CN106565821A - N(2)-L-alanyl-L-glutamine novel crystal form and preparing method thereof - Google Patents
N(2)-L-alanyl-L-glutamine novel crystal form and preparing method thereof Download PDFInfo
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- CN106565821A CN106565821A CN201610861653.8A CN201610861653A CN106565821A CN 106565821 A CN106565821 A CN 106565821A CN 201610861653 A CN201610861653 A CN 201610861653A CN 106565821 A CN106565821 A CN 106565821A
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- 239000013078 crystal Substances 0.000 title claims abstract description 81
- 238000000034 method Methods 0.000 title claims abstract description 31
- 108010044940 alanylglutamine Proteins 0.000 title abstract description 14
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 title abstract description 13
- 238000002347 injection Methods 0.000 claims abstract description 11
- 239000007924 injection Substances 0.000 claims abstract description 11
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 10
- 229910002483 Cu Ka Inorganic materials 0.000 claims abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 67
- 239000007788 liquid Substances 0.000 claims description 54
- 238000001914 filtration Methods 0.000 claims description 47
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- 239000000243 solution Substances 0.000 claims description 25
- 239000012043 crude product Substances 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 23
- 238000004042 decolorization Methods 0.000 claims description 20
- 238000001179 sorption measurement Methods 0.000 claims description 20
- 239000008215 water for injection Substances 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 16
- 238000005406 washing Methods 0.000 claims description 16
- 238000002425 crystallisation Methods 0.000 claims description 14
- 230000008025 crystallization Effects 0.000 claims description 14
- 239000000463 material Substances 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 9
- 230000001954 sterilising effect Effects 0.000 claims description 9
- 238000007664 blowing Methods 0.000 claims description 7
- 239000003610 charcoal Substances 0.000 claims description 7
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 6
- 239000011229 interlayer Substances 0.000 claims description 6
- 230000001186 cumulative effect Effects 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 2
- 239000002245 particle Substances 0.000 abstract description 6
- 238000009826 distribution Methods 0.000 abstract description 5
- 230000005855 radiation Effects 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 238000007670 refining Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 description 18
- 239000012065 filter cake Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229960002648 alanylglutamine Drugs 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- -1 Amide compound Chemical class 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000005286 illumination Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 229910052719 titanium Inorganic materials 0.000 description 4
- 239000010936 titanium Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 235000016236 parenteral nutrition Nutrition 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 206010020674 Hypermetabolism Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 102000008934 Muscle Proteins Human genes 0.000 description 1
- 108010074084 Muscle Proteins Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000001980 alanyl group Chemical group 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention belongs to the technical field of medicines and particularly relates to an N(2)-L-alanyl-L-glutamine novel crystal form and a preparing method thereof. Cu-Ka radiation is used, and X-ray powder diffraction expressed through the 2theta angle has the characteristic peak at the angles of 13.76, 15.58, 18.58, 18.72, 19.66, 20.72, 21.34, 21.42, 21.70, 22.52, 23.28, 23.34, 24.12, 24.86, 25.54, 26.12, 27.66, 30.46, 30.64, 32.56, 33.10, 34.26, 34.62, 34.86, 36.60, 36.90 and 37.48 (+/-0.1 degrees). The N(2)-L-alanyl-L-glutamine novel crystal form obtained through refining in the method is good in crystal form, higher in bulk density, even in particle size distribution, not likely to absorb moisture and convenient to store; in addition, the crystal purity is high, the organic residual quantity is small, clarity is good, and subsequent processing of products is better facilitated; and meanwhile the safety of N(2)-L-alanyl-L-glutamine used for injection is improved.
Description
Technical field
The invention belongs to pharmaceutical technology field, specifically, is related to a kind of N (2)-Ala-Gln newly brilliant
Type and preparation method thereof.
Background technology
N (2)-Ala-Gln molecular formula is C8H15N3O4, and molecular weight is 217.22, and structural formula is：
N (2)-Ala-Gln is an ingredient of parenteral nutrition, it is adaptable to require supplementation with glutamy
The patient of amine, including the patient in catabolism and hypermetabolism situation.Such as：Wound, burn, big-and-middle-sized Post operation, bone marrow and
Other organs transplanting, gastrointestinal tract syndrome, tumor, severe infections and other ICU patients in stress state.
The eighties in 20th century, Germany professor PeterFurst proposed the concept of double peptides, i.e., be used as paddy by double peptides of synthesis
The donor of glutamine is the preferable succedaneum of human body glutamine, and is developed in nineteen ninety-five as parenteral nutrition medication.Because of it
Can naturally dissolve in water, and be resistant to 121 DEG C of heat sterilizations and do not decompose；So as to effectively overcome glutamine in parenteral battalion
Use shortcoming in supporting.The glutamine of vein input be hydrolyzed to rapidly in the presence of the double peptidase of glutamy alanine and
Glutamine, and it is fully absorbed utilization.So the medicine has promotes muscle protein synthesis, improve the clinic of critical patient with
Biochemical indicator；Function of intestinal canal, the composition of promotion organization is maintained to keep body nitrogen balance；Strengthen the effect such as immune system, exist at present
World's every country is widely used.
Patent CN201110384393.7 is provided the present invention relates to have the high-purity alanyl paddy ammonia of following structural formula
Amide compound and its preparation method, the preparation method is comprised the following steps：1, with N- (α-chlorine)-propiono-glutamine as raw material, select
Hydrazine compound is reacted at ambient pressure as aminating agent, and Alanyl-Glutamine crude product is obtained；2, at 0 DEG C to room temperature
At a temperature of, absolute methanol is added in Alanyl-Glutamine crude product, stir, sucking filtration removes methanol solution, obtains and contains third
The filter cake of aminoacyl glutamine；3, the filter cake containing Alanyl-Glutamine is soluble in water, and the aqueous solution for being obtained is warming up to not
Higher than 80 DEG C, keep certain hour to be concentrated, be subsequently adding ethanol, make aqueous solution be 1: 1～3 with the volume ratio of ethanol, and
Gradient reduces temperature, carries out recrystallization, obtains the Alanyl-Glutamine of purification.The target of very high purity is obtained by the method
Product, and then formulation products quality is optimized, toxic and side effects are reduced, it is ensured that the safety of clinical application, by second in the patent
Alcohol to be added and carry out gradient cooling again after aqueous solution, it is demonstrated experimentally that N (2)-L- alanyl-L- paddy ammonia prepared by the method recrystallization
Amide crystal has the following problems：Purity is low, Residual organic solvent is big, clarity difference the shortcomings of；Product hygroscopicity after crystallization is strong,
It is not easy to maintain；When carrying out illumination and hot test, relevant content of material incrementss are big, cause the probability of side effect larger.
In view of this it is special to propose the present invention.
The content of the invention
The technical problem to be solved in the present invention is to overcome the deficiencies in the prior art, there is provided a kind of N (2)-L- alanyl-L-
Glutamine novel crystal forms and preparation method thereof, the crystal habit is good, and heap density is higher, even particle size distribution, and crystal purity
High, Residual organic solvent is little, and clarity is good, is more beneficial for the following process of product；Hygroscopicity difference is easy to storage.
To solve above-mentioned technical problem, the present invention is using the basic conception of technical scheme：
A kind of N (2)-Ala-Gln novel crystal forms, are radiated using Cu-Ka, with the X-ray that 2 θ angles are represented
Powder diffraction 13.76,15.58,18.58,18.72,19.66,20.72,21.34,21.42,21.70,22.52,23.28,
23.34,24.12,24.86,25.54,26.12,27.66,30.46,30.64,32.56,33.10,34.26,34.62,
34.86,36.60,36.90,37.48 (± 0.1 degree) have characteristic peak, and it has powder x-ray diffraction figure as shown in Figure 1.
In the X-ray powder diffraction pattern, the diffraction spectrogram for being obtained by crystalline compounds is for specific crystal formation is often
Distinctive, wherein the relative intensity of bands of a spectrum (especially in low angle) may be because of crystallization condition, particle diameter and other measure
The difference of condition and the advantage orientation effect that produces and change.Therefore, the relative intensity of diffraction maximum to targeted crystal formation not
Distinctive, when judging whether identical with known crystal formation, it should be noted that the relative position at peak rather than they
Relative intensity.Generally represent peak position with 2 θ angles in the X-ray powder diffraction pattern.
The crystal formation of crystal prepared by the present invention has powder x-ray diffraction figure as shown in Figure 1.
The method for preparing above-mentioned N (2)-Ala-Gln novel crystal forms is：
Step (1) dissolves：It is permanent in taking the water for injection that N (2)-Ala-Gln crude product adds uniform temperature
Temperature stirring is until N (2)-Ala-Gln crude product is completely dissolved；
Step (2) decolorization adsorption：Keeping temperature is constant, and activated carbon is added in solution obtained in step (1), stirs one section
Time, obtain decolorization adsorption liquid；
Step (3) is filtered：Keeping temperature is constant, and decolorization adsorption liquid obtained in step (2) is filtered, and obtains aseptic essence
Filtrate；
Step (4) is crystallized：Aseptic fine straining liquid is placed in crystallization apparatus, with filtration temperature as initial temperature, in gradient drop
While warm in batches in the aseptic fine straining liquid obtained by step (3) add sterile alcohol make N (2)-L- alanyl-L- glutamy
Amine is crystallized, and obtains N (2)-Ala-Gln crystal solution；
Step (5):Under sterile conditions, crystal solution Jing is filtered, washing, drying process, obtain dry aseptic N (2)-
Ala-Gln crystal.
Add ethanol in the method in batches, and control the addition and method of ethanol, it is therefore intended that strict control is different
At a temperature of ethanol and water for injection proportioning, while the two act under, just can prepare the present invention novel crystal forms, make this new
The particle size distribution of crystal formation is more uniform, and heap density is higher；The residual quantity of organic solvent is little in crystal, and clarity is good；The novel crystal forms
Hygroscopicity difference be easy to storage；Under high temperature, illumination and super-humid conditions, relevant material increases few, and product content reduces little, property
It is more stable, using safer.
N (2)-Ala-Gln crude product weight described in step (1) is 1Kg with injection water weight ratio：2
～2.5Kg.
When claimed N (2)-Ala-Gln novel crystal forms of the invention are prepared, injection is strictly controlled
With the quality of water, the quality difference of water for injection, can change water for injection in crystallization process affects crystal formation with the proportioning of ethanol, real
It is 1Kg only in N (2)-Ala-Gln crude product weight and injection water weight ratio to issue after examination and approval existing：During 2～2.5Kg,
With reference to the claimed gradient cooling process of the present invention, claimed N (2)-L- alanyl-L- paddy of the invention can be obtained
Glutamine novel crystal forms.
N (2)-Ala-Gln crude product weight described in step (4) is 1kg with the volume ratio of sterile alcohol:
8～15L,
Preferably, N (2)-Ala-Gln crude product weight and the volume ratio of sterile alcohol are 1kg:10L.
By the addition volume of strict control ethanol, it is ensured that the N (2) in solution-Ala-Gln is all analysed
Go out, and the purity of crystal that the proportion relation of the solvent is obtained is high, and organic residue is little.
Gradient cooling process, the addition of sterile alcohol and feed postition in the step (4) is as follows：
First stage：Aseptic fine straining liquid squeeze into after crystallization apparatus open cooling, with filtration temperature as initial temperature, temperature with
7-9 DEG C/h of speed is uniformly down to 45-50 DEG C, the uniform Deca sterile alcohol in this temperature-fall period, adds sterile alcohol
Volume is the 1/3-1/2 of sterile alcohol cumulative volume；
Second stage：Temperature is uniformly down to 35-40 DEG C from 45-50 DEG C with 2-4 DEG C/h of speed, in this temperature-fall period
Uniform Deca sterile alcohol, adds the volume of sterile alcohol for the 1/4-1/3 of sterile alcohol cumulative volume；
Phase III：After second stage terminates, remaining sterile alcohol is disposably added in crystallization apparatus, has been fed
Bi Hou, temperature is uniformly down to 25-30 DEG C from 35-40 DEG C with 7-9 DEG C/h of speed, and then constant temperature is stirred 2～3 hours.
Above-mentioned temperature-fall period, the addition of sterile alcohol and feed postition are strictly controlled, being capable of the effective control novel crystal forms
Forming process, make the high crystal formation heap crystalline substance degree, even particle size distribution and purity high, and the novel crystal forms prepared with upper type
Clarity more preferably, meets the requirement of injection N (2)-Ala-Gln.
Water for injection is heated to into 70-80 DEG C, preferred 73-75 DEG C in the step (1).
Control at this temperature, can make N (2)-Ala-Gln dissolution velocity faster, and impurity therein is molten
Solution is limited, is more beneficial for consequent activities charcoal remove impurity.
The addition weight of activated carbon is the 0.5- of N (2)-Ala-Gln crude product weight in the step (2)
2%,
Preferably, the addition weight of activated carbon is the 1% of the N (2)-Ala-Gln crude product weight.
The addition of strict control activated carbon within the above range, can effectively remove the impurity in solution, and and energy
Reduce the loss of N (2)-Ala-Gln in solution.
Filtration in the step (3) is divided into three steps：De- charcoal is carried out to decolorization adsorption liquid initially with titanium rod, coarse filtration is obtained
Liquid；Again coarse filtration liquid is carried out into secondary filter by cartridge filter, further remove activated carbon, obtain fine straining liquid；Finally by essence
Filtrate carries out aseptic filtration by sterilizing filter, obtains aseptic fine straining liquid.
By filtering twice, reduce the residual of activated carbon, after remove impurity with active carbon, carry out sterilization while hot, it is degerming after
Solution when being crystallized, resulting novel crystal forms crystallization is more preferably, heap density is more preferable, organic residue is less.
The drying process of the step (5) be initially with certain pressure compressed air material is carried out it is pre- dry up, it is empty
Compressed air is closed after blowing a period of time, then is done by filtration washing drying machine vacuum system and interlayer circulation
It is dry, circulating water temperature is set as 50-60 DEG C, start timing when temperature of charge reaches preset temperature, keeping temperature is dried 10～
15 hours.
By way of first carrying out that pre-blowing is dry and being dried again, organic residue can be effectively reduced, shortening drying time, institute
The clarity of the crystal for obtaining is more preferable.
The compressed air pressure is 0.5-1.0MPa, and sky blows the time for 0.5-2.0 hours；
Preferably, compressed air pressure is 0.8MPa；Sky blew the time for 1.0 hours.
After above-mentioned technical proposal, the present invention has the advantages that compared with prior art：The method of the present invention
The N (2) being refining to obtain-Ala-Gln novel crystal forms crystal formation is good, and heap density is higher, even particle size distribution, and
Crystal purity is high, Residual organic solvent is little, and clarity is good, is more beneficial for the following process of product, at the same improve injection N (2)-
The safety of Ala-Gln.
The specific embodiment of the present invention is described in further detail below in conjunction with the accompanying drawings.
Description of the drawings
, used as the part of the present invention, for providing further understanding of the invention, the present invention's is schematic for accompanying drawing
Embodiment and its illustrate for explaining the present invention, but do not constitute inappropriate limitation of the present invention.Obviously, drawings in the following description
Only some embodiments, to those skilled in the art, on the premise of not paying creative work, can be with
Other accompanying drawings are obtained according to these accompanying drawings.In the accompanying drawings：
Fig. 1 is the X-ray diffraction spectrogram of N (2)-Ala-Gln novel crystal forms prepared by the present invention.
It should be noted that these accompanying drawings and word description are not intended as limiting the design model of the present invention by any way
Enclose, but be that those skilled in the art illustrate idea of the invention by reference to specific embodiment.
Specific embodiment
To make purpose, technical scheme and the advantage of the embodiment of the present invention clearer, below in conjunction with the embodiment of the present invention
In accompanying drawing, the technical scheme in embodiment is clearly and completely described, following examples be used for illustrate the present invention, but
It is not limited to the scope of the present invention.
Hereinafter the instrument and device used in experiment is through sterilization, it is ensured that aseptic shape is in instrument and device
State, N (2)-Ala-Gln crude product used in the present invention is to implement according in patent CN201110384393.7
Crude product Alanyl-Glutamine prepared by the method for example 6, it is 88.80% that Jing HPLC measure the content of Alanyl-Glutamine.
Embodiment one：
The preparation method of N (2)-Ala-Gln novel crystal forms is as follows：
Step (1) dissolves：Water for injection 162.5kg is added in the material-compound tank for having cleaned, material-compound tank stirring is opened, is opened
Heating system, by water for injection 73-75 DEG C is heated to, and N (2)-L- alanyl-L- are added in keeping temperature not break-in water for injection
Glutamine crude product 65kg, stirring is completely dissolved it；
Step (2) decolorization adsorption：Keeping temperature is constant, and activated carbon 0.65kg is added in solution obtained in step (1), stirs
Mix 20 minutes, obtain decolorization adsorption liquid；
(1) filter：The 3 μm of titanium rods of Jing first of decolorization adsorption liquid obtained in step (2) are carried out into de- charcoal, coarse filtration liquid is obtained；Again
Coarse filtration liquid is carried out into secondary filter by filtering holes for 0.45 μm of cartridge filter, activated carbon is further removed, fine straining liquid is obtained；
Finally fine straining liquid is carried out into aseptic filtration by 0.22 μm of sterilizing filter, obtain aseptic fine straining liquid；
(2) crystallize：Aseptic fine straining liquid is delivered in crystallizer, prepares 650.0L sterile alcohols, open cooling, first temperature
Degree is uniformly down to 50 DEG C with 8 DEG C/h of speed, the uniform Deca sterile alcohol in this temperature-fall period, adds sterile alcohol
Volume 325L；Afterwards temperature is uniformly down to 40 DEG C from 50 DEG C with 3 DEG C/h of speed, and uniform Deca is aseptic in this temperature-fall period
Ethanol, adds sterile alcohol 216L；Finally, remaining sterile alcohol is disposably added in crystallizer, after charging is finished, temperature
30 DEG C are uniformly down to from 40 DEG C with 8 DEG C/h of speed, then constant temperature is stirred 3 hours, obtain N (2)-L- alanyl-L- paddy ammonia
Amide crystal solution；
Crystallization bottom valve is opened, crystallizer compressed air is opened, crystal solution press-in filtration washing drying machine in tank is passed through
Filter cake is obtained after filter, after filter cake is washed into three times with sterile alcohol, open filtration washing drying machine compressed air is carried out to material
Dry up in advance, adjust compressed air pressure 0.8MPa, sky blows the time for 1.0 hours, after empty blowing beam compressed air is closed, opened
Filter washing drying machine vacuum system and interlayer circulation, set 60 DEG C of circulating water temperature, reach after 60 DEG C after temperature of charge,
Continue to be dried 15 hours, discharge aseptic N (the 2)-Ala-Gln crystal 55.8kg that must be dried.Using powder X-ray-
Ray diffraction method determines refined N (2)-Ala-Gln crystal formation, as a result sees Fig. 1, is radiated using Cu-Ka, with 2 θ
The X-ray powder diffraction that angle is represented 13.76,15.58,18.58,18.72,19.66,20.72,21.34,21.42,
21.70,22.52,23.28,23.34,24.12,24.86,25.54,26.12,27.66,30.46,30.64,32.56,
33.10,34.26,34.62,34.86,36.60,36.90,37.48 (± 0.1 degree) has characteristic peak.
Fusing point is 215.5-215.8 DEG C, and HPLC detection purity is 99.98%.
Embodiment two：The preparation method of N (2)-Ala-Gln novel crystal forms is as follows：
(1) dissolve：Water for injection 162.5kg is added in the material-compound tank for having cleaned, material-compound tank stirring is opened, heating is opened
System, by water for injection 73-75 DEG C is heated to, and N (2)-L- alanyl-L- paddy ammonia is added in keeping temperature not break-in water for injection
Crude amide 65kg, stirring is completely dissolved it；
(2) decolorization adsorption：Keeping temperature is constant, and activated carbon 0.65kg, stirring 20 are added in solution obtained in step (1)
Minute, obtain decolorization adsorption liquid；
(3) filter：The 3 μm of titanium rods of Jing first of decolorization adsorption liquid obtained in step (2) are carried out into de- charcoal, coarse filtration liquid is obtained；Again
Coarse filtration liquid is carried out into secondary filter by filtering holes for 0.45 μm of μm of cartridge filter, activated carbon is further removed, fine straining is obtained
Liquid；Finally fine straining liquid is carried out into aseptic filtration by 0.22 μm of sterilizing filter, obtain aseptic fine straining liquid；
(4) crystallize：Aseptic fine straining liquid is delivered in crystallizer, prepares 650.0L sterile alcohols, open cooling, first temperature
Degree is uniformly down to 50 DEG C with 8 DEG C/h of speed, the uniform Deca sterile alcohol in this temperature-fall period, adds sterile alcohol
Volume 216L；Afterwards temperature is uniformly down to 40 DEG C from 50 DEG C with 3 DEG C/h of speed, and uniform Deca is aseptic in this temperature-fall period
Ethanol, adds sterile alcohol 162.5L；Finally, remaining sterile alcohol is disposably added in crystallizer, after charging is finished,
Temperature is uniformly down to 30 DEG C from 40 DEG C with 8 DEG C/h of speed, and then constant temperature is stirred 3 hours, obtains N (2)-L- alanyl-L-
Glutamine crystal solution；
(5) crystallization bottom valve is opened, crystallizer compressed air is opened, by crystal solution press-in filtration washing drying machine in tank,
Filter cake is obtained after filtering, after filter cake is washed into three times with sterile alcohol, opens filtration washing drying machine compressed air to material
Carry out it is pre- dry up, adjust compressed air pressure 0.8MPa, sky blows the time for 1.0 hours, after empty blowing beam compressed air is closed, opens
Filtration washing drying machine vacuum system and interlayer circulation are opened, 60 DEG C of circulating water temperature is set, treats that temperature of charge reaches 60 DEG C
After, continue to be dried 15 hours, discharge aseptic N (the 2)-Ala-Gln crystal 55.2kg that must be dried.Using powder
Last X-ray diffraction method determines the crystal formation of N (2)-Ala-Gln.
Fusing point is 215.5-215.8 DEG C, and HPLC detection purity is 99.95%.
To the crystal formation of N (2)-Ala-Gln obtained in the embodiment also using Cu-Ka radiation detections its
X-ray powder diffraction pattern, it is basically identical with embodiment one.
Embodiment three：
The preparation method of N (2)-Ala-Gln novel crystal forms is as follows：
(1) dissolve：Water for injection 130kg is added in the material-compound tank for having cleaned, material-compound tank stirring is opened, heating system is opened
System, by water for injection 80 DEG C are heated to, and N (2)-Ala-Gln is added in keeping temperature not break-in water for injection
Crude product 65kg, stirring is completely dissolved it；
(2) decolorization adsorption：Keeping temperature is constant, and activated carbon 1.3Kg, stirring 20 are added in solution obtained in step (1)
Minute, obtain decolorization adsorption liquid；
(3) filter：The 3 μm of titanium rods of Jing first of decolorization adsorption liquid obtained in step (2) are carried out into de- charcoal, coarse filtration liquid is obtained；Again
Coarse filtration liquid is carried out into secondary filter by filtering holes for 0.22 μm of cartridge filter, activated carbon is further removed, fine straining liquid is obtained；
Finally fine straining liquid is carried out into aseptic filtration by two 0.22 μm of series connection of sterilizing filter, obtain aseptic fine straining liquid；
(4) crystallize：Aseptic fine straining liquid is delivered in crystallizer, prepares sterile alcohol 975L, open cooling, first temperature
45 DEG C are uniformly down to 9 DEG C/h of speed, the uniform Deca sterile alcohol in this temperature-fall period adds the body of sterile alcohol
Product 487.5L；Afterwards temperature is uniformly down to 35 DEG C from 45 DEG C with 4 DEG C/h of speed, and uniform Deca is aseptic in this temperature-fall period
Ethanol, the volume for adding sterile alcohol is 325L；Finally, remaining sterile alcohol is disposably added in crystallizer, has been fed
Bi Hou, temperature is uniformly down to 30 DEG C from 35 DEG C with 7 DEG C/h of speed, then keeps 30 DEG C of constant, constant temperature stirrings 3 hours, obtains
Obtain N (2)-Ala-Gln crystal solution；
(5) crystallization bottom valve is opened, crystallizer compressed air is opened, by crystal solution press-in filtration washing drying machine in tank,
Filter cake is obtained after filtering, after filter cake is washed into three times with sterile alcohol, opens filtration washing drying machine compressed air to material
Carry out it is pre- dry up, adjust compressed air pressure 0.5MPa, sky blows the time for 0.5 hour, after empty blowing beam compressed air is closed, opens
Filtration washing drying machine vacuum system and interlayer circulation are opened, 55 DEG C of circulating water temperature is set, treats that temperature of charge reaches 55 DEG C
After, continue to be dried 10 hours, discharge aseptic N (the 2)-Ala-Gln crystal 54.5kg that must be dried.
Fusing point is 215.4-216.0 DEG C, and HPLC detection purity is 99.92%.
To the crystal formation of N (2)-Ala-Gln obtained in the embodiment also using Cu-Ka radiation detections its
X-ray powder diffraction pattern, it is basically identical with embodiment one.
Example IV：
The preparation method of N (2)-Ala-Gln novel crystal forms is as follows：
(1) dissolve：Water for injection 162.5kg is added in the material-compound tank for having cleaned, material-compound tank stirring is opened, heating is opened
System, by water for injection 70 DEG C are heated to, and N (2)-L- alanyl-L- glutamy is added in keeping temperature not break-in water for injection
Amine crude product 65kg, stirring is completely dissolved it；
(2) decolorization adsorption：Keeping temperature is constant, and activated carbon 325g is added in solution obtained in step (1), stirs 20 points
Clock, obtains decolorization adsorption liquid；
(3) filter：The 3 μm of titanium rods of Jing first of decolorization adsorption liquid obtained in step (2) are carried out into de- charcoal, coarse filtration liquid is obtained；Again
Coarse filtration liquid is carried out into secondary filter by filtering holes for 0.1 μm of cartridge filter, activated carbon is further removed, fine straining liquid is obtained；
Finally fine straining liquid is carried out into aseptic filtration by 0.22 μm of sterilizing filter, obtain aseptic fine straining liquid；
(4) crystallize：Aseptic fine straining liquid is delivered in crystallizer, sterile alcohol 520L need to be added, open cooling, first temperature
Degree is uniformly down to 50 DEG C with 7 DEG C/h of speed, the uniform Deca sterile alcohol in this temperature-fall period, adds sterile alcohol
260L；Afterwards temperature is uniformly down to 35 DEG C from 45 DEG C with 2 DEG C/h of speed, uniform Deca sterile alcohol in this temperature-fall period,
The volume for adding sterile alcohol is 173.3L；Finally, remaining sterile alcohol is disposably added in crystallizer, charging is finished
Afterwards, temperature is uniformly down to 25 DEG C from 35 DEG C with 7 DEG C/h of speed, then keeps 25 DEG C of constant, constant temperature stirrings 2 hours, obtains
N (2)-Ala-Gln crystal solution；
(5) crystallization bottom valve is opened, crystallizer compressed air is opened, by crystal solution press-in filtration washing drying machine in tank,
Filter cake is obtained after filtering, after filter cake is washed into three times with sterile alcohol, opens filtration washing drying machine compressed air to material
Carry out it is pre- dry up, adjust compressed air pressure 1.0MPa, sky blows the time for 2 hours, after empty blowing beam compressed air is closed, and opens
Filtration washing drying machine vacuum system and interlayer circulation, set 50 DEG C of circulating water temperature, treat temperature of charge reach 50 DEG C with
Afterwards, continue to be dried 15 hours, discharge aseptic N (the 2)-Ala-Gln crystal 54.9kg that must be dried.
Fusing point is 215.3-215.8 DEG C, and HPLC detection purity is 99.95%.
To the crystal formation of N (2)-Ala-Gln obtained in the embodiment also using Cu-Ka radiation detections its
X-ray powder diffraction pattern, it is basically identical with embodiment one.
Comparative example：
Using identical N (2)-Ala-Gln crude product, according to the reality in patent CN201110384393.7
The subtractive process for applying example 6 is refined to crude product, and fusing point is 215.2-216.2 DEG C after refining, and HPLC detections purity is
99.58%.
Can be drawn by above-mentioned experiment, prepared by the process for purification of N (2)-Ala-Gln of the present invention
Crystal compared with comparative example, crystalline melting point that this method is obtained is concentrated, and purity more preferably, improves injection N (2)-L- third
The safety of aminoacyl-L-glutaminate.
Experimental example 1：Study on Hygroscopicity
The present invention is to N (the 2)-L- third prepared by embodiment one, embodiment two, embodiment three, example IV and comparative example
Aminoacyl-L-glutaminate hygroscopicity is investigated, and investigates condition relative humidity 75% (RH) with relative humidity 95.2% (RH), temperature
40 DEG C of degree, inspection target is the water content in N (2)-Ala-Gln, as shown in table 1.
Water content in the N of table 1 (2)-Ala-Gln
Have been found through experimentation that, the hygroscopicity of N (2)-Ala-Gln novel crystal forms prepared by the present invention is bright
Show N (the 2)-Ala-Gln prepared less than comparative example, the characteristic makes the novel crystal forms of present invention preparation be more convenient for storing up
Deposit, be more suitable for pharmaceutical preparation raw material.
The factors influencing of experimental example 2
N (the 2)-L- third that the present invention is refined to embodiment one, embodiment two, embodiment three, example IV and comparative example
Aminoacyl-L-glutaminate carries out factors influencing, investigates high temperature (60 DEG C ± 2 DEG C), illumination (4500Lx ± 500Lx) and high humidity
(92.5%RH), inspection target is content and relevant content of material, as shown in table 2.
The N of table 2 (2)-Ala-Gln content and relevant content of material
Experimental result shows that the novel crystal forms of N (the 2)-Ala-Gln prepared by the present invention are in above-mentioned height
Temperature, illumination, physics and chemistry form is more stable under super-humid conditions, illustrate this it is new be unlikely to deteriorate, stability more preferably, is more suitable for preparing injection
Preparation.
Under these conditions relevant material contains the novel crystal forms of N (the 2)-Ala-Gln prepared by the present invention
Amount increases few, and because relevant content of material is big, changing over conference makes the probability of product generation side effect big, it is seen that by this
Crystal formation prepared by inventive method is when injection preparation is prepared, and the probability that product produces side effect is little, using safer.
The clarity of test example 3, organic residue, loss on drying are investigated
The crystal formation that one-example IV of embodiment and comparative example prepare crystal comparison test is carried out into respectively, as a result such as table 3
It is shown：
The clarity of table 3, organic residue and loss on drying
| Inspection project | Clarity | Organic residue | Loss on drying |
| Embodiment one | 0.5# | 0.01% | 0.02% |
| Embodiment two | 0.5# | 0.02% | 0.03% |
| Embodiment three | 0.5# | 0.02% | 0.02% |
| Example IV | 0.5# | 0.02% | 0.03% |
| Comparative example | 1# | 0.20% | 0.09% |
As can be seen from the above table, the crystal formation of N (2)-Ala-Gln prepared by one-example IV of embodiment
Clarity is good, organic residue is low, and loss on drying is few, and above indices are superior to the crystal formation of comparative example.
Clarity is good, reduces the probability for producing adverse effect；The low effective reduction of organic residue is born to the poison of human body
Effect, makes the injection of present invention preparation safer.
The above is only presently preferred embodiments of the present invention, and any pro forma restriction is not made to the present invention, though
So the present invention is disclosed above with preferred embodiment, but is not limited to the present invention, any technology people for being familiar with this patent
Member in the range of without departing from technical solution of the present invention, when using the technology contents of above-mentioned prompting make it is a little change or be modified to
The Equivalent embodiments of equivalent variations, as long as being the content without departing from technical solution of the present invention, according to the technical spirit pair of the present invention
Any simple modification, equivalent variations and modification that above example is made, still fall within the range of the present invention program.
Claims (10)
1. a kind of N (2)-Ala-Gln novel crystal forms, it is characterised in that：Radiated using Cu-Ka, with 2 θ angle tables
The X-ray powder diffraction shown 13.76,15.58,18.58,18.72,19.66,20.72,21.34,21.42,21.70,
22.52,23.28,23.34,24.12,24.86,25.54,26.12,27.66,30.46,30.64,32.56,33.10,
34.26,34.62,34.86,36.60,36.90,37.48 (± 0.1 degree) have characteristic peak, its have powder X-ray as shown in Figure 1-
X ray diffration pattern x.
2. the method for preparing N (the 2)-Ala-Gln novel crystal forms described in claim 1, it is characterised in that：It is described
Preparation method is：
Step (1) dissolves：In taking the water for injection that N (2)-Ala-Gln crude product adds uniform temperature, constant temperature is stirred
Mix until N (2)-Ala-Gln crude product is completely dissolved；
Step (2) decolorization adsorption：Keeping temperature is constant, and activated carbon is added in solution obtained in step (1), when stirring one section
Between, obtain decolorization adsorption liquid；
Step (3) is filtered：Keeping temperature is constant, and decolorization adsorption liquid obtained in step (2) is filtered, and obtains aseptic fine straining
Liquid；
Step (4) is crystallized：Aseptic fine straining liquid is placed in crystallization apparatus, with filtration temperature as initial temperature, in gradient cooling
While adding sterile alcohol to make N (2)-Ala-Gln knot in the aseptic fine straining liquid obtained by step (3) in batches
Crystalline substance, obtains N (2)-Ala-Gln crystal solution；
Step (5):Under sterile conditions, by the filtration of crystal solution Jing, washing, drying process, dry aseptic N (2)-L- third is obtained
Aminoacyl-L-glutaminate crystal.
3. preparation N (2) according to claim 2-Ala-Gln novel crystal forms method, it is characterised in that：Step
Suddenly N (2) described in (1)-Ala-Gln crude product weight and injection water weight ratio are 1Kg：2～2.5Kg.
4. according to arbitrary described preparation N (the 2)-Ala-Gln novel crystal forms method of claim 2-3, its feature
It is：N (2)-Ala-Gln crude product weight described in step (4) is 1kg with the volume ratio of sterile alcohol:8～
15L,
Preferably, N (2)-Ala-Gln crude product weight and the volume ratio of sterile alcohol are 1kg:10L.
5., according to the arbitrary described method for preparing N (2)-Ala-Gln novel crystal forms of claim 2-4, it is special
Levy and be：Gradient cooling process, the addition of sterile alcohol and feed postition in the step (4) is as follows：
First stage：Aseptic fine straining liquid is squeezed into after crystallization apparatus and opens cooling, and with filtration temperature as initial temperature, temperature is with 7-9
DEG C/h speed be uniformly down to 45-50 DEG C, the uniform Deca sterile alcohol in this temperature-fall period, add sterile alcohol body
Product is the 1/3-1/2 of sterile alcohol cumulative volume；
Second stage：Temperature is uniformly down to 35-40 DEG C from 45-50 DEG C with 2-4 DEG C/h of speed, uniform in this temperature-fall period
Deca sterile alcohol, adds the volume of sterile alcohol for the 1/4-1/3 of sterile alcohol cumulative volume；
Phase III：After second stage terminates, remaining sterile alcohol is disposably added in crystallization apparatus, charging is finished
Afterwards, temperature is uniformly down to 25-30 DEG C from 35-40 DEG C with 7-9 DEG C/h of speed, and then constant temperature is stirred 2～3 hours.
6. the method for preparing N (2)-Ala-Gln novel crystal forms according to claim 2-5 any one,
It is characterized in that：Water for injection is heated to into 70-80 DEG C, preferred 73-75 DEG C in the step (1).
7. the method for preparing N (2)-Ala-Gln novel crystal forms according to claim 2-6 any one,
It is characterized in that：The addition weight of activated carbon is N (2)-Ala-Gln crude product weight in the step (2)
0.5-2%,
Preferably, the addition weight of activated carbon is the 1% of the N (2)-Ala-Gln crude product weight.
8. the method for preparing N (2)-Ala-Gln novel crystal forms according to claim 2-7 any one,
It is characterized in that：Filtration in the step (3) is divided into three steps：De- charcoal is carried out to decolorization adsorption liquid initially with titanium rod, is obtained
Coarse filtration liquid；Again coarse filtration liquid is carried out into secondary filter by cartridge filter, further remove activated carbon, obtain fine straining liquid；Finally
Fine straining liquid is carried out into aseptic filtration by sterilizing filter, aseptic fine straining liquid is obtained.
9. the method for preparing N (2)-Ala-Gln novel crystal forms according to claim 2-8 any one,
It is characterized in that：The drying process of the step (5) be initially with certain pressure compressed air material is carried out it is pre- dry up,
Sky closes compressed air after blowing a period of time, then is done by filtration washing drying machine vacuum system and interlayer circulation
It is dry, circulating water temperature is set as 50-60 DEG C, start timing when temperature of charge reaches preset temperature, keeping temperature is dried 10～
15 hours.
10. the method for preparing N (2)-Ala-Gln novel crystal forms according to claim 9, its feature exists
In：The compressed air pressure is 0.5-1.0MPa；Sky blows the time for 0.5-2.0 hours；
Preferably, compressed air pressure is 0.8MPa；Sky blew the time for 1.0 hours.
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Denomination of invention: A new crystal form of N (2) - L-alanyl-L-glutamine and its preparation method Granted publication date: 20200410 Pledgee: Zhuhai Branch of China Construction Bank Co.,Ltd. Pledgor: ZHUHAI TONGYUAN PHARMACEUTICAL CO.,LTD. Registration number: Y2024980016363 |