CN105481725B - The crystal form and preparation method thereof of L-arginine phenylacetate - Google Patents
The crystal form and preparation method thereof of L-arginine phenylacetate Download PDFInfo
- Publication number
- CN105481725B CN105481725B CN201410475736.4A CN201410475736A CN105481725B CN 105481725 B CN105481725 B CN 105481725B CN 201410475736 A CN201410475736 A CN 201410475736A CN 105481725 B CN105481725 B CN 105481725B
- Authority
- CN
- China
- Prior art keywords
- arginine
- phenylacetate
- crystal form
- preparation
- added
- 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
- ZSLCTQMUUDGWHO-VWMHFEHESA-N OC(=O)Cc1ccccc1.N[C@@H](CCCN=C(N)N)C(O)=O Chemical compound OC(=O)Cc1ccccc1.N[C@@H](CCCN=C(N)N)C(O)=O ZSLCTQMUUDGWHO-VWMHFEHESA-N 0.000 title claims abstract description 52
- 239000013078 crystal Substances 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 43
- 239000007787 solid Substances 0.000 claims description 37
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 34
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 21
- 235000014852 L-arginine Nutrition 0.000 claims description 21
- 229930064664 L-arginine Natural products 0.000 claims description 20
- 235000019441 ethanol Nutrition 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 19
- 238000010792 warming Methods 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 230000001476 alcoholic effect Effects 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 claims description 4
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 claims description 4
- 229940049953 phenylacetate Drugs 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 210000004185 liver Anatomy 0.000 claims description 2
- 210000004556 brain Anatomy 0.000 claims 1
- 238000010521 absorption reaction Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 23
- 229960003424 phenylacetic acid Drugs 0.000 description 15
- 239000003279 phenylacetic acid Substances 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 9
- 206010020575 Hyperammonaemia Diseases 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 239000004475 Arginine Substances 0.000 description 6
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 6
- 235000009697 arginine Nutrition 0.000 description 6
- 229960003121 arginine Drugs 0.000 description 6
- ITIONVBQFUNVJV-UHFFFAOYSA-N Etomidoline Chemical compound C12=CC=CC=C2C(=O)N(CC)C1NC(C=C1)=CC=C1OCCN1CCCCC1 ITIONVBQFUNVJV-UHFFFAOYSA-N 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 229940006198 sodium phenylacetate Drugs 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 208000007386 hepatic encephalopathy Diseases 0.000 description 3
- 208000019423 liver disease Diseases 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 206010000489 Acidosis hyperchloraemic Diseases 0.000 description 2
- 206010016803 Fluid overload Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 208000028547 Inborn Urea Cycle disease Diseases 0.000 description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 2
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 2
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 229960003624 creatine Drugs 0.000 description 2
- 239000006046 creatine Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229960003104 ornithine Drugs 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 208000030954 urea cycle disease Diseases 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- CDNQOMJEQKBLBN-UHFFFAOYSA-N 3-(hydroxymethyl)benzaldehyde Chemical compound OCC1=CC=CC(C=O)=C1 CDNQOMJEQKBLBN-UHFFFAOYSA-N 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical class OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- 102000004452 Arginase Human genes 0.000 description 1
- 108700024123 Arginases Proteins 0.000 description 1
- KWTQSFXGGICVPE-WCCKRBBISA-N Arginine hydrochloride Chemical compound Cl.OC(=O)[C@@H](N)CCCN=C(N)N KWTQSFXGGICVPE-WCCKRBBISA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- CQESGIKXPYZPQB-WCCKRBBISA-N C1=CC=CC=C1.N[C@@H](CCCNC(N)=N)C(=O)O Chemical compound C1=CC=CC=C1.N[C@@H](CCCNC(N)=N)C(=O)O CQESGIKXPYZPQB-WCCKRBBISA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- BRPMGWKECPTJGE-RGMNGODLSA-N Cl.C(CC)N[C@@H](CCO)C(=O)O Chemical compound Cl.C(CC)N[C@@H](CCO)C(=O)O BRPMGWKECPTJGE-RGMNGODLSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 206010014418 Electrolyte imbalance Diseases 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 150000008535 L-arginines Chemical class 0.000 description 1
- PTSRBZOZSRJCKX-JTQLQIEISA-N N-Phenylacetylglutamic acid Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)CC1=CC=CC=C1 PTSRBZOZSRJCKX-JTQLQIEISA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960003589 arginine hydrochloride Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229940126678 chinese medicines Drugs 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- RHLFTMGPBSLHRS-UHFFFAOYSA-M sodium;2-phenylbutanoate Chemical compound [Na+].CCC(C([O-])=O)C1=CC=CC=C1 RHLFTMGPBSLHRS-UHFFFAOYSA-M 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229940045136 urea Drugs 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides a kind of crystal forms and preparation method thereof of L-arginine phenylacetate.The X-ray powder diffraction figure of the crystal form has absorption peak 7.2 ° ± 0.2 °, 16.1 ° ± 0.2 °, 16.1 ° ± 0.2 °, 19.0 ° ± 0.2 °, 21.7 ° of ± 0.2 ° of positions including 2 θ；The preparation method of the crystal form includes by L-arginine phenylacetate in C1~3Alcoholic solution is dissolving crystallized, obtains the crystal form.Stability of crystal form prepared by the present invention is good, and preparation method is easy to operate, reproducible, is suitble to industrialized production.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of crystal form of L-arginine phenylacetate and its preparation side
Method.
Background technique
L-arginine phenylacetate molecular formula is C8H8O2·C6H14N4O2, structural formula such as following formula I:
。
It is known in addition to hyperammonemia caused by arginase defect, remaining hyperammonemia case can be used arginine and control
It treats, arginine not only can promote the discharge of ammonia, but also supplement internal essential amino acid.Arginine participates in ornithine in human body and follows
Ring promotes the formation of urea, makes one the ammonia generated in vivo, is transformed into nontoxic urea through ornithine circulation, by being discharged in urine, from
And reduce ammonia concentration；When hepatosis, human body is mainly to reduce blood ammonia by the synthesis of glutamine.It is excessive in vivo
Glutamine it is not only unfavorable to human body, but also can enteron aisle decompose generate ammonia ammonia concentration is gone up.Sodium phenylacetate and paddy
Propylhomoserin is easy to be discharged from urine in conjunction with phenylacetyl glutamic acid is formed, to reduce the toxic level of ammonia.
Leonard J V and Morris A A M is in document Urea cycle disorders(Semin Neonatol
2002;Phenylacetate, benzenebutanoic acid salt and arginine are disclosed in 7:27-35) to be used in combination, and can be used for treating hyperammonemia；
Document Alternative pathway therapy for urea cycle disorders:Twenty years later
(St. Louis, MO, United States. Journal of Pediatrics, 2001, Volume:138, Issue:
1, Pages:S46-S55) it discloses sodium phenylacetate to be used in combination with arginine, for treating hyperammonemia.
At present when clinical use arginine hydrochloride injection treatment hyperammonemia, hyperchloremic acidosis and blood can be caused
The side reactions such as middle urea, creatine, creatine concentration raising, thus limit its use in hyperchloremic acidosis patient.
In addition, some salts (such as arginine monohydrochloride, sodium phenylacetate, phenylbutyrate sodium), especially sodium salt or chloride salt,
When they are for treating disease (such as hepatic encephalopathy) related with hepatopathy, there are disadvantages.Firstly, since certain salts (such as sodium
Salt) intake of high concentration is to endanger very much to the hepatopath that inherently may have ascites, body fluid overload or electrolyte imbalance
Danger；Secondly as increasing for osmotic pressure is more difficult from so that being injected intravenously, and diluted by tank solution again for vein
Injection then will cause fluid overload again.Therefore, disease related with hepatopathy can effectively be prevented or be treated to urgent clinical needs one kind
(such as hepatic encephalopathy), and it is avoided that the drug of above-mentioned side effect.
The present inventor is found surprisingly that, L-arginine phenylacetate (compound shown in Formulas I), when treating hyperammonemia,
With synergistic effect, and it can significantly overcome defect when L-arginine and phenylacetic acid or sodium phenylacetate exclusive use.
The present inventor is found through experiments that, L-arginine and corresponding carboxylic acid mild heat in ethanol are vigorously stirred
After reaction, by evaporating solvent under reduced pressure, obtained product L-arginine phenylacetate is unstable, is easy the moisture absorption, and repeat
Property it is poor, be not suitable for industrialization generate.
Currently without the document report about L-arginine phenylacetate crystal form.Also, many documents teach many medicines
The amorphous and crystal habit of object shows different solubility and different bioavilabilities, so that it is living to generate different biologies
Property.The drug of crystal habit is better than nodeless mesh form above-mentioned in nature under normal circumstances, has preferable physics and chemistry steady
It is qualitative, there is very big benefit in terms of preparation.Therefore it needs to study many kinds of solids form of L-arginine phenylacetate.
Summary of the invention
It is an object of that present invention to provide a kind of novel crystal forms of L-arginine phenylacetate, the X-ray powder of the crystal form spreads out
Penetrating figure has absorption peak 7.1 ° ± 0.2 °, 14.2 ° ± 0.2 °, 18.1 ° ± 0.2 °, 21.4 ° of ± 0.2 ° of positions including 2 θ.
The crystal form of the L-arginine phenylacetate, X-ray powder diffraction figure include 2 θ 7.1 ° ±
0.2°、14.2°±0.2°、18.1°±0.2°、19.0°±0.2°、20.3°±0.2°、21.4°±0.2°、23.9°±0.2°
There is absorption peak in position.
Further, the crystal form of the L-arginine phenylacetate, X-ray powder diffraction figure include that 2 θ exist
7.1°±0.2°、11.1°±0.2°、11.8°±0.2°、13.1°±0.2°、14.2°±0.2°、15.2°±0.2°、16.5°
± 0.2 °, 18.1 ° ± 0.2 °, 19.0 ° ± 0.2 °, 20.3 ° ± 0.2 °, 21.4 ° ± 0.2 °, 23.9 ° of ± 0.2 ° of positions have absorption
Peak, wherein the crystal form of the L-arginine phenylacetate has X-ray powder diffraction figure as shown in Figure 1.
On the other hand, the present invention provides the preparation methods of the crystal form of the L-arginine phenylacetate, it is characterised in that:
L-arginine phenylacetate is dissolved in C1~3It is crystallized in alcoholic solution, prepares the crystal form of L-arginine phenylacetate.Wherein, institute
The C stated1~3Alcohol is selected from methanol, ethyl alcohol, propyl alcohol or isopropanol；It is preferred that the C1~3The ethyl alcohol that alcoholic solution is 90% ~ 100% is water-soluble
Liquid.The method specifically includes the following steps:
L-arginine phenylacetate is added in 90% ~ 100% ethanol water of 2.5 ~ 12 times of w/vs, is heated
To reflux, the water of optional 1% ~ 12% ethyl alcohol volume of addition, stirring to solid is all dissolved, and is subsequently cooled to -20 DEG C ~ 30 DEG C,
- 5 DEG C ~ 5 DEG C are preferably cooled to, is more preferably cooled to 0 DEG C, continues 0.5 ~ 3h of stir about, filtering, 40 DEG C ~ 60 DEG C dryings obtain white
Color crystalline solid.
On the other hand, the preparation of the crystal form of L-arginine phenylacetate of the present invention can also by by L-arginine with
After phenylacetic acid or its reactant salt, C is directly added into reaction solution1~3Alcoholic solution carries out crystallization acquisition.Specifically include following step
It is rapid:
1) L-arginine and phenylacetic acid or its salt, are added to C with the molar ratio of 1:1 ~ 1:21~3In alcoholic solution, it is warming up to
10 ~ 80 DEG C, 40 DEG C are preferably warming up to, 0.1 ~ 5 hour, preferably reaction 2.0h are reacted in stirring；
2), C is added into the solution of step 1)1~3Alcoholic solution is heated to reflux to 5 ~ 20 times (v/w) of L-arginine to solid
Body is entirely molten, is cooled to -20 DEG C ~ 30 DEG C, is preferably cooled to -5 DEG C ~ 5 DEG C, optional addition or is added without crystal seed, stirs 0.5 ~ 3h,
Filtering, it is dry, obtain white solid.
Wherein, the C1~3Alcoholic solution is methanol, ethyl alcohol, the aqueous solution of propyl alcohol or isopropanol, preferred concentration is 90% ~
100%；The further preferred C1~3The ethanol solution that alcoholic solution is 90% ~ 100%.
Further, the C1~3Alcoholic solution be 98% ~ 100%(v/v) ethanol solution when, it is preferable that in step 2 plus
Heat be back to solid it is complete it is molten before, water (such as 0 ~ 12% v of appropriate volume is added into crystallizing systemAlcohol/vWater).
Wherein, the crystal seed of the L-arginine phenylacetate can be prepared by the following method acquisition:
L-arginine and phenylacetic acid are reacted in ethanol solution with the molar ratio of 1:1 ~ 1:1.2, are warming up to 10 DEG C ~ 80
DEG C, it stirs 0.1 ~ 5.0 hour, it is cooling, it filters, it is dry, obtain white solid, the as crystal seed of L-arginine phenylacetate.
Phenylacetic acid of the present invention or its salt, phenylacetate therein includes the univalent metal salt of phenylacetic acid, such as benzene second
Acid sodium-salt, sylvite etc..
On the other hand, the present invention also provides a kind of amorphous solid of L-arginine phenylacetate, the L-arginines
The crystal form comprising at least one characteristic peak, the spy is presented in the X-ray powder diffraction figure of the amorphous solid of phenylacetate
Levy peak be selected from 2 θ about 7.1 ° ± 0.2 °, 14.2 ° ± 0.2 °, 15.6 ± 0.2 °, 18.3 ° ± 0.2 °, 21.4 ° ± 0.2 °,
23.9°±0.2°。
Further, the X-ray powder diffraction spectrogram of the amorphous solid of the L-arginine phenylacetate such as attached drawing 2
It is illustrated.
On the other hand, the present invention also provides the preparation method of the amorphous solid of the L-arginine phenylacetate, packets
It includes:
By L-arginine (1.0eq.), it is added in ethyl alcohol, is stirred at room temperature；Into above-mentioned solution be added phenylacetic acid (1.0 ~
1.2eq), nitrogen protection is stirred at room temperature, until reaction solution becomes clarification, evaporating solvent under reduced pressure obtains white solid, X-ray powder
Last diffraction pattern is as shown in Fig. 2.
On the other hand, the present invention provides the crystal forms of the L-arginine phenylacetic acid in preparation prevention and/or treatment liver property
Purposes in the drug of encephalopathy；It is preferred that improving and/or treating the purposes in hyperammonemia drug in preparation.It is diagnosed including giving
The crystal form of the L-arginine phenylacetate provided by the invention of subject's effective dose with hepatic encephalopathy or hyperammonemia or
Its pharmaceutical composition containing therapeutically effective amount.The crystal form of the L-arginine phenylacetate or its pharmaceutical composition can take orally
Or intravenously administrable, wherein the therapeutically effective amount of oral administration is within the scope of about 500mg to about 50g；The treatment of intravenously administrable is effective
Dosage is no more than 500ml L-arginine phenylacetate solution, and the solution includes the L-arginine phenylacetic acid of at least 25mg/ml
Salt, and the solution and body fluid are isotonic.The usage and dosage of the L-arginine phenylacetate, can according to clinical needs,
It is determined according to method known to persons of ordinary skill in the art, it should be understood that these usages and dosage should not limit this hair
It is bright.
The L-arginine phenylacetate novel crystal forms that the present invention prepares are with good stability, experiments have shown that, for a long time
Storage (6 months or more) crystal form is basically unchanged, and L-arginine phenylacetate provided by the present invention does not contain sodium or chloride, because
This, it is contemplated that L-arginine phenylacetate provides the safety improved compared with other salt of L arginine and phenylacetic acid, with L- essence
Other salt such as propylhomoserin hydrochloride or sodium phenylacetate are compared and show lower toxicity, and therefore can be given with higher concentration vein.
L-arginine phenylacetate provided by the present invention is used for intravenously administrable, has insignificant sodium load, and therefore
So that required intravenous fluids amount is minimum；There is significant clinical improvement to stemness cerebropathy therapeutic.
In addition, the preparation method of the crystal form of L-arginine phenylacetate provided by the invention, easy to operate, it is reproducible,
Recrystallisation solvent is done using lower alcohol, production cost is low, and reaction condition is mild, and it is low for equipment requirements, it is suitble to industrialized production；And
And method provided by the invention, the L-arginine phenylacetate crystal form purity of preparation is high, and it is good to obtain stability of crystal form.
Detailed description of the invention
The X-ray powder diffraction figure of L-arginine phenylacetate crystal form is shown in Fig. 1.
The X-ray powder diffraction figure of L-arginine phenylacetate amorphous solid is shown in Fig. 2.
Specific embodiment
In order to which the technical problems, technical solutions and beneficial effects solved by the present invention is more clearly understood, below in conjunction with
Specific embodiment, the present invention is further illustrated.
In following embodiments, unless otherwise indicated, the test method is usually according to normal condition or manufacturer builds
The condition of view is implemented；L-arginine is bought in Anji chemically-resistant, purity: 99%；Phenylacetic acid purchase has in Chinese medicines group chemical reagent
Limit company, purity: 98%；Other raw materials used, reagent can be obtained by the method for commercially available purchase.
X-ray powder diffraction (XRPD) figure of the present invention is in Panalytical (Panaco) company
It is acquired on Empyrean type X-ray powder diffraction instrument；About 10mg sample is evenly laid out on monocrystal silicon sample disk, in 45kV
It is scanned with 40mA.
The preparation of the crystal form of 1 L-arginine phenylacetate of embodiment:
(1) preparation of L-arginine phenylacetate crystal seed: by L-arginine (3.48g, 20mmol) and phenylacetic acid
(2.99g, 22mmol) is dissolved in 99% ethyl alcohol (27.84ml), is warming up to 40 DEG C, has a large amount of solids to be precipitated, and stirs 2.0h, is cooled to
Room temperature, filtering, 40 DEG C of dry 2.0h, obtaining white solid, (5.86g, yield: 94.5%), as L-arginine phenylacetate is brilliant
Kind.
(2) preparation of the crystal form of L-arginine phenylacetate: by L-arginine (3.48g, 20mmol) and phenylacetic acid
(2.99g, 22mmol) is dissolved in 99% ethyl alcohol (20.88ml), is warming up to 40 DEG C, insulated and stirred 10min, has a large amount of solids to be precipitated,
It is added ethyl alcohol (7.0ml), is heated to flowing back, be added water (1.5ml), solid is entirely molten, is cooled to 0 DEG C, is added crystal seed (0.1g), stirs
Mix 1.5h, filter, 40 DEG C of dry 2.0h, obtain white solid (5.7g, yield: 91.9%), and X-ray powder diffraction figure such as attached drawing
Shown in 1.
Its X-ray powder diffraction data is as shown in table 1 below:
Table 1:
。
The preparation of the crystal form of 2 L-arginine phenylacetate of embodiment
(1) preparation of L-arginine phenylacetate: by L-arginine (3.48g, 20mmol) and phenylacetic acid (2.99g,
It 22mmol) is dissolved in ethyl alcohol (27.84ml), is warming up to 40 DEG C, there are a large amount of solids to be precipitated, is filtered, it is dry, obtain L-arginine benzene second
Hydrochlorate solid powder.
(2) L-arginine phenylacetate solid powder (5.5g) prepared by step 1) is added to 90% ethanol water
It is heated to flowing back in (29.4ml), solid is entirely molten, is cooled to 0 DEG C, stirs 1.5h, filtering, and 40 DEG C of dry 2.0h obtain white crystalline substance
Body, X-ray powder diffraction figure are identical as attached drawing 1.
The preparation of the crystal form of 3 L-arginine phenylacetate of embodiment
L-arginine (3.48g, 20mmol) and phenylacetic acid (2.99g, 22mmol) are added to 95% ethyl alcohol
In (20.88ml) solution, stirring is warming up to 40 DEG C, continues insulated and stirred 0.1h, has a large amount of solids to be precipitated, and 95% ethyl alcohol is added
(20.88ml) is heated to flowing back, and stirring, solid is entirely molten, is cooled to 0 DEG C, stirs 3h, filtering, and 40 DEG C of dry 2.0h are obtained white
(5.4g, yield: 87.2%), X-ray powder diffraction figure is identical as attached drawing 1 for color solid.
The preparation of the crystal form of 4 L-arginine phenylacetate of embodiment
L-arginine (3.48g, 20mmol) and phenylacetic acid (2.99g, 22mmol) are added to 90% ethanol water
In (20.88ml), stirring is warming up to 10 DEG C, continues insulated and stirred 5h, has a large amount of solids to be precipitated, and 90% ethanol water is added
(8.5ml) is heated to flowing back, and solid is entirely molten, is cooled to -20 DEG C, stirs 0.5h, filtering, and 40 DEG C of dry 2.0h obtain white crystalline substance
(5.5g, yield: 88.7%), X-ray powder diffraction figure is identical as attached drawing 1 for body.
The preparation of the crystal form of 5 L-arginine phenylacetate of embodiment
L-arginine (3.48g, 20mmol) and phenylacetic acid (5.44g, 40mmol) are dissolved in 98% ethyl alcohol (20.88ml),
10 DEG C, insulated and stirred 5h are warming up to, there are a large amount of solids to be precipitated, is added 98% ethyl alcohol (7.0ml), is added water (3.3ml), is heated to
Reflux, solid is entirely molten, is cooled to 0 DEG C, is added crystal seed (0.1g), stirs 0.5h, filtering, and 40 DEG C of dry 2.0h obtain white crystalline substance
(5.3g, yield: 85.6%), X-ray powder diffraction figure is identical as attached drawing 1 for body.
The preparation of the crystal form of 6 L-arginine phenylacetate of embodiment
L-arginine (3.48g, 20mmol) and phenylacetic acid (4.08g, 30mmol) are added to 90% ethanol water
In (17.40ml), stirring is warming up to 80 DEG C, continues insulated and stirred 3h, has a large amount of solids to be precipitated, is heated to flowing back, solid is complete
It is molten, 30 DEG C are cooled to, stirs 2.5h, filtering, 40 DEG C of dry 2.0h, obtaining white crystal, (5.6g, yield: 90.3%), X- is penetrated
Line powder diagram is identical as attached drawing 1.
Comparative example 1
17.42g L-arginine (0.1mol, 1.0eq.) is added into 250ml there-necked flask, 100ml ethyl alcohol is stirred at room temperature
30min；13.61g phenylacetic acid (0.1mol, 1.0eq.) is added into above-mentioned solution, nitrogen protection is stirred at room temperature, and solid is rapid
Dissolution after reaction solution becomes clarification, continues to stir 20min, evaporating solvent under reduced pressure at 35 DEG C obtains white solid 20.00g, this is white
Color solid is exposed at easy to absorb moisture in air.Its X-ray powder diffraction figure is as shown in Fig. 2.
Its X-ray powder diffraction data is as shown in table 2 below:
Table 2
。
It should be noted that the foregoing is merely illustrative of the preferred embodiments of the present invention, it is not intended to limit the invention, it is all
Made any modifications, equivalent replacements, and improvements etc. within the spirit and principles in the present invention should be included in guarantor of the invention
Within the scope of shield.
Claims (4)
1. a kind of crystal form of L-arginine phenylacetate (Formulas I),
It is characterized in that, the crystal form has X-ray powder diffraction figure as shown in Figure 1.
2. the preparation method of the crystal form of L-arginine phenylacetate described in a kind of claim 1, which is characterized in that can also pass through
After reaction by L-arginine and phenylacetic acid, C is directly added into reaction solution1~3Alcoholic solution is crystallized, and L-arginine is obtained
The crystal form of phenylacetate, specifically includes the following steps:
1) L-arginine and phenylacetic acid, are added to C with the molar ratio of 1:1~1:21~3In alcoholic solution, 10~80 DEG C are warming up to,
Stirring is reacted 0.1~5 hour；
2), C is added into the solution of step 1)1~3Alcoholic solution to L-arginine 5~20 times of envelope-bulk to weight ratio, be heated to reflux to
Solid is entirely molten, is cooled to -20 DEG C~30 DEG C, optional addition or is added without crystal seed, stirs 0.5~3h, filters, dry, obtains
White solid,
The C1~3Alcoholic solution is the ethanol water of 90%~100% volume ratio.
3. preparation method according to claim 2, which is characterized in that can also be heated to reflux in step 2) entirely molten to solid
Before, the water of 1%~12% ethyl alcohol volume is added into crystallizing system.
4. the L-arginine phenylacetate with crystal form described in claim 1, in preparation for preventing or treating liver property brain
Purposes in the drug of disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410475736.4A CN105481725B (en) | 2014-09-18 | 2014-09-18 | The crystal form and preparation method thereof of L-arginine phenylacetate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410475736.4A CN105481725B (en) | 2014-09-18 | 2014-09-18 | The crystal form and preparation method thereof of L-arginine phenylacetate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105481725A CN105481725A (en) | 2016-04-13 |
| CN105481725B true CN105481725B (en) | 2019-01-22 |
Family
ID=55669047
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410475736.4A Active CN105481725B (en) | 2014-09-18 | 2014-09-18 | The crystal form and preparation method thereof of L-arginine phenylacetate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105481725B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102421432A (en) * | 2009-04-03 | 2012-04-18 | 欧塞拉治疗有限公司 | L-ornithine phenyl acetate and methods of making thereof |
| CN102993037A (en) * | 2012-11-20 | 2013-03-27 | 万红贵 | Preparation method for L-ornithine phenylacetate |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MXPA03009902A (en) * | 2003-10-29 | 2005-05-03 | Manuel Francisco Lara Och Jose | Compounds for reducing hyperammonemia in patients having cirrhosis or any inability for eliminating ammonium. |
-
2014
- 2014-09-18 CN CN201410475736.4A patent/CN105481725B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102421432A (en) * | 2009-04-03 | 2012-04-18 | 欧塞拉治疗有限公司 | L-ornithine phenyl acetate and methods of making thereof |
| CN104230730A (en) * | 2009-04-03 | 2014-12-24 | 欧塞拉治疗有限公司 | L-ornithine phenyl acetate and methods of making thereof |
| CN102993037A (en) * | 2012-11-20 | 2013-03-27 | 万红贵 | Preparation method for L-ornithine phenylacetate |
Non-Patent Citations (2)
| Title |
|---|
| L-Ornithine phenylacetate (OP): A novel treatment for hyperammonemia and hepatic encephalopathy;R. Jalan et al;《Medical Hypotheses》;20071231;第69卷(第5期);1064-1069 |
| 一种新型治疗肝性脑病的药物:L-鸟氨酸苯乙酸;万红贵等;《中国新药杂志》;20131231;第22卷(第11期);1274-1277 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105481725A (en) | 2016-04-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102249975B (en) | (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I and preparation method and application thereof | |
| JP5860821B2 (en) | Chlorite formulation and method and use of this preparation | |
| AU2011312042B2 (en) | Methods of making L-ornithine phenyl acetate | |
| WO2008031284A1 (en) | A process for resolution of 5-methyltetrahydrofolic acid and its salification | |
| CN114081881B (en) | Organic acid lithium amino acid salt, crystal form, composition and application | |
| ES2548881T3 (en) | Dihydroetorphins and their preparation | |
| CN102180832A (en) | Compound for protecting cerebral ischemia and preparation method thereof | |
| CN103864760A (en) | Hydroxyfasudil compound | |
| KR20150142691A (en) | Tetrandrine family pharmaceutical formulations and method | |
| ES2278297T3 (en) | USE OF DERIVATIVES OF 2-AMINO-2H-QUINAZOLINE FOR THE PRODUCTION OF THERAPEUTIC AGENTS. | |
| CN103265483A (en) | Co-crystal of norfloxacin and phthalic acid and preparation method thereof | |
| CN105481725B (en) | The crystal form and preparation method thereof of L-arginine phenylacetate | |
| CN102924295B (en) | Bromhexine hydrochloride crystal as well as preparation method and application of crystal | |
| CN102775408B (en) | Stable 5-methyltetrahydrofolate crystal formation and preparation method thereof | |
| RU2439063C1 (en) | Method of obtaining medication | |
| CN103191051B (en) | Nelarabine injection composition and preparation method thereof | |
| CN101486644A (en) | Preparation of arginine acetylsalicylate | |
| Mann et al. | β β'β"-Triaminotriethylamine and its complex metallic compounds | |
| CN102746227A (en) | Dimemorfan phosphate crystal form II and preparation method thereof, and pharmaceutical composition | |
| CN104974050A (en) | Water-soluble butylphthalide prodrug choline salt, preparation method therefor and application thereof in medicine | |
| CN104370792B (en) | Oxiracetam compound | |
| US11066352B2 (en) | Processes of making L-ornithine phenylacetate | |
| CN105439889A (en) | Vanillylamine type new compound as well as preparation method and medical appliance thereof | |
| CN107344920A (en) | A kind of Peramivir sesquialter hydrate compound | |
| RU2045268C1 (en) | Antihistamine and antiallergic agent and method for preparing of glutaminate of hinuclidise-3-diphenylcarbinol as solution for injections |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder |
Address after: Building C25, nanotechnology Park, 218 Xinghu street, Suzhou Industrial Park, Jiangsu Province Patentee after: Borui biomedical (Suzhou) Co.,Ltd. Patentee after: Borui Pharmaceutical (Suzhou) Co., Ltd Address before: Building C25, nanotechnology Park, 218 Xinghu street, Suzhou Industrial Park, Jiangsu Province Patentee before: Borui biomedical (Suzhou) Co.,Ltd. Patentee before: XINTAI PHARMACEUTICAL (SUZHOU) Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder |