CN106632556A - Nelarabine compound of nelarabine powder injection composition used for antitumor drug - Google Patents

Nelarabine compound of nelarabine powder injection composition used for antitumor drug Download PDF

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CN106632556A
CN106632556A CN201611003344.3A CN201611003344A CN106632556A CN 106632556 A CN106632556 A CN 106632556A CN 201611003344 A CN201611003344 A CN 201611003344A CN 106632556 A CN106632556 A CN 106632556A
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nelarabine
compound
powder
crystal
injection composition
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杨献美
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Linyi Caozhimei Pharmaceutical Technology Co Ltd
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Linyi Caozhimei Pharmaceutical Technology Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • 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
    • C07H19/19—Purine radicals with arabinosyl as the saccharide radical
    • 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 relates to a nelarabine compound of a nelarabine powder injection composition used for an antitumor drug, and belongs to the technical field of medicine. The nelarabine is crystal, an X-ray powder diffraction pattern measured by Cu-K alpha ray is shown in a drawing 1. The new crystal of the nelarabine provided by the invention is different from a crystal form structure in the prior art. An experiment proves that the new crystal form compound has the advantages of high purity, good liquidity and water solubility, high stability and small possibility of moisture absorption and is safe and reliable in clinical application.

Description

A kind of nelarabine compound for antineoplastic nelarabine powder-injection composition
Technical field
The invention belongs to pharmaceutical technology field, is related to a kind of antineoplastic nelarabine compound.
Background technology
The entitled 2- amino -9- β-D- arabinofuranosidases glycosyl -6- methoxyl group -9H- purine of nelarabine chemistry, is deoxyguanosine Analog 9- β-D-R furanose guanine（ara-G）Precursor medicine, go through within 2005 listing, can be used for treat T it is thin Born of the same parents' acute lymphatic leukemia（T-ALL）With T cell LBL（T-LBL）.Structural formula is as follows：
Nelarabine is white or off-white color crystalline powder, is slightly soluble in water, and solubility is about 8-9mg/ml in water（25 DEG C, pH= 4-10）.Because dissolubility of the nelarabine in water is poor, this limits to a certain extent it in application pharmaceutically.
" progress of synthesis of nelarabine " [Liangping, Yin Xianqing, Li Weijia. fine-chemical intermediate, 2008,38（5）： 8-10], CN101348511A, CN101092441A disclose it is a kind of nelarabine addition methyl alcohol is mixed and heated to into backflow, stir Mixing makes material dissolution, filters while hot, filtrate concentration, and stirring is lower to add absolute ethyl alcohol, ether, the method that crystallization is placed in cooling.
Patent CN101348511A discloses the synthesis of nelarabine and refined, the preparation method bag that wherein nelarabine is crystallized Include：Nelarabine adds methyl alcohol to be mixed and heated to backflow, filters while hot after dissolving, filtrate concentration, and stirring is lower to add ethanol or ether, Cooling crystallization is placed, is filtered, with absolute ethanol washing, be dried, obtain nelarabine crystallization.
Patent CN103172687A discloses a kind of Nelarabine crystalline compound and preparation method thereof, and its preparation method is： Nelarabine crude product is taken, in input absolute methanol, backflow is heated to；Activated carbon backflow is added after nelarabine dissolving crude product, while hot mistake Filter, is down to room temperature, and ice salt bath cooling, crystallization, suction filtration, ice methyl alcohol washing filter cake obtains Nelarabine crystalline compound.
Patent CN103191051A discloses a kind of nelarabine injection composition and preparation method thereof, its pharmaceutically active into It is divided into nelarabine and sodium chloride, wherein, the nelarabine is a kind of Nelarabine crystalline compound, and the crystalline compounds adopt powder X-ray diffraction determination method is determined, and the X-ray powder diffraction pattern for obtaining is as shown in Figure 5.
As it is known by the man skilled in the art that the polymorph of medicine has become drug research process and pharmaceutical production quality control Requisite important component part in system and detection process.It is biological living that research polymorphic to medicine contributes to new drug compound Property selection, be favorably improved bioavilability, promote clinical efficacy, contribute to the selection and design of drug administration approach, with And the determination of pharmaceutical preparation technology parameter, so as to improve pharmaceutical production quality.Same medicine crystalline form is different, and its bioavilability can Can significant difference.Same medicine, some crystalline forms may possess higher biologically active than other crystalline forms.
The present invention has obtained a kind of new crystalline compounds of nelarabine different from prior art through substantial amounts of research, leads to Overtesting verifies that find new crystalline compounds purity height, mobility and good water solubility, stability is high, is difficult moisture absorption, and clinic should With safe and reliable, using the powder-injection composition obtained in new crystalline compounds, not only purity is high, impurity content is low, clarity It is good, and can guarantee that the packing efficiency in production, content uniformity are little, adverse reaction rate is substantially reduced, and stability is more preferable.
The content of the invention
The goal of the invention of the present invention is to provide a kind of antineoplastic nelarabine compound.
In order to complete the purpose of the present invention, the technical scheme for adopting for：
The present invention discloses a kind of antineoplastic nelarabine compound, and described nelarabine is crystal, is measured using Cu-K alpha rays The X-ray powder diffraction figure for obtaining is as shown in Figure 1.
The present invention discloses the preparation method of above-mentioned antineoplastic nelarabine compound, comprises the steps：
（1）Nelarabine crude product is added in organic solvent 1,70-80 DEG C is heated to, 0.5-1.5 hours are stirred；
（2）Treat that nelarabine crude product is completely dissolved, add activated carbon, be continuously heating to backflow, be incubated 10-30 minutes, filter while hot, Filtrate concentrates；
（3）Stirring is lower to add organic solvent 2, placement to be cooled to room temperature；
（4）Continue to place 1-3 hours, ice bath is cooled to -15 DEG C -- 5 DEG C of crystallizations, growing the grain 6-10 hours, filter, with a small amount of cooling To 0 DEG C of absolute ethanol washing crystal at least 1 time, it is dried, obtains nelarabine crystal.
Further, step（1）Described in the mass volume ratio of nelarabine crude product and organic solvent 1 be 1g:10-12ml.
Further, step（2）Described in activated carbon quality for nelarabine crude product quality 0.1-0.3%.
Further, step（3）Described in the volume ratio of organic solvent 2 and organic solvent 1 be 1:0.25-0.50.
Further, step（4）Described in be dried be drying under reduced pressure, baking temperature control below 50 DEG C, Stress control In 5-15mmHg, drying time is 10-15 hours.
Further, step（1）Described in organic solvent 1 be ethanol or acetonitrile or the two 1:1 mixture, step（3） Described in organic solvent 2 be isopropanol.
In the present invention, described nelarabine crude product can be the synthesis of the nelarabine disclosed in the method using prior art Nelarabine, or commercially available nelarabine bulk drug that method is prepared.
Invention additionally discloses a kind of antineoplastic nelarabine powder-injection composition, the composition of described powder-injection composition For：The weight portion of nelarabine 1, arginine 0.1-0.3 weight portions；Described nelarabine is crystal, is obtained using Cu-K alpha ray measurements X-ray powder diffraction figure it is as shown in Figure 1.
Further, described powder-injection is consisted of：The weight portion of nelarabine 1, the weight portion of arginine 0.2.
Further, the preparation method of described powder-injection composition is comprised the following steps：
（1）Nelarabine crystal and arginine are weighed in proportion, are sufficiently mixed；
（2）Dispense in the cillin bottle to sterilizing and jump a queue.
The polymorphism of solid chemical is the natural phenomena that a kind of universal material is present, and this phenomenon refers to one kind Solid chemical there may be 2 kinds or two or more crystal form state, be also called the polymorphic state of material, the polymorphic of material State is also referred to as " allomorph " phenomenon.Although allomorphous solid matter its chemical nature is identical, its physics and chemistry Matter is probably different." the allomorph medicine " different for physicochemical property, can also clinically show different preventing and treatings The curative effect of disease, directly affects application and the clinical effectiveness of medicine.
The present invention has found the nelarabine crystalline compounds of the present invention compared with prior art further by embodiment and experimental example Compare and improve water solubility, and bioavilability height, good stability, high income, purity are high, widened to a certain extent its Application pharmaceutically.
Compared with prior art, the invention has the advantages that：
（1）Nelarabine crystal provided by the present invention is a kind of nelarabine crystal different from prior art, and the crystal can be significantly Solubility of the nelarabine in water, and good fluidity are improved, moisture absorption is difficult.
（2）Nelarabine crystal provided by the present invention has bioavilability height, drug effect is notable, stability is high, high income, The advantages of purity is high, contributes to the selection design and the determination of pharmaceutical preparation technology parameter of drug administration approach, so as to improve Pharmaceutical production quality.
（3）The preparation method of nelarabine crystalline compounds provided by the present invention is easy to operate, is a kind of economically feasible, fits The method for closing industrialized production.
（4）Using powder-injection composition obtained in the new crystalline compounds of nelarabine, not only purity is high, impurity content is low, clear and bright Spend, and can guarantee that the packing efficiency in production, content uniformity are little, adverse reaction rate is substantially reduced, and stability is more preferable.
Description of the drawings
Fig. 1 is the X-ray powder diffraction collection of nelarabine crystal prepared by the embodiment of the present invention 1.
Fig. 2 is the heat analysis collection of illustrative plates of nelarabine crystalline compounds prepared by the embodiment of the present invention 1.
Specific embodiment
The content of the invention of the present invention is described in further detail below by specific embodiment, but is not therefore limited Determine present disclosure.
Embodiment 1：The preparation of nelarabine crystal
（1）10g nelarabines crude product is added into 110ml ethanol and acetonitrile（1:1）Mixture in, be heated to 75 DEG C, stirring 1 is little When；
（2）Treat that nelarabine crude product is completely dissolved, add activated carbon 0.02g, be continuously heating to backflow, be incubated 20 minutes, while hot mistake Filter, filtrate concentration；
（3）Stirring is lower to add 330ml isopropanols, placement to be cooled to room temperature；
（4）Continue to place 2 hours, ice bath is cooled to -10 DEG C of crystallizations, growing the grain 8 hours, filter, with being cooled to 0 DEG C anhydrous on a small quantity Ethanol washing crystal at least 1 time, drying under reduced pressure（Baking temperature is controlled below 50 DEG C, and Stress control is in 10mmHg, drying time For 12 hours）, obtain nelarabine crystalline compounds 9.875g, yield 98.75%, purity 99.99%.
Obtained nelarabine crystalline compounds are existed with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction are represented 6.9 °, 8.9 °, 11.5 °, 19.1 °, 25.6 °, 29.7 °, show characteristic diffraction peak at 33.9 °, measured using Cu-K alpha rays To X-ray powder diffraction pattern as shown in Figure 1, its purity of high-performance liquid chromatogram determination is 99.9%.With each crystal formation of prior art X-ray powder diffraction collection contrasted, hence it is evident that find nelarabine crystal-form compound of the present invention different from prior art.
Karl Fischer aquametry is adopted to determine KF for 0.39%, so nelarabine crystal-form compound of the present invention is not contained The crystallization water.
Obtained nelarabine crystalline compounds are adopted into Perkin-Elmer companies of U.S. PE Pyris Diamond The thermogravimetric analysis figure that TG thermal analyzers are obtained is as shown in Figure 2.
Embodiment 2：The preparation of nelarabine crystal
（1）10g nelarabines crude product is added into 105ml ethanol and acetonitrile（1:1）Mixture in, be heated to 78 DEG C, stirring 0.8 is little When；
（2）Treat that nelarabine crude product is completely dissolved, add activated carbon 0.025g, be continuously heating to backflow, be incubated 15 minutes, while hot mistake Filter, filtrate concentration；
（3）Stirring is lower to add 420ml isopropanols, placement to be cooled to room temperature；
（4）Continue to place 2.5 hours, ice bath is cooled to -15 DEG C of crystallizations, growing the grain 7 hours is filtered, with the nothing for being cooled to 0 DEG C on a small quantity Water-ethanol washing crystal at least 1 time, drying under reduced pressure（Baking temperature control below 50 DEG C, Stress control in 12mmHg, when being dried Between be 13 hours）, obtain nelarabine crystalline compounds 9.856g, yield 98.56%, purity 99.99%.
X-ray powder diffraction spectrogram and reality that obtained nelarabine crystalline compounds are obtained using Cu-K alpha ray measurements Apply example 1 similar；The thermogravimetric analysis obtained using Perkin-Elmer companies of U.S. PE Pyris Diamond TG thermal analyzers Figure is similar to Example 1.
Embodiment 3：The preparation of nelarabine crystal
（1）10g nelarabines crude product is added into 115ml ethanol and acetonitrile（1:1）Mixture in, be heated to 72 DEG C, stirring 1.2 is little When；
（2）Treat that nelarabine crude product is completely dissolved, add activated carbon 0.015g, be continuously heating to backflow, be incubated 25 minutes, while hot mistake Filter, filtrate concentration；
（3）Stirring is lower to add 230ml isopropanols, placement to be cooled to room temperature；
（4）Continue to place 1.5 hours, ice bath is cooled to -5 DEG C of crystallizations, growing the grain 9 hours is filtered, with the nothing for being cooled to 0 DEG C on a small quantity Water-ethanol washing crystal at least 1 time, drying under reduced pressure（Baking temperature control below 50 DEG C, Stress control in 8mmHg, when being dried Between be 11 hours）, obtain nelarabine crystalline compounds 9.849g, yield 98.49%, purity 99.99%.
X-ray powder diffraction spectrogram and reality that obtained nelarabine crystalline compounds are obtained using Cu-K alpha ray measurements Apply example 1 similar；The thermogravimetric analysis obtained using Perkin-Elmer companies of U.S. PE Pyris Diamond TG thermal analyzers Figure is similar to Example 1.
Embodiment 4：The preparation of nelarabine crystal
（1）10g nelarabines crude product is added in 100ml ethanol, 70 DEG C are heated to, is stirred 0.5 hour；
（2）Treat that nelarabine crude product is completely dissolved, add activated carbon 0.01g, be continuously heating to backflow, be incubated 30 minutes, while hot mistake Filter, filtrate concentration；
（3）Stirring is lower to add 350ml isopropanols, placement to be cooled to room temperature；
（4）Continue to place 1 hour, ice bath is cooled to -12 DEG C of crystallizations, growing the grain 10 hours is filtered, with the nothing for being cooled to 0 DEG C on a small quantity Water-ethanol washing crystal at least 1 time, drying under reduced pressure（Baking temperature control below 50 DEG C, Stress control in 5mmHg, when being dried Between be 15 hours）, obtain nelarabine crystalline compounds 9.827g, yield 98.27%, purity 99.85%.
X-ray powder diffraction spectrogram and reality that obtained nelarabine crystalline compounds are obtained using Cu-K alpha ray measurements Apply example 1 similar；The thermogravimetric analysis obtained using Perkin-Elmer companies of U.S. PE Pyris Diamond TG thermal analyzers Figure is similar to Example 1.
Embodiment 5：The preparation of nelarabine crystal
（1）10g nelarabines crude product is added in 120ml acetonitriles, 80 DEG C are heated to, is stirred 1.5 hours；
（2）Treat that nelarabine crude product is completely dissolved, add activated carbon 0.03g, be continuously heating to backflow, be incubated 10 minutes, while hot mistake Filter, filtrate concentration；
（3）Stirring is lower to add 300ml isopropanols, placement to be cooled to room temperature；
（4）Continue to place 3 hours, ice bath is cooled to -8 DEG C of crystallizations, growing the grain 6 hours, filter, with being cooled to 0 DEG C anhydrous on a small quantity Ethanol washing crystal at least 1 time, drying under reduced pressure（Baking temperature is controlled below 50 DEG C, and Stress control is in 15mmHg, drying time For 10 hours）, obtain nelarabine crystalline compounds 9.832g, yield 98.32%, purity 99.99%.
X-ray powder diffraction spectrogram and reality that obtained nelarabine crystalline compounds are obtained using Cu-K alpha ray measurements Apply example 1 similar；The thermogravimetric analysis obtained using Perkin-Elmer companies of U.S. PE Pyris Diamond TG thermal analyzers Figure is similar to Example 1.
Example of formulations 1：The preparation of nelarabine powder-injection：
Consist of：The weight portion of nelarabine crystal 1 prepared by the present invention, the weight portion of arginine 0. 1.
Preparation method is：
（1）Nelarabine crystal and arginine are weighed in proportion, are sufficiently mixed；
（2）Dispense in the cillin bottle to sterilizing and jump a queue.
Example of formulations 2：The preparation of nelarabine powder-injection：
Consist of：The weight portion of nelarabine crystal 1 prepared by the present invention, the weight portion of arginine 0.2.
Preparation method is：
（1）Nelarabine crystal and arginine are weighed in proportion, are sufficiently mixed；
（2）Dispense in the cillin bottle to sterilizing and jump a queue.
Example of formulations 3：The preparation of nelarabine powder-injection：
Consist of：The weight portion of nelarabine crystal 1 prepared by the present invention, the weight portion of arginine 0. 3.
Preparation method is：
（1）Nelarabine crystal and arginine are weighed in proportion, are sufficiently mixed；
（2）Dispense in the cillin bottle to sterilizing and jump a queue.
Trial target 1：Nelarabine crystalline compounds prepared by the embodiment of the present invention 1.
Trial target 2：Nelarabine crystalline compounds prepared by the embodiment of the present invention 4.
Reference substance 1：Method according to CN101348511A embodiments 19 is obtained nelarabine crystalline compounds.
Reference substance 2：Method according to CN103172687A embodiments 1 is obtained nelarabine crystalline compounds.
Reference substance 3：Commercially available nelarabine
Experimental example 1：Fluidity test
This experimental example evaluates the mobility of sample by the angle of repose of determination sample, and concrete grammar is as follows：Sample particle is taken, from During the surface plate of circle is flowed in fixed little funnel, until obtaining highest cone, cone height H and radius R is measured, Angle of repose α is calculated by tan α=H/R, 1 is the results are shown in Table, angle of repose is bigger, and mobility is poorer.
The fluidity test result of table 1
As known from Table 1, compared with nelarabine of the prior art, the nelarabine crystalline compounds mobility prepared by the present invention shows Write and improve, be conducive to the preparation of preparation, dissolution rate, the raising of bioavilability.
Experimental example 2：Dissolubility test
Appropriate distilled water is added in the low capacity bottle with constant temperature jacket, nelarabine is added at 25 DEG C to being no longer dissolved as Only, start magnetic stirrer, persistently stir under constant temperature, in experimentation system all the time in two-phase coexistent state, 70 points The concentration of nelarabine solubility as at this temperature in the liquid phase of system after clock.Analysis is sampled after 2 hours, is taken adjacent The close mean value of two times result is not molten after stopping stirring in order that solid-liquid is sufficiently separated before sampling as measured value of experiment Nelarabine be deposited to the bottom of low capacity bottle, extract a small amount of upper clear supernate with syringe, filtered with 0.45 micron of filter, from Sample is taken in filtrate, the content of nelarabine is measured by HPLC（Concentration（mg/ml））.The results are shown in Table 2.
The water-soluble contrast of the new crystalline compounds of nelarabine of the present invention and prior art crystal formation under the room temperature of table 2
From table 2 it can be seen that the water solubility of the new crystalline compounds of nelarabine of the present invention is compared with prior art, it is significantly increased.
Experimental example 3：Wettability test
Each sample opening is put in clean culture dish ,≤5mm thick thin layer is spread out into, each two parts, constant humidity closed container is respectively put into In, place 10 days under conditions of relative humidity 75% and 92.5% at 25 DEG C, sampled in the 5th day and the 10th day, to take Xie Erfa determines the moisture of each sample, and result of the test compared with 0 day, and experimental result is shown in Table 3.
The hygroscopicity test results of table 3
As can be seen from the above table, the present invention prepare nelarabine crystalline compounds it is substantially non-hygroscopic under high humidity conditions, its Stability under high humidity environment is substantially better than using the nelarabine of prior art.
Experimental example 4：Influence factor is tested
By trial target and reference substance simulation listing packaging, in 60 DEG C of high temperature, illumination 4500Lx, high humidity（RH90%±5%）Under the conditions of Place 10 days, detected by stability high spot reviews project, compare with 0 day sample, the results are shown in Table 4.
Relevant substance-measuring method：
According to high performance liquid chromatography（Two annex VD of China's coastal port）Determine.
Chromatographic condition is tested with system suitability：With octadecylsilane chemically bonded silica as filler；With 0.02mol/L phosphorus The aqueous solution of acid dihydride sodium：Methyl alcohol（83:17）For mobile phase；Detection wavelength：210nm.Nelarabine peak theoretical cam curve should not be low In 1500.
Determine：It is appropriate that precision weighs nelarabine, with flowing phased soln and dilutes and makes 0.125mg containing nelarabine in every 1ml Solution, as need testing solution.Precision measures above-mentioned need testing solution in right amount, plus mobile phase is made and contain in every 1ml 1.25 μ g Solution as contrast solution；According to the μ l of contrast solution 20 injection liquid chromatographs about the chromatographic condition under material item, are taken, adjust Detector sensitivity, the peak height for making main composition chromatographic peak is about the 15% of full scale, then precision measures need testing solution and compares molten The each 20 μ l of liquid, are injected separately into liquid chromatograph, and chromatographic peak is recorded respectively to 3 times of main composition peak retention time.
The influence factor result of the test of table 4
The height of drug quality is directly connected to the health of millions upon millions of working people's bodies, be also related to China's economic construction into Effect, the consolidation of national defence and nationality it is flourishing；It has been far from the thing of medical industry enterprise scope itself, but the whole people Race, the major issue in the world.Those skilled in the art clearly know that, in the present age that pharmaceutical technology is flourishing, drug safety standard is not by Disconnected to be lifted, the purity of prepared medicine also more and more higher is effectively reduced impurity content, even several percentage points of zero point, The generation of bad reaction can also be effectively reduced, therefore impurity content is most important to drug quality and people's drug safety. Medicine needs to store and transport just to cure the sickness to save the patient from production in the process of circulation, therefore, medicine in storage and transportation Quality is particularly important, and stability is the key for determining drug quality quality, in medicine storage and transportation, stability Bad, impurity change directly affects greatly people's drug safety.
As can be seen from the above table, list using nelarabine crystalline compounds obtained in the method for the present invention is miscellaneous, total miscellaneous etc. contain Amount is very low, and stability is significantly better than the nelarabine of prior art, effectively improves stablizing for drug safety and storage Property, reduce the generation of bad reaction.
Above-mentioned experimental example 1-4 is also carried out to the nelarabine crystalline compounds of other embodiments of the present invention, its knot for obtaining It is really similar.
Experimental example 6：Powder-injection influence factor is tested
Formulation test product 1：Nelarabine powder-injection prepared by invention formulation embodiment 1.
Formulation test product 2：Nelarabine powder-injection prepared by invention formulation embodiment 2.
Preparations. Control product 1：Powder-injection is prepared using preparation method of the present invention, except that changing arginine into chlorination Sodium.
Preparations. Control product 2：Powder-injection is prepared using preparation method of the present invention, except that the nelarabine crystal for adopting for Method according to CN103172687A embodiments 1 is obtained nelarabine crystalline compounds.
Preparations. Control product 3：Powder-injection is prepared using preparation method of the present invention, except that the nelarabine crystal for adopting for Method according to CN103172687A embodiments 1 is obtained nelarabine crystalline compounds, and changes arginine into sodium chloride.
By formulation test product simulation listing packaging, in 60 DEG C of high temperature, illumination 4500Lx, high humidity（RH90%±5%）Under the conditions of Place 10 days, detected by stability high spot reviews project, compare with 0 day sample, the results are shown in Table 5.
The preparation influence factor result of the test of table 5
Found by result above, the powder-injection purity containing the nelarabine crystalline compounds prepared by the present invention is high, impurity contains Measure low, good stability.
Above-mentioned test is also carried out to the nelarabine powder-injection of other example of formulations of the invention, its result phase for obtaining Seemingly.

Claims (7)

1. a kind of nelarabine compound for antineoplastic nelarabine powder-injection composition, it is characterised in that：It is described how Drawing shore compound is crystal, and the X-ray powder diffraction figure obtained using Cu-K alpha ray measurements is as shown in Figure 1.
2. the nelarabine compound for antineoplastic nelarabine powder-injection composition according to claim 1, it is special Levy and be, the nelarabine compound crystal has the following steps prepared：
（1）Nelarabine crude product is added in organic solvent 1,70-80 DEG C is heated to, 0.5-1.5 hours are stirred；
（2）Treat that nelarabine crude product is completely dissolved, add activated carbon, be continuously heating to backflow, be incubated 10-30 minutes, filter while hot, Filtrate concentrates；
（3）Stirring is lower to add organic solvent 2, placement to be cooled to room temperature；
（4）Continue to place 1-3 hours, ice bath is cooled to -15 DEG C -- 5 DEG C of crystallizations, growing the grain 6-10 hours, filter, with a small amount of cooling To 0 DEG C of absolute ethanol washing crystal at least 1 time, it is dried, obtains nelarabine crystal.
3. the nelarabine compound of antineoplastic nelarabine powder-injection composition, its feature are used for as claimed in claim 2 It is：The preparation method step（1）Described in the mass volume ratio of nelarabine crude product and organic solvent 1 be 1g:10-12ml.
4. the nelarabine compound of antineoplastic nelarabine powder-injection composition, its feature are used for as claimed in claim 2 It is：The preparation method step（2）Described in activated carbon quality for nelarabine crude product quality 0.1-0.3%.
5. the nelarabine compound of antineoplastic nelarabine powder-injection composition, its feature are used for as claimed in claim 2 It is：The preparation method step（3）Described in the volume ratio of organic solvent 2 and organic solvent 1 be 1:0.25-0.50.
6. the nelarabine compound of antineoplastic nelarabine powder-injection composition, its feature are used for as claimed in claim 2 It is：The preparation method step（4）Described in be dried be drying under reduced pressure, baking temperature control below 50 DEG C, Stress control In 5-15mmHg, drying time is 10-15 hours.
7. the nelarabine compound of antineoplastic nelarabine powder-injection composition, its feature are used for as claimed in claim 2 It is：The preparation method step（1）Described in organic solvent 1 be ethanol or acetonitrile or the two 1:1 mixture, step（3） Described in organic solvent 2 be isopropanol.
CN201611003344.3A 2016-11-15 2016-11-15 Nelarabine compound of nelarabine powder injection composition used for antitumor drug Pending CN106632556A (en)

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