CN105541945A - Crystal form compound of Ara-ATP - Google Patents
Crystal form compound of Ara-ATP Download PDFInfo
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- CN105541945A CN105541945A CN201610125180.5A CN201610125180A CN105541945A CN 105541945 A CN105541945 A CN 105541945A CN 201610125180 A CN201610125180 A CN 201610125180A CN 105541945 A CN105541945 A CN 105541945A
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- form compound
- vidarabine phosphate
- vidarabine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention belongs to the technical field of medicine and particularly relates to a crystal form compound, shown in a formula (I), of Ara-ATP. According to the compound, an X-ray powder diffraction spectrum measured with Cu-K alpha rays is shown in a drawing 1. The crystal form compound of Ara-ATP has improved solubility and stability and has better medical value.
Description
Technical field
The invention belongs to medical art, be specifically related to crystal-form compound of a kind of vidarabine phosphate and preparation method thereof.
Background technology
Vidarabine is purine nucleoside analog derivative, is insoluble in water, has good antivirus action, suppresses copying of virus gene genome nucleic acid, has the effect of the anti-herpesvirus of wide spectrum.All restraining effect is had to being in the hsv of replicative phase, varicella zoster virus and cytomegalovirus, still effective to the virus infection of part acyclovir resistance.
Vidarabine phosphate is the mono-phosphorylated compound of vidarabine, define vidarabine phosphate (Ara-ATP) at 5 introducing one phosphorus adenosines (AMP) of vidarabine (Ara-A), water-soluble higher than Ara-A 400 times, more easily be converted into activity form triphosphoric acid vidarabine in vivo, antivirus action comparatively Ara-A is strong, and cytotoxicity is starkly lower than Ara-A.
Vidarabine phosphate chemical name is: 9-(β-D-arbinofuranose) gland fat purine 5 '-phosplate monohydrate.Molecular formula: C
10h
14n
5o
7pH
2o, molecular weight: 365.26, vidarabine phosphate is white or off-white color crystalline powder, odorless, soluble,very slightly in water, and almost insoluble in methyl alcohol, ethanol, ether, its structural formula is:
Formula I
Vidarabine monophosphate for injection is anti-thymus nucleic acid (DNA) viral medicine, and its pharmacological action is combined with the deoxyribonucleic acid polymerase of virus, makes its active reduction and suppresses DNA to synthesize.After vidarabine phosphate enters cell, generate vidarabine bisphosphate (Ara-ADP) and vidarabine triphosphoric acid (Ara-ATP) through phosphorylation.Antiviral activity is primarily of caused by vidarabine triphosphoric acid (Ara-ATP), Ara-ATP and deoxyadenosine triphosphate (dATP) are attached on viral DNA P with competing, thus inhibit the activity of enzyme and the synthesis of viral DNA, suppress the activity of viral nucleotide reductase enzyme simultaneously and suppress the synthesis of viral DNA, the activity of viral DNA end Deoxynucleotidyl transferase can also be suppressed, Ara-A penetrated in the DNA of virus and is connected to the end of DNA chain 3 '-OH position, inhibit the continuation of viral DNA to synthesize.Be used for the treatment of the stomatitis caused by herpesvirus infection, dermatitis, encephalitis and cytomegalovirus infection.
But because vidarabine phosphate is slightly soluble in water, solution is muddy, and clarity is bad, makes vidarabine monophosphate for injection in actual production process, need use sodium hydroxide solution adjust ph; And vidarabine monophosphate for injection particulate matter in long-term storage process can increase, against regulation, cause solution muddy, clarity is bad, and in " Chinese Pharmacopoeia " 2010 editions, the particulate matter of injection is had higher requirement, because the particulate matter in intravenous infusion can work the mischief to human body, as larger particulate matter can cause local circulation obstacle, cause blood vessel embolism; Particulate is crossed and can be caused local stoppages and blood supply insufficiency at most, and causes histanoxia further, produces oedema and phlebitis, also can cause granuloma, anaphylaxis, the reaction of thermal source sample etc., all can work the mischief to human body.
CN201310093504.8 provides a kind of new crystalline compounds, this compound has better solvability, the solubleness in vidarabine phosphate water (20 DEG C) is made to be promoted to 115.6mg/mL by 98.5mg/mL, can solubleness improves limitation, solve Problems existing in above-mentioned preparation doubtful.
CN201310048253.1 provides a kind of process for purification of new vidarabine phosphate, attempt to solve prior art by the problem of water as the higher generation by product of solvent temperature, the vidarabine phosphate crystal that this patent obtains does not provide solubility data.
The quantity of vidarabine phosphate is comparatively large, because its deliquescent problem need further raising in Clinical practice safety issue, therefore researchs and develops better crystalline compounds and has certain market requirement.
Summary of the invention
Polymorph in pharmaceuticals phenomenon is ubiquitous problem in present drug research.The polymorphism of medicine can affect its physico-chemical property, and then may have influence on the clinical efficacy of medicine.Material due to by the impact of various factors, makes in molecule or molecular linkage mode changes when crystallization, cause molecule or atom different in lattice vacancy arrangement, form different crystalline structure.The present inventor is after having carried out large quantifier elimination to vidarabine phosphate, obtain a kind of vidarabine phosphate crystal compound being different from the crystalline structure of prior art by change recrystallisation solvent, crystallization condition, and surprisingly found that in the water of this new vidarabine phosphate crystal-form compound, solubleness is obviously better than the vidarabine phosphate of prior art.
The object of the present invention is to provide a kind of vidarabine phosphate crystal-form compound, this crystal-form compound is a kind of new crystal structure of vidarabine phosphate, and this crystalline structure has the solubleness of improvement.
Meanwhile, the preparation method of described vidarabine phosphate crystal-form compound is provided provide.
For realizing object of the present invention, the present invention adopts following technical scheme:
Vidarabine phosphate crystal-form compound shown in a kind of formula (I), wherein,
Formula (I)
The X-ray powder diffractogram that described vidarabine phosphate crystal-form compound uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
Further, the X-ray powder diffractogram data of this vidarabine phosphate crystal-form compound are as follows:
In some embodiments, vidarabine phosphate crystal-form compound of the present invention can be formed pharmaceutical composition together with other pharmaceutically acceptable auxiliary materials.
In some embodiments, vidarabine phosphate crystal-form compound of the present invention can be applied in preparation treatment hsv, varicella zoster virus and cytomegalovirus medicine.
In some embodiments, the pharmaceutical composition of vidarabine phosphate crystal-form compound of the present invention can be applied in preparation treatment hsv, varicella zoster virus and cytomegalovirus medicine.
In some embodiments, vidarabine phosphate crystal-form compound of the present invention can be applied in stomatitis, dermatitis, encephalitis and the cytomegalovirus infection medicine caused by preparation treatment herpesvirus infection.
In some embodiments, the pharmaceutical composition of vidarabine phosphate crystal-form compound of the present invention can be applied in stomatitis, dermatitis, encephalitis and the cytomegalovirus infection medicine caused by preparation treatment herpesvirus infection.
In some embodiments, vidarabine phosphate crystal-form compound of the present invention can be applied in preparation treatment is to the virus infective medicament of acyclovir resistance.
In some embodiments, the pharmaceutical composition of vidarabine phosphate crystal-form compound of the present invention can be applied in preparation treatment is to the virus infective medicament of acyclovir resistance.
The present invention also provides the preparation method of described vidarabine phosphate crystal-form compound further, and the method comprises the steps:
Getting vidarabine phosphate adds in 10 times amount DMF, be heated to be back to entirely molten, under return stirring condition, slow dropping methyl alcohol and acetonitrile volume ratio are the mixing solutions of 1:3.6, until solution occurs muddy, in the bath of agitation condition underlying cryosel, soldier is cold, slowly rise to room temperature, hold over night, filters, drying and get final product.
Related substance and the detection method of content of vidarabine phosphate crystal formation composition of the present invention are:
(1) related substance detection method:
Chromatographic condition and system suitability experiment octadecylsilane chemically bonded silica are weighting agent; With the potassium primary phosphate of 0.05mol/L (add 10% tetrabutylammonium and regulate pH to 6.5)-methyl alcohol (90:10) for moving phase; Flow velocity is 1.0ml/min, and determined wavelength is 259nm.The resolution of vidarabine phosphate peak and other impurity peaks should conform with the regulations, and theoretical plate number, should lower than 1500 by vidarabine phosphate peak.
It is appropriate that assay method precision takes vidarabine phosphate sample, adds moving phase and dissolve and dilute the solution made about containing 160 μ g in every 1ml, as need testing solution; Precision measures test liquid 1mL again, puts in 100mL volumetric flask, adds moving phase and is diluted to scale, shake up, as 1% own control solution.Measure contrast solution 20 μ L, injection liquid chromatograph, record color atlas.Peak height is regulated to be 20 ~ 25% of full range, precision measures need testing solution 20 μ L injecting chromatograph again, record color atlas is to 2.5 times of need testing solution principal constituent peak retention time, need testing solution is as aobvious impurity peaks, and impurity peak area summation should be greater than 5 times (5.%) of reference substance solution main peak area.
(2) method of assay
Chromatographic condition and system suitability are tested with above-mentioned related substance detection method
Assay method precision takes this product appropriate (about vidarabine phosphate 20mg), put in 50mL volumetric flask, add moving phase dissolve and be diluted to scale, shake up, precision measures 5mL and puts in 50mL volumetric flask, adds moving phase constant volume, shake up, as trial-product, precision measures 20 μ L injecting chromatographs, record color atlas; Separately get vidarabine phosphate reference substance appropriate, add moving phase and dissolve and dilute the solution making about 20 μ g in every 1mL, product solution in contrast; Be measured in the same method.By external standard method with calculated by peak area, to obtain final product.
Accompanying drawing explanation
Fig. 1: the X-ray powder diffraction pattern of the vidarabine phosphate crystal-form compound that the embodiment of the present invention 1 is obtained.
Specific embodiments
Following is in conjunction with specific embodiments and experimental example, sets forth the present invention further.But these embodiments are only limitted to the present invention instead of for limiting the scope of the invention is described.The experimental technique of unreceipted specific experiment condition in the following example, usually conveniently condition.
Embodiment 1: vidarabine phosphate crystal-form compound
Getting vidarabine phosphate adds in 10 times amount DMF, be heated to be back to entirely molten, under return stirring condition, slow dropping methyl alcohol and acetonitrile volume ratio are the mixing solutions of 1:3.6, until solution occurs muddy, in the bath of agitation condition underlying cryosel, soldier is cold, slowly rise to room temperature, hold over night, filters, drying and get final product.Detecting purity with HPLC is 99.8%.
The vidarabine phosphate crystal-form compound obtained is used the X-ray powder diffraction that the measurement of Cu-K alpha-ray obtains, as shown in Figure 1.
Embodiment 2: the medicinal compositions of vidarabine monophosphate for injection
Vidarabine phosphate crystal-form compound 2g
Methionin 6g
N.F,USP MANNITOL 50g
Sodium phosphate dibasic 2g
SODIUM PHOSPHATE, MONOBASIC 0.2g.
Vidarabine phosphate freeze-dried powder preparation technology
Example 1 vidarabine phosphate crystal-form compound adds appropriate water for injection, then slowly Methionin is added under stirring, add N.F,USP MANNITOL, all dissolve, get the PH of PH conditioning agent (Sodium phosphate dibasic-SODIUM PHOSPHATE, MONOBASIC) regulator solution in 7.0 ~ 7.5 scopes, stirring at room temperature, centrifugal, get supernatant liquor, after sterile filtration, in filtrate packing cillin bottle, then lyophilize.
Vidarabine phosphate drug solution partition is dressed up 2mL/ bottle, and freeze-drying obtains powder injection.
Comparative example 1:
Preparing ozagrel sodium crystal by patent CN201310093504.8 specification sheets embodiment 1 method, obtain white powder, is comparative example 1 sample.
Comparative example 2:
Preparing ozagrel sodium crystal by patent CN201310048253.1 specification sheets embodiment 1 method, obtain white powder, is comparative example 2 sample.
Comparative example 3:
Commercially available vidarabine phosphate.
Comparative example 4:
Comparative example 1 vidarabine phosphate crystal-form compound 2g
Methionin 6g
N.F,USP MANNITOL 50g
Sodium phosphate dibasic 2g
SODIUM PHOSPHATE, MONOBASIC 0.2g.
Vidarabine phosphate freeze-dried powder preparation technology is with embodiment 2.
Test example 1: dissolubility test
With reference to Chinese Pharmacopoeia version in 2000 two note on the use parts, take testing sample appropriate, accurately weighed, be placed in the water of 25 DEG C ± 2 certain capacities, be placed in every five minutes on vibrator and vibrated for 30 seconds; Sample dissolution situation in investigating 30 minutes, during as cannot see particles of solute, is namely considered as dissolving completely.Experimental result is in table 1:
Solubility experiment in table 1 water
Found out by above-mentioned experimental data, the solubleness of crystal-form compound of the present invention is greater than comparative example.
Test example 2: stability test
Stability test object investigates product time dependent rule under the impact of temperature, humidity, light, for pharmaceutical production, packaging, transport condition provide scientific basis.
1, illumination experiment
Operation: get vidarabine phosphate crystal-form compound of the present invention and comparative example is laid in (about 2mm thickness) in culture dish in right amount, places 10 days under being placed in 4500Lx scholar 500Lx strong illumination condition, detects in sampling in the 5th day, 10 days.Detection method is described above.
Table 2 illumination experiment result
2, high temperature experiment
Get vidarabine phosphate crystal-form compound of the present invention and comparative example is laid in (about 2mm thickness) in culture dish in right amount, the thermostat container being placed in 60 DEG C is placed 10 days, detects in sampling in the 5th, 10 day.The same illumination experiment of detection method.
Table 3 high temperature experimental result
3, high humidity experiment
Get vidarabine phosphate crystal-form compound of the present invention and comparative example is laid in (about 2mm thickness) in culture dish, place 10 days under being placed in the condition of room temperature 25 DEG C of scholars 2 DEG C, relative humidity RH90% scholar 5%, detect in sampling in the 5th, 10 day.The same illumination experiment of detection method.
Table 4 high humidity experimental result
4, Acceleration study
Get vidarabine phosphate crystal-form compound of the present invention and comparative example, under putting temperature 40 DEG C ± 2 DEG C, relative humidity RH75% ± 5% condition, place 6 months, in sampling at the 1st, 2,3,6 the end of month once, the same illumination experiment of detection method.
Table 5 Acceleration study result
From above-mentioned experimental data, vidarabine phosphate crystal-form compound of the present invention is better at illumination, high temperature, high humidity and Acceleration study condition stability inferior, is conducive to the long storage periods of finished product.
Test example 3: solubility is tested
This experimental example has investigated the impact of the solubility of the embodiment of the present invention 2 vidarabine monophosphate for injection and comparative example 4 vidarabine monophosphate for injection.The results are shown in Table 6, table 7.
Table 6, performance (dissolution rate) result of redissolving
Table 7, performance (solid precipitation) result of redissolving
As can be seen from the above table, after placement for some time, vidarabine monophosphate for injection of the present invention speed of redissolving is greater than comparative example vidarabine monophosphate for injection redissolution speed.Therefore, the product solvability adopting preparation method of the present invention to prepare is more stable, not easily separates out solid matter, thus substantially increases the drug safety of patient.
Should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (9)
1. the vidarabine phosphate crystal-form compound shown in formula I,
Formula I
It is characterized in that, the X-ray powder diffraction that described vidarabine phosphate crystal-form compound uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
2. one kind comprises the pharmaceutical composition of vidarabine phosphate crystal-form compound described in power 1.
3. preparing the application in treatment hsv, varicella zoster virus and cytomegalovirus medicine as weighed vidarabine phosphate crystal-form compound as described in 1 for one kind.
4. one kind as weighed the application in preparation treatment hsv, varicella zoster virus and cytomegalovirus medicine of pharmaceutical composition as described in 2.
5. preparing the application in stomatitis, dermatitis, encephalitis and cytomegalovirus infection medicine caused by treatment herpesvirus infection as weighed vidarabine phosphate crystal-form compound as described in 1 for one kind.
6. one kind as weighed the application in stomatitis, dermatitis, encephalitis and the cytomegalovirus infection medicine caused by preparation treatment herpesvirus infection of pharmaceutical composition as described in 2.
7. treat the application in the virus infective medicament of acyclovir resistance in preparation as weighed vidarabine phosphate crystal-form compound as described in 1 for one kind.
8. one kind as weighed pharmaceutical composition as described in 2 in preparation treatment to the application in the virus infective medicament of acyclovir resistance.
9. one kind as weighed the preparation method of vidarabine phosphate crystal-form compound as described in 1: it is characterized in that comprising following steps:
Getting vidarabine phosphate adds in 10 times amount DMF, be heated to be back to entirely molten, under return stirring condition, slow dropping methyl alcohol and acetonitrile volume ratio are the mixing solutions of 1:3.6, until solution occurs muddy, in the bath of agitation condition underlying cryosel, soldier is cold, slowly rise to room temperature, hold over night, filters, drying and get final product.
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| CN201610125180.5A CN105541945B (en) | 2016-03-07 | 2016-03-07 | Crystal form compound of Ara-ATP |
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| CN201610125180.5A CN105541945B (en) | 2016-03-07 | 2016-03-07 | Crystal form compound of Ara-ATP |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107141328A (en) * | 2017-06-14 | 2017-09-08 | 上海华理生物医药有限公司 | A kind of Vidarabine Monophosphate novel crystal forms and preparation method thereof |
| CN113171347A (en) * | 2021-04-06 | 2021-07-27 | 海南锦瑞制药有限公司 | Preparation method of vidarabine monophosphate freeze-dried powder injection for injection |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4123609A (en) * | 1976-11-03 | 1978-10-31 | Warner-Lambert Company | Process for the production of 9-(β-D-arabinofuranosyl)adenine, 5'-phosphate |
| CN103122017A (en) * | 2013-02-06 | 2013-05-29 | 广东先强药业股份有限公司 | Refining method of vidarabine monophosphate |
| CN103159815A (en) * | 2013-03-22 | 2013-06-19 | 海南中化联合制药工业股份有限公司 | Monophosphate vidarabine crystalline compound, medical composition and preparation method thereof |
| CN105039466A (en) * | 2015-06-10 | 2015-11-11 | 海南中化联合制药工业股份有限公司 | Preparation method of vidarabine monophosphate |
-
2016
- 2016-03-07 CN CN201610125180.5A patent/CN105541945B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4123609A (en) * | 1976-11-03 | 1978-10-31 | Warner-Lambert Company | Process for the production of 9-(β-D-arabinofuranosyl)adenine, 5'-phosphate |
| CN103122017A (en) * | 2013-02-06 | 2013-05-29 | 广东先强药业股份有限公司 | Refining method of vidarabine monophosphate |
| CN103159815A (en) * | 2013-03-22 | 2013-06-19 | 海南中化联合制药工业股份有限公司 | Monophosphate vidarabine crystalline compound, medical composition and preparation method thereof |
| CN105039466A (en) * | 2015-06-10 | 2015-11-11 | 海南中化联合制药工业股份有限公司 | Preparation method of vidarabine monophosphate |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107141328A (en) * | 2017-06-14 | 2017-09-08 | 上海华理生物医药有限公司 | A kind of Vidarabine Monophosphate novel crystal forms and preparation method thereof |
| CN113171347A (en) * | 2021-04-06 | 2021-07-27 | 海南锦瑞制药有限公司 | Preparation method of vidarabine monophosphate freeze-dried powder injection for injection |
| CN113171347B (en) * | 2021-04-06 | 2022-11-29 | 海南锦瑞制药有限公司 | Preparation method of vidarabine monophosphate freeze-dried powder injection for injection |
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Application publication date: 20160504 Assignee: HAINAN HULUWA PHARMACEUTICAL GROUP CO., LTD. Assignor: Deng Aixiang Contract record no.: 2017410000004 Denomination of invention: Crystal form compound of Ara-ATP Granted publication date: 20170208 License type: Exclusive License Record date: 20170220 |
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