention is done; or be correspondingly improved, still fall within protection scope of the present invention.
Embodiment 1: the preparation of cefathiamidine crystal compound
(1) N, N '-diisopropyl sulfur 5.0g adds in 120mL dichloromethane, stirring and dissolving, it is added thereto to bromacetamido Cephalosporanic acid 10.1g and enters triethylamine 3g, 45 DEG C of insulation reaction 1.5h, are down to reaction temperature to 5 DEG C of insulation crystallize 1h, form crystal solution. Sucking filtration, washing with acetone 2 times, each 20ml, 40 DEG C of vacuum dryings obtain cefathiamidine crude product 9.4g.
(2) in reactor, add water for injection 50ml and cefathiamidine 5.0g, stirring and dissolving, add 0.1g medicinal charcoal, stirring decolouring 30min, adopts sterilizing filter to be filtered destaining solution, and regulating filtrate pH value with hydrochloric acid is 4.1, isopropanol 200ml is added in filtrate, it is cooled to 0��5 DEG C, stirs 1 hour, crystallization, with washing with acetone 2 times, each 50ml, with ethanol for solvent, recrystallization obtains cefathiamidine 4.4g.
X-ray powder diffraction (XRPD) is adopted to study and characterize the new crystal form of Cefuroxime Sodium.
Instrument and equipment: EMPYREAN (sharp shadow) X-ray diffractometer (Panalytical company of Holland).
Measurement result: the X-ray powder diffraction pattern of embodiment 1 cefathiamidine represents at 8.82 �� with the 2 �� angles of diffraction, 11.39 ��, 16.94 ��, 17.72 ��, 18.79 ��, 21.09 ��, 21.64 ��, 24.65 �� of place's display characteristic diffraction peaks. Referring specifically to Figure of description 1.
The concrete data of described XRPD diffraction are shown in following table:
Table 1 cefathiamidine crystal formation
Numbering | D value | 2��(��) | I/I0% |
1 | 10.03 | 8.82 | 23.11 |
2 | 7.77 | 11.39 | 82.63 |
3 | 5.24 | 16.94 | 56.65 |
4 | 5.01 | 17.72 | 19.74 |
5 | 4.72 | 18.79 | 63.72 |
6 | 4.21 | 21.09 | 58.04 |
7 | 4.11 | 21.64 | 100.00 |
8 | 3.61 | 24.65 | 16.46 |
Embodiment 2: the preparation of cefathiamidine crystal compound
(1) N, N '-diisopropyl sulfur 10.2g adds in 120mL dichloromethane, stirring and dissolving, it is added thereto to bromacetamido Cephalosporanic acid 10.1g and enters triethylamine 3.1g, 50 DEG C of insulation reaction 1.5h, are down to reaction temperature to 0 DEG C of insulation crystallize 1h, form crystal solution. Sucking filtration, washing with acetone 2 times, each 20ml, 40 DEG C of vacuum dryings obtain cefathiamidine crude product 10.5g.
(2) in reactor, add water for injection 50ml and cefathiamidine 5.5g, stirring and dissolving, add 0.1g medicinal charcoal, stirring decolouring 30min, adopts sterilizing filter to be filtered destaining solution, and regulating filtrate pH value with hydrochloric acid is 3.5, isopropanol 200ml is added in filtrate, it is cooled to 0��5 DEG C, stirs 1 hour, crystallization, with washing with acetone 2 times, each 50ml, with ethanol for solvent, recrystallization obtains cefathiamidine 4.8g.
The X-ray powder diffraction pattern of embodiment 2 cefathiamidine represents at 8.82 �� with the 2 �� angles of diffraction, 11.39 ��, 16.94 ��, 17.72 ��, 18.79 ��, 21.09 ��, 21.64 ��, 24.65 �� of place's display characteristic diffraction peaks.
Embodiment 3: the preparation of cefathiamidine crystal compound
(1) N, N '-diisopropyl sulfur 5.4g adds in 120mL dichloromethane, stirring and dissolving, it is added thereto to bromacetamido Cephalosporanic acid 15.3g and enters triethylamine 4.0g, 50 DEG C of insulation reaction 1.5h, are down to reaction temperature to 0 DEG C of insulation crystallize 1h, form crystal solution. Sucking filtration, washing with acetone 2 times, each 20ml, 40 DEG C of vacuum dryings obtain cefathiamidine crude product 5.4g.
(2) in reactor, add water for injection 50ml and cefathiamidine 5.1g, stirring and dissolving, add 0.1g medicinal charcoal, stirring decolouring 30min, adopts sterilizing filter to be filtered destaining solution, and regulating filtrate pH value with hydrochloric acid is 5.5, isopropanol 200ml is added in filtrate, it is cooled to 0��5 DEG C, stirs 1 hour, crystallization, with washing with acetone 2 times, each 50ml, with ethanol for solvent, recrystallization obtains cefathiamidine 4.6g.
The X-ray powder diffraction pattern of embodiment 3 cefathiamidine represents at 8.82 �� with the 2 �� angles of diffraction, 11.39 ��, 16.94 ��, 17.72 ��, 18.79 ��, 21.09 ��, 21.64 ��, 24.65 �� of place's display characteristic diffraction peaks.
Embodiment 4: the preparation of Cefathiamidine for injection
Prepare cefathiamidine crystal compound according to the step of embodiment 1, adopt this raw material to prepare Cefathiamidine for injection, specification 0.5g.
Prescription:
Preparation process:
(1) get the raw materials ready: after converting according to crude drug content and moisture, weigh cefathiamidine by recipe quantity;
(2) subpackage: be sub-packed under the protection of nitrogen charging and clean and in the cillin bottle of dry sterilization, tamponade;
(3) lid is rolled;
Comparative example 1: the preparation of cefathiamidine compound
Method described in CN104530082A prepares cefathiamidine compound.
Preparation process:
Triethanolamine 100g is joined stirring and dissolving in 140g acetone, it is subsequently added into deionized water 30g, stirring and dissolving, keep solution temperature 26 DEG C, it is gradually added cefathiamidine crude product 250g (purity 92.3%) again to react, after stirring and dissolving, continue stirring 20min, mixed liquor is dripped in 30g acetone, precipitate out white precipitate, filter, with 650ml washing with acetone secondary, filter, drying under reduced pressure, drying under reduced pressure temperature is 32 DEG C, and the drying under reduced pressure time is 4h, obtains cefathiamidine triethanolamine salt 284g.
By cefathiamidine triethanolamine salt 284g, join in the mixed solvent of 100g water and 700g isopropanol, under agitation with the salt acid for adjusting pH of concentration 4% to 4.6, add activated carbon 16.8g at 26 DEG C of temperature decolouring 35min, filter, filtrate is added 436.7g isopropanol carries out crystallize, once lower the temperature with 0.8 DEG C/min, be stirred with the mixing speed of 35rpm simultaneously. After being cooled to 4 DEG C, reducing temperature twice is carried out to-3 DEG C with 0.3 DEG C/min, it is stirred with the mixing speed of 65rpm simultaneously, keeps temperature stirring and crystallizing 1.5h after completing reducing temperature twice, filter, with 700ml washing with acetone three times, draining, drying under reduced pressure, drying under reduced pressure temperature is 26 DEG C, the drying under reduced pressure time is 5h, obtains highly purified cefathiamidine compound 195g.
Comparative example 2: the preparation of Cefathiamidine for injection
Take comparative example 1 and prepare cefathiamidine compound, adopt this raw material to prepare Cefathiamidine for injection, specification 0.5g.
Prescription:
Preparation process:
(1) get the raw materials ready: after converting according to crude drug content and moisture, weigh cefathiamidine by recipe quantity;
(2) subpackage: be sub-packed under the protection of nitrogen charging and clean and in the cillin bottle of dry sterilization, tamponade;
(3) lid is rolled;
Test example 1:
Cefathiamidine compound prepared by the embodiment of the present invention 1 and comparative example 1 has been carried out purity detecting by the present inventor. Purity detecting result is shown in following table:
Table 2 purity detecting result
Result: the cefathiamidine compound that cefathiamidine crystal compound purity prepared by the present invention is prepared apparently higher than prior art.
Test example 2:
The mobility of cefathiamidine prepared by the embodiment of the present invention 1 and comparative example 1 has been studied by the present inventor. Angle of repose, detection method was be placed in by granule in fixing funnel so that it is freely drop down onto on horizontal plane, formed the disc accumulation body that a bottom radius is r, and the height measuring accumulation body is H, calculated according to formula tan ��=H/r. Angle of repose, testing result was shown in following table:
Table 3 testing result angle of repose
Embodiment | Height H | Radius r | Angle of repose �� |
Embodiment 1 | 30mm | 59.0mm | 27.0�� |
Comparative example 1 | 30mm | 44.6mm | 33.9�� |
Result: the mobility of cefathiamidine crystal compound prepared by the present invention is apparently higher than the cefathiamidine compound of prior art, in the preparation process of preparation, it is possible to meet the needs of preparation method.
Test example 3:
Cefathiamidine for injection prepared by the embodiment of the present invention 4 and comparative example 2 has been carried out accelerated stability and has investigated test by the present inventor. Investigation condition is temperature 40 DEG C �� 2 DEG C, relative humidity 75% �� 5%. Place 6 months, sample respectively at 0,1,2,3,6 the end of month. Inspection target is character, visible foreign matters, acidity, content and has related substance. Accelerated test is investigated result and is seen following table:
Table 4 accelerated test investigates result
Result: embodiment and comparative example product are placed 6 months at the conditions of the experiments described above, content and have related substance and other indices all to meet regulation, quality is more stable. Embodiment content and have related substance compared with comparative example change little.
The cefathiamidine 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 (8)
1. a cefathiamidine crystal compound, it is characterized in that, the X-ray powder diffraction pattern represented with the 2 �� angles of diffraction is at 8.82 �� �� 0.2 ��, 11.39 �� �� 0.2 ��, 16.94 �� �� 0.2 ��, 17.72 �� �� 0.2 ��, 18.79 �� �� 0.2 ��, 21.09 �� �� 0.2 ��, 21.64 �� �� 0.2 ��, 24.65 �� �� 0.2 �� place's display characteristic diffraction peak.
2. a kind of cefathiamidine crystal compound as claimed in claim 1, it is characterised in that preparation method concretely comprises the following steps:
(1) N, N '-diisopropyl sulfur adds in dichloromethane, and stirring and dissolving is added thereto to bromacetamido Cephalosporanic acid and enters triethylamine, insulation reaction, is down to reaction temperature to 0 DEG C of insulation crystallize, forms crystal solution, sucking filtration, washing with acetone, vacuum drying obtains cefathiamidine crude product;
(2) being dissolved in water for injection by cefathiamidine crude product, medicinal charcoal decolours, and adopts sterilizing filter to be filtered destaining solution, regulate filtrate pH value with reagent 1, in filtrate, add isopropanol, crystallization, with washing with acetone, with ethanol for solvent, recrystallization must refine cefathiamidine.
3. a kind of method preparing cefathiamidine crystal compound as claimed in claim 2, it is characterised in that the weight ratio of N, the N in step (1) '-diisopropyl sulfur and bromacetamido Cephalosporanic acid is 1:1��1:3.
4. a kind of method preparing cefathiamidine crystal compound as claimed in claim 2, it is characterised in that the insulation reaction temperature in step (1) is 30��50 DEG C.
5. a kind of method preparing cefathiamidine crystal compound as claimed in claim 2, it is characterised in that the recrystallization temperature in step (1) is 0��10 DEG C.
6. a kind of method preparing cefathiamidine crystal compound as claimed in claim 2, it is characterised in that the reagent 1 in step (2) is the one in hydrochloric acid, formic acid, glacial acetic acid.
7. a kind of method preparing cefathiamidine crystal compound as claimed in claim 2, it is characterised in that adjust pH to be 3��5 with reagent 1 in step (2).
8. a Cefathiamidine for injection, it is characterised in that it contains the cefathiamidine crystal compound that the cefathiamidine crystal compound described in claim 1 or the preparation method described in claim 2��7 any one prepare.
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WO2017140073A1 (en) * | 2016-02-18 | 2017-08-24 | 海南灵康制药有限公司 | Cefathiamidine novel crystal compound using particle process crystal product molecular assembly and morphology optimisation technology and formulation thereof |
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