CN105237617B - A kind of monohydrate of N (2)-Ala-Gln and preparation method thereof - Google Patents
A kind of monohydrate of N (2)-Ala-Gln and preparation method thereof Download PDFInfo
- Publication number
- CN105237617B CN105237617B CN201510687700.7A CN201510687700A CN105237617B CN 105237617 B CN105237617 B CN 105237617B CN 201510687700 A CN201510687700 A CN 201510687700A CN 105237617 B CN105237617 B CN 105237617B
- Authority
- CN
- China
- Prior art keywords
- gln
- ala
- product
- monohydrate
- dissolved
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides monohydrate and the crystallization preparation method thereof of a kind of N (2) L alanyl L glutamine.By X-ray powder diffraction pattern, DSC, thermogravimetric curve, scanning electron microscope and size distribution curve describe its feature.N (2) L alanyl L glutamine is dissolved in good solvent, in the device of ultrasound wave under the steady temperature of 40～60 DEG C after stirring and dissolving, solution is cooled to 20～25 DEG C；Dripping dissolved agent again in the solid-liquid suspension of gained, dissolved agent consumption is 1～4 times of good solvent volume；1～5 DEG C it is cooled to after adding dissolved agent；The solid suspension obtained after crystallization is separated, is dried, obtains N (2) L alanyl L glutamine hydrate crystallization product.Product appearance is bar-shaped, and crystal formation is complete, purity is high, degree of crystallinity is high, even particle size distribution, good fluidity, and bulk density is high, and the packaging making product is more convenient with transport.
Description
Technical field
The invention belongs to crystallization technique field, particularly to the monohydrate of a kind of N (2)-Ala-Gln
And preparation method thereof.
Background technology
N (2)-Ala-Gln (L-Alany-L-glutamine) molecular formula is C8H15N3O4, molecular weight is
217.22, its chemical structural formula is as shown in (I).
N (2)-Ala-Gln is an important ingredient of parenteral nutrition, and people have been proven that
N (2)-ALA-GLN has regulation body protein synthesis, maintenance body nitrogen balance, safeguards gut integrity, increasing
Strong immunity of organisms and liver-protective function.
Glutamine is one of aminoacid of enriching the most of in-vivo content, but due to the water solublity (36g/L) of glutamine
Bad, therefore directly glutamine is used as parenteral nutrition agent effect bad.And glutamine and alanine condensation are formed two
Peptide prod N (2)-ALA-GLN has preferable water solublity (586g/L)., ALA-GLN is entering
Alanine and glutamine can well be decomposed in entering human body, and there is no any side effect.ALA-GLN is made
Many significant effects have been given play in treatment and auxiliary treatment numerous disease for a kind of parenteral nutrition agent.
The preparation of N (2)-Ala-Gln is at home and abroad it has been reported that patent CN10222844 discloses one
Kind of injection N (2)-Ala-Gln preparation and preparation method thereof, solve product freezes that type is bad, stability and
The problems such as rehydration difference.Ala-Gln is dried crude product and adds distilled water, 40～60 by patent CN101062938A
DEG C stirring and dissolving, is placed in 0～5 DEG C of refrigerator placement 10～12 hours, separates out crystal, filters；Add dehydrated alcohol to filtrate again to stir
Mixing 2 hours, separate out white crystal, sucking filtration, collect crystallisation by cooling product and dilution crystallization product, 60 DEG C are vacuum dried 6 hours.
The method is by crystallisation by cooling and dilution crystallization separate operations, and refining crystallization process is loaded down with trivial details, adds crude crystalline, experienced by 3 times altogether
Refining crystallization purifies, the longest.In patent CN1786019A, crude product is soluble in water, and by acetone or isopropanol dissolved, productivity is only
90% and 85%.
Crystallization process is the most strictly controlled by above-mentioned literature method, the product granularity obtained habit heterogeneity less, brilliant, product
Purity is low, and yield is low, degree of crystallinity is low and dissolvent residual is high, thus affects post processing and the using effect of product.
For overcoming the deficiencies in the prior art, it is necessary to invention a kind of epigranular, good fluidity, be difficult to coalescence, safety can
The new solid forms of medicinal Ala-Gln.The invention provides a kind of N (2)-Ala-Gln
The preparation method of monohydrate, prepares that granularity is relatively big, brilliant practises complete crystal product, and preparation method is simple, efficiency is high,
Yield is high.
Summary of the invention
In order to solve these problems, it is an object of the invention to provide a water of a kind of N (2)-Ala-Gln
Compound and preparation method thereof.The purity of this hydrate is more than 99.9%, and meanwhile, the outward appearance of this hydrate crystal is bar-shaped, and
Tradition stable crystal form is coalescence shape, and therefore hydrate product has more preferable mobility and higher bulk density, and this significantly improves
The packaging of product and convenient transportation.
Technical scheme is as follows:
A kind of monohydrate of N (2)-Ala-Gln；Every mole of N (2)-Ala-Gln
Containing 1 mole of water molecule in molecule, structural formula is as follows:
Crystal formation with X-ray powder diffraction measure, its X-ray powder diffraction in the angle of diffraction 2 θ=7.8 ± 0.1,10.9 ±
0.1,11.9 ± 0.1,13.6 ± 0.1,20.6 ± 0.1,21.3 ± 0.1,21.7 ± 0.1,22.2 ± 0.1,23.3 ± 0.1,
23.6 ± 0.1,24.2 ± 0.1,26.4 ± 0.1,27.3 ± 0.1,27.7 ± 0.1,32.2 ± 0.1,32.6 ± 0.1 and 38.6 ±
Characteristic peak is had at 0.1.As shown in Figure 1.
DSC has endothermic peak at 140-170 DEG C, as shown in Figure 2.
The thermogravimetric curve of N of the present invention (2)-Ala-Gln monohydrate is shown in Fig. 3, and its weightlessness is 7.8%, N
(2)-Ala-Gln monohydrate theoretical water content is 7.65%, the most identical with hot analysis result, permissible
Determining in novel crystal forms of the present invention that each glutamine dipeptide molecule combines 1 water of crystallization, i.e. novel crystal forms is glutamine dipeptide monohydrate.
The electromicroscopic photograph of N of the present invention (2)-Ala-Gln monohydrate is shown in Fig. 4.
The particle size distribution of N of the present invention (2)-Ala-Gln monohydrate and commercially available prod is shown in Fig. 5.
The monohydrate preparation method of N (the 2)-Ala-Gln of the present invention, by N (2)-L-alanyl-L-
Glutamine is dissolved in good solvent, in the device of ultrasound wave under the steady temperature of 40～60 DEG C after stirring and dissolving, by solution
It is cooled to 20～25 DEG C；Dripping dissolved agent again in the solid-liquid suspension of gained, dissolved agent consumption is the 1～4 of good solvent volume
Times；With 1～3min/ DEG C of rate of temperature fall, solution is cooled to 1～5 DEG C after adding dissolved agent, continues stirring 1～2h；Then will knot
The solid suspension obtained after crystalline substance separates, and is dried, and obtains N (2)-Ala-Gln hydrate crystallization and produces
Product.
A kind of or the most several in ultra-pure water, dimethyl sulfoxide, trifluoroacetic acid or acetonitrile of good solvent in described method
Mixed solvent.
The described dissolved agent mixture of one or more in ethanol, chloroform or butyl acetate.
The power of ultrasound wave is 30～100W.
Described drying condition is: temperature is 40～80 DEG C, and vacuum is 0.05～0.1MPa, and drying time is 12～24h.
Described dissolved agent drop rate is 1～5mL/min.
N (2)-Ala-Gln monohydrate crystal that the present invention provides has the advantage that (1) crystal
Main granularity increases, and Granularity Distribution is uniform, and Dv (50) increases by more than 360%；(2) good product mobility, bulk density improves
More than 18%；(3) degree of crystallinity is high, and purity reaches more than 99.5%, Heat stability is good；Product yield is more than 95% simultaneously；(4)
Magma is easily filtered, washed and dried, and the labor intensity of workman is low.
N (2)-Ala-Gln hydrate crystallization preparation method that the present invention provides, product crystalline substance is practised more
Good, bulk density is higher, and particle size distribution evenly, is more beneficial for the post processing of product, has the biggest advantage in pharmaceutical preparation；With
Time product purity is high, process yield high.
Accompanying drawing explanation
The X-ray powder diffraction pattern of Fig. 1: N (2)-Ala-Gln novel crystal forms；
The DSC collection of illustrative plates of Fig. 2: N (2)-Ala-Gln novel crystal forms；
The TG collection of illustrative plates of Fig. 3: N (2)-Ala-Gln novel crystal forms；
The SEM photograph figure of Fig. 4: N (2)-Ala-Gln novel crystal forms；
Fig. 5: N (2)-Ala-Gln novel crystal forms and the particle size distribution figure of commercially available prod；
Detailed description of the invention
Embodiment 1
10g N (2)-Ala-Gln is added in the ultra-pure water of 100ml, under 60 DEG C of stationary temperatures
Stirring and dissolving is complete, and ultrasonic power is 100W, then solution is cooled to 25 DEG C, drips 100ml not in solid-liquid suspension
Good solvent, poor solvent be volume ratio be ethanol and the mixed solvent of butyl acetate of 8:1, drop rate is 1mL/min；Add
With 1 DEG C/min rate of temperature fall, solution is cooled to 5 DEG C after ethanol, continues stirring 1h；Suspension obtained by sucking filtration, filters out
Wet crystal product is at 40 DEG C, and vacuum is to be dried to constant weight during 0.08MPa, obtains N (2)-Ala-Gln one
Hydrate product.Its X-ray powder diffraction in the angle of diffraction 2 θ=7.7,10.8,11.9,13.6,20.6,21.4,21.8,22.2,
Having characteristic peak at 23.3,23.6,24.2,26.5,27.3,27.8,32.1,32.6 and 38.6, DSC has suction at 142-165 DEG C
Thermal spike, TGA analyzes and shows the moisture containing 7.73%.Its Dv of the hydrate product that the method obtains (50) is higher than common crystal formation
About 348%, bulk density is high by 18.2%；The purity of final crystal product is 99.9%, process yield 95.5%.
Embodiment 2
10g N (2)-Ala-Gln is added in the good solvent of 100ml, good solvent be volume ratio be 4:1
Dimethyl sulfoxide and the mixed solvent of ultra-pure water, under 50 DEG C of stationary temperatures, stirring and dissolving is complete, and ultrasonic power is 30W,
Then solution being cooled to 20 DEG C, drip 300ml ethanol in solid-liquid suspension, drop rate is 3mL/min；After adding ethanol
With 3min/ DEG C of rate of temperature fall, solution is cooled to 5 DEG C, continues stirring 1h；Suspension obtained by sucking filtration, the wet crystal filtered out
Product is at 60 DEG C, and vacuum is to be dried to constant weight during 0.07MPa, obtains N (2)-Ala-Gln monohydrate
Product.Its X-ray powder diffraction in the angle of diffraction 2 θ=7.7,10.9,11.9,13.5,20.6,21.3,21.7,22.1,23.3,
Having characteristic peak at 23.6,24.1,26.5,27.3,27.6,32.2,32.6 and 38.7, DSC has endothermic peak at 145-170 DEG C,
TGA analyzes and shows the moisture containing 7.82%.Its Dv of the hydrate product that the method obtains (50) is higher about than common crystal formation
357%, bulk density is high by 18.9%；The purity of final crystal product is 99.8%, process yield 96.6%.
Embodiment 3
10g N (2)-Ala-Gln is added in the ultra-pure water of 100ml, under 45 DEG C of stationary temperatures
Stirring and dissolving is complete, and ultrasonic power is 50W, then solution is cooled to 25 DEG C, drips 200ml chlorine in solid-liquid suspension
Imitative, drop rate is 5mL/min；With 2min/ DEG C of rate of temperature fall, solution is cooled to 2 DEG C after adding chloroform, continues stirring 1h；Take out
Suspension obtained by filter, the wet crystal product filtered out is at 70 DEG C, and vacuum is to be dried to constant weight during 0.1MPa, obtains N
(2)-Ala-Gln monohydrate product.Its X-ray powder diffraction in the angle of diffraction 2 θ=7.9,11.0,11.8,
Spy is had at 13.6,20.6,21.4,21.7,22.3,23.3,23.7,24.2,26.5,27.3,27.7,32.1,32.6 and 38.8
Levying peak, DSC has endothermic peak at 140-166 DEG C, and TGA analyzes and shows the moisture containing 7.76%.The hydrate that the method obtains
Its Dv of product (50) is higher than common crystal formation by about 374%, and bulk density is high by 18.5%；The purity of final crystal product is 99.8%,
Process yield 96.2%..
Embodiment 4
10g N (2)-Ala-Gln is added in the trifluoroacetic acid of 100ml, 40 DEG C of stationary temperatures
Lower stirring and dissolving is complete, and ultrasonic power is 60W, then solution is cooled to 20 DEG C, drips 400ml second in solid-liquid suspension
Alcohol, drop rate is 4mL/min；With 3min/ DEG C of rate of temperature fall, solution is cooled to 5 DEG C after adding ethanol, continues stirring 1h；Take out
Suspension obtained by filter, the wet crystal product filtered out is at 80 DEG C, and vacuum is to be dried to constant weight during 0.09MPa, obtains N
(2)-Ala-Gln monohydrate product.Its X-ray powder diffraction in the angle of diffraction 2 θ=7.8,10.8,11.9,
Spy is had at 13.6,20.5,21.4,21.8,22.2,23.4,23.6,24.3,26.5,27.4,27.8,32.2,32.5 and 38.7
Levying peak, DSC has endothermic peak at 146-168 DEG C, and TGA analyzes and shows the moisture containing 7.65%.The hydrate that the method obtains
Its Dv of product (50) is higher than common crystal formation by about 361%, and bulk density is high by 18.8%；The purity of final crystal product is 99.9%,
Process yield 94.9%.
Embodiment 5
10g N (2)-Ala-Gln is added in the acetonitrile of 100ml, stir under 55 DEG C of stationary temperatures
Mixing dissolving completely, ultrasonic power is 80W, then solution is cooled to 25 DEG C, drips 300ml acetic acid fourth in solid-liquid suspension
Ester, drop rate is 2mL/min；With 1min/ DEG C of rate of temperature fall, solution is cooled to 5 DEG C after adding butyl acetate, continues stirring
1h；Suspension obtained by sucking filtration, the wet crystal product filtered out is at 60 DEG C, and vacuum is to be dried to perseverance during 0.05MPa
Weight, obtains N (2)-Ala-Gln monohydrate product.Its X-ray powder diffraction in the angle of diffraction 2 θ=7.7,
10.9,11.9,13.5,20.6,21.3,21.7,22.2,23.3,23.6,24.2,26.4,27.3,27.7,32.2,32.6 Hes
Having characteristic peak at 38.6, DSC has endothermic peak at 140-170 DEG C, and TGA analyzes and shows the moisture containing 7.85%.The method obtains
Its Dv of the hydrate product arrived (50) is higher than common crystal formation by about 352%, and bulk density is high by 18.5%；The purity of final crystal product
It is 99.7%, process yield 97.1%.
N (2)-Ala-Gln monohydrate of present invention disclosure and proposition and preparation method thereof, this area
Technical staff can be by link realizations such as reference present disclosure, suitable feed change, technological parameters.The method of the present invention and product
Being described by preferred embodiment, person skilled substantially can be without departing from present invention, spirit and scope
In method described herein and product be modified or suitably change and combine, realize the technology of the present invention.Need especially to refer to
Going out, all similar replacements and change apparent to those skilled in the art, they are considered as bag
Include in present invention spirit, scope and content.
Claims (4)
- The preparation method of the monohydrate of 1.N (2)-Ala-Gln, is characterized in that N (2)-L-alanyl-L- Glutamine is dissolved in good solvent, in the device of ultrasound wave under the steady temperature of 40～60 DEG C after stirring and dissolving, by solution It is cooled to 20～25 DEG C；Dripping dissolved agent again in the solid-liquid suspension of gained, dissolved agent consumption is the 1～4 of good solvent volume Times；With 1～3min/ DEG C of rate of temperature fall, solution is cooled to 1～5 DEG C after adding dissolved agent, continues stirring 1～2h；Then will knot The solid suspension obtained after crystalline substance separates, and is dried, and obtains N (2)-Ala-Gln hydrate crystallization and produces Product；A kind of or the most several mixing in ultra-pure water, dimethyl sulfoxide, trifluoroacetic acid or acetonitrile of the wherein said good solvent is molten Agent, the wherein said dissolved agent mixture of one or more in ethanol, chloroform or butyl acetate；Wherein N (2)-L-third The feature of aminoacyl-L-glutaminate monohydrate be X-ray powder diffraction in the angle of diffraction 2 θ=7.8 ± 0.1,10.9 ± 0.1, 11.9 ± 0.1,13.6 ± 0.1,20.6 ± 0.1,21.3 ± 0.1,21.7 ± 0.1,22.2 ± 0.1,23.3 ± 0.1,23.6 ± 0.1,24.2 ± 0.1,26.4 ± 0.1,27.3 ± 0.1,27.7 ± 0.1,32.2 ± 0.1, at 32.6 ± 0.1 and 38.6 ± 0.1 Having characteristic peak, its DSC has endothermic peak at 140-170 DEG C.
- 2. the method for claim 1, is characterized in that the power of ultrasound wave is 30～100W.
- 3. the method for claim 1, is characterized in that drying condition is: temperature is 40～80 DEG C, vacuum be 0.05～ 0.1MPa, drying time is 12～24h.
- 4. the method for claim 1, is characterized in that dissolved agent drop rate is 1～5mL/min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510687700.7A CN105237617B (en) | 2015-10-21 | 2015-10-21 | A kind of monohydrate of N (2)-Ala-Gln and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510687700.7A CN105237617B (en) | 2015-10-21 | 2015-10-21 | A kind of monohydrate of N (2)-Ala-Gln and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105237617A CN105237617A (en) | 2016-01-13 |
| CN105237617B true CN105237617B (en) | 2016-11-16 |
Family
ID=55035481
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510687700.7A Active CN105237617B (en) | 2015-10-21 | 2015-10-21 | A kind of monohydrate of N (2)-Ala-Gln and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105237617B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107805275B (en) * | 2016-09-08 | 2023-07-21 | 重庆莱美隆宇药业有限公司 | Novel N (2) -L-alanyl-L-glutamine crystal form and preparation method thereof |
| EP3974439A1 (en) * | 2016-12-20 | 2022-03-30 | Kyowa Hakko Bio Co., Ltd. | L-alanyl-l-glutamine crystals and method for producing same |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101062938A (en) * | 2006-04-25 | 2007-10-31 | 福建三爱药业有限公司 | Preparation method of N(2)-L-alanyl-L-glutamine |
-
2015
- 2015-10-21 CN CN201510687700.7A patent/CN105237617B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101062938A (en) * | 2006-04-25 | 2007-10-31 | 福建三爱药业有限公司 | Preparation method of N(2)-L-alanyl-L-glutamine |
Non-Patent Citations (2)
| Title |
|---|
| L-丙酰胺-L-谷氨酰胺结晶过程研究;王如帆;《中国优秀硕士学位论文全文数据库 工程科技I辑》;20090316;第31-46页 * |
| 超声波对结晶过程部分热力学和动力学性质的影响;郭志超等;《河北化工》;20030420;第3页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105237617A (en) | 2016-01-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7625911B2 (en) | Amorphous form of erlotinib hydrochloride and its solid amorphous dispersion | |
| Wang et al. | Improving the dissolution and bioavailability of 6-mercaptopurine via co-crystallization with isonicotinamide | |
| CN105237617B (en) | A kind of monohydrate of N (2)-Ala-Gln and preparation method thereof | |
| WO2016107289A1 (en) | Method for preparing sofosbuvir crystal form-6 | |
| CN103553951B (en) | Method of extracting and preparing lysine sulphate from fermenting liquid containing lysin | |
| CN106336396A (en) | Alogliptin benzoate preparation method | |
| JP2008505078A (en) | Crystalline form of (3R) -1- (2-methylalanyl-D-tryptophyll) -3- (phenylmethyl) -3-piperidinecarboxylic acid 1,2,2-trimethylhydrazide | |
| CN110041320B (en) | Preparation method of azilsartan crystals | |
| CN101663314A (en) | crystalline forms of the mono-sodium salt of d-isoglutamyl-d-tryptophan | |
| CN111303097A (en) | Crystal form C of michelia lactone fumarate dimethylamine and preparation method thereof | |
| CN103755609B (en) | Crystal formation of tartaric acid valnemulin and preparation method thereof | |
| CN105566098A (en) | Method for combined production of high purity crystalline calcium acetate and waterless calcium acetate | |
| WO2020233288A1 (en) | Torsemide sodium monohydrate, crystal form thereof and composition thereof | |
| CN103980166B (en) | A kind of novel crystal forms of florfenicol and preparation method thereof | |
| WO2012171377A1 (en) | Crystal forms of asiatic acid trometamol salt and preparation methods thereof | |
| CN103059023B (en) | A kind of method preparing ganciclovir crystal form II | |
| CN102321083B (en) | Preparation method of new anhydrous moxifloxacin hydrochloride crystal F | |
| CN104140429B (en) | Lixivaptan crystalline form V and its production and use | |
| RU2007103177A (en) | METHOD FOR PRODUCING PURE TYPE OF CRYSTAL FORMS OF TORSEMID | |
| CN112898168B (en) | Salt of 2-hydroxybenzylamine-succinic acid and preparation method thereof | |
| CN104610210B (en) | A kind of sodium dehydroacetate anhydride preparation method | |
| CN108636383A (en) | A kind of lightweight bamboo charcoal powder and preparation method thereof | |
| CN107445984A (en) | A kind of preparation method of creatinol-o-phosphate | |
| CN104130168B (en) | A kind of oxalic acid valnemulin crystal and preparation method thereof | |
| WO2018082096A1 (en) | NEW γ-PROPALANINE CRYSTAL FORM AND PREPARATION METHOD THEREFOR |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |