WO2019135405A1 - Procédé de détection d'un analogue dérivé de la trifluridine - Google Patents

Procédé de détection d'un analogue dérivé de la trifluridine Download PDF

Info

Publication number
WO2019135405A1
WO2019135405A1 PCT/JP2019/000010 JP2019000010W WO2019135405A1 WO 2019135405 A1 WO2019135405 A1 WO 2019135405A1 JP 2019000010 W JP2019000010 W JP 2019000010W WO 2019135405 A1 WO2019135405 A1 WO 2019135405A1
Authority
WO
WIPO (PCT)
Prior art keywords
salt
analog
trifluridine
mobile phase
deoxy
Prior art date
Application number
PCT/JP2019/000010
Other languages
English (en)
Japanese (ja)
Inventor
武田　大典
章代 小島
Original Assignee
大鵬薬品工業株式会社
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US16/040,734 external-priority patent/US10816517B2/en
Priority claimed from CN201810821041.5A external-priority patent/CN110007010A/zh
Application filed by 大鵬薬品工業株式会社 filed Critical 大鵬薬品工業株式会社
Priority to EP19736109.0A priority Critical patent/EP3736568B1/fr
Priority to JP2019563983A priority patent/JP7257969B2/ja
Publication of WO2019135405A1 publication Critical patent/WO2019135405A1/fr

Links

Images

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/26—Conditioning of the fluid carrier; Flow patterns
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/26—Conditioning of the fluid carrier; Flow patterns
    • G01N30/28—Control of physical parameters of the fluid carrier
    • G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
    • 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
    • C07H19/06—Pyrimidine radicals
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical

Definitions

  • the present invention relates to a method for measuring a related substance of a trifluridine-containing preparation by high performance liquid chromatography.
  • Non-patent Document 1 5-trifluoromethyluracil and 5-carboxyuracil are known as analogues of trifluridine, and there is a report that they are measured by high performance liquid chromatography.
  • Non-patent Document 2 5-trifluoromethyluracil, which is an analogue of trifluridine, can be measured under various reverse phase liquid chromatography conditions.
  • Non-patent Document 3 It has been reported that liquid chromatography is used to measure uptake of trifluridine into tumor cells.
  • Non-patent Document 4 It has been reported that liquid chromatography is used to determine the substrate specificity of trifluridine TK1 (Non-patent Document 4).
  • Non-patent Document 5 It has been reported that liquid chromatography is used in the measurement of trifluridine in enzyme synthesis.
  • Non-patent Document 2 Various high performance liquid chromatography conditions using acetonitrile have been reported for the measurement of 5-trifluoromethyluracil, which is an analogue of trifluridine.
  • Non-patent Document 3 Conditions for high performance liquid chromatography using acetonitrile have been reported to measure uptake of trifluridine into tumor cells.
  • Non-patent Document 5 In order to confirm trifluridine in enzyme synthesis, conditions of high performance liquid chromatography with gradient added with trimethyl ammonium acetate have been reported (Non-patent Document 5).
  • Non-patent Documents 9 and 10 Conditions of high performance liquid chromatography using methanol have been reported for trifluridine as eye drops.
  • Patent Document 7 high performance liquid chromatography is used to confirm the purity of trifluridine, but the conditions are not described.
  • the problem to be solved by the present invention is to provide a novel method capable of detecting trifluridine-derived analogues from a sample containing trifluridine or a salt thereof by high performance liquid chromatography by steps using two gradient conditions. It is.
  • the present inventors are able to detect trifluridine or its salt analogues efficiently by using high performance liquid chromatography under specific conditions, and a detection method suitable for assuring the quality thereof Found out.
  • the present invention provides the following [1] to [31].
  • a method for detecting a related substance derived from trifluridine comprising the step of subjecting a sample containing trifluridine or a salt thereof to high performance liquid chromatography using a mobile phase consisting of an organic phase and an aqueous phase, the method comprising the steps of:
  • the method wherein the step of subjecting to high performance liquid chromatography comprises steps 1 and 2 meeting the following requirements: Step 1: The ratio of the organic phase to the total mobile phase is 1 to 14% by volume. Step 2: After step 1, apply a gradient to increase the ratio of organic phase to total mobile phase.
  • analogue is at least one selected from the group consisting of the following analogues 1 to 6: Related substances 1: 5-carboxyuracil, Analogs 2: 5-Carboxy-2'-deoxy-uridine, Related substances 3: 2'-deoxy-5-methoxycarbonyluridine, Related substances 4: trifluorothymine, Related substances 5: 5-methoxycarbonyluracil, Analogs 6: 5 '-(4-chlorophenylcarboxy) -2'-deoxy-5-trifluoromethyluridine.
  • a method for producing a compounding preparation containing trifluridine or a salt thereof which comprises the step of performing the method according to any one of [1] to [12].
  • a method of quality control of a compounding agent comprising trifluridine or a salt thereof, and tipiracil or a salt thereof which comprises the step of performing the method according to any one of [1] to [12].
  • the present invention is a high-performance liquid chromatography using a mobile phase consisting of an organic phase and an aqueous phase, which is capable of efficiently detecting trifluridine or its salt analogues, and which is suitable for assuring the quality thereof. is there.
  • Example 1 shows a chromatogram in Example 1-1.
  • 7 shows a chromatogram in Example 1-3.
  • the chromatogram in Example 2-1 is shown.
  • Trifluridine (FTD) in the present invention is ⁇ , ⁇ , ⁇ -trifluorothymidine, which is a compound having the following structure.
  • any isomer or a mixture is also a compound of the present invention unless otherwise specified. Is included.
  • a salt means a pharmaceutically acceptable salt and can include a base addition salt or an acid addition salt.
  • the base addition salt examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine And salts thereof, organic amine salts such as diethanolamine salt, triethanolamine salt, procaine salt, N, N'-dibenzylethylenediamine salt and the like.
  • alkali metal salts such as sodium salts and potassium salts
  • alkaline earth metal salts such as calcium salts and magnesium salts
  • ammonium salts such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine And salts thereof, organic amine salts such as diethanolamine salt, triethanolamine salt, procaine salt, N, N'-dibenzylethylenediamine salt and the like.
  • the acid addition salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate; for example, acetate, formate, maleate, fumarate, tartrate, citric acid Organic acid salts such as salts of ascorbate and trifluoroacetate; and sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate and the like.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate
  • Organic acid salts such as salts of ascorbate and trifluoroacetate
  • sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate and the like.
  • trifluridine or a salt thereof to be used in the present invention is preferably a free form of trifluridine which has not formed a salt.
  • the sample in the present invention may contain a trifluridine analogue.
  • the analogues include compounds of analogues 1 to 6.
  • 5-carboxyuracil It may also be referred to as 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid.
  • Analog substance 2 is 5-carboxy-2'-deoxy-uridine. 1-((2R, 4R, 5R) -4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and It is sometimes called.
  • Analog 3 is 2'-deoxy-5-methoxycarbonyluridine. 1-((2R, 4R, 5R) -4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester It is sometimes called.
  • the related substance 4 is trifluorothymine. Sometimes referred to as 5- (trifluoromethyl) pyrimidine-2,4 (1H, 3H) -dione.
  • the related substance 5 is 5-methoxycarbonyluracil. It may also be referred to as methyl 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate.
  • Analog 6 is 5 '-(4-chlorophenylcarboxy) -2'-deoxy-5-trifluoromethyluridine.
  • 4-chlorobenzoic acid ((2R, 3R, 5R) -5- (2,4-dioxo-5- (trifluoromethyl) -3,4-dihydropyrimidin-1 (2H) -yl) -3-hydroxytetrahydrofuran Sometimes referred to as -2-yl) methyl.
  • the samples used in the present invention are not only samples prepared from the preparation and drug substance themselves, but also samples prepared in a test for confirming the stability etc., each for confirming the retention time of each related substance, etc. It can also be used as a sample to which a related substance is added, a sample prepared to confirm the preparation process of a drug product or drug substance, and the like.
  • the sample may contain, be substantially free of, or not contain tipiracil or a salt thereof formulated in Ronsurf (registered trademark).
  • Formulations that can be used in the present invention include trifluridine or a salt thereof. And, if necessary, a pharmaceutically acceptable carrier can be blended, and various administration forms can be adopted according to the purpose of prevention or treatment, and as such forms, for example, oral agents, eye drops, injections, Any of suppositories, ointments, patches and the like may be used, and preferably oral preparations are employed. Each of these dosage forms can be prepared by conventional formulation methods known to those skilled in the art.
  • the pharmaceutically acceptable carrier various organic or inorganic carrier substances conventionally used as pharmaceutical ingredients are used, and excipients in solid preparations, binders, disintegrants, lubricants, coloring agents, solvents in liquid preparations, It is formulated as a solubilizer, suspending agent, tonicity agent, buffer, soothing agent and the like.
  • formulation additives such as preservatives, antioxidants, colorants, sweeteners and stabilizers can also be used, if necessary.
  • the eye drop When the eye drop is prepared, it can be produced by using a solubilizing agent, a tonicity agent, a buffer, a preservative and the like with trifluridine or a salt thereof.
  • the daily dose of the drug having the above-mentioned administration form can be appropriately determined depending on the condition, weight, age, sex and the like of the patient.
  • the high performance liquid chromatography column that can be used in the present invention is a silica gel column, a silica gel column whose surface is modified with octadecylsilyl group (ODS column or C18 column), a silica gel column whose surface is modified with octyl group (C8 column), Silica gel column whose surface is modified with cyanopropyl group (CN column), silica gel column whose surface is modified with phenethyl group (Ph column), silica gel column whose surface is modified with aminopropyl group (NH column), dihydroxy surface It is selected from a silica gel column modified with propyl group (Diol column), a column packed with various polymers (polymer column), a column packed with ion exchange resin (ion exchange column), etc. In the present invention, ODS columns are preferred.
  • ODS column various types of silica gel particles different in particle diameter, pore diameter, octadecylsilyl group bonding method, octadecylsilyl group substitution degree and the like can be used.
  • high purity silica gel is used, and an ODS column (end-capped ODS column) in which silanol remaining after octadecylation is treated with a low molecular weight silylating agent is preferable.
  • the average particle diameter of the silica gel is, for example, preferably 2 to 10 ⁇ m, and more preferably 3 to 5 ⁇ m.
  • the average particle size of silica gel can be measured by a laser diffraction method or the like.
  • the average pore diameter of the silica gel is, for example, preferably 6 to 20 nm, and more preferably 8 to 13 nm.
  • the average pore size of silica gel can be measured by a gas adsorption method or the like.
  • bonding method of the octadecyl silyl group in a silica gel for example, a monomeric form, polymeric form etc. are preferable.
  • the degree of substitution of the octadecylsilyl group can be measured by various methods.
  • the amount of carbon in silica gel is, for example, preferably 3% or more, and more preferably 10% or more.
  • the amount of carbon in the silica gel is, for example, preferably 25% or less, more preferably 20% or less.
  • the carbon content of silica gel can be measured by various methods.
  • the organic phase used in the mobile phase of high performance liquid chromatography includes nonpolar solvents such as hexane, cyclohexane, heptane, diethyl ether, tetrahydrofuran, chloroform and methylene chloride; aprotic polar solvents such as acetone, dimethylsulfoxide and acetonitrile; Acetic acid, methanol, ethanol, isopropanol, acetonitrile and the like can be used.
  • One of these solvents may be used alone, or two or more thereof may be used as a mixed solvent.
  • methanol or acetonitrile is preferable, and acetonitrile is more preferable.
  • the organic phase may contain 10% or less of water.
  • the aqueous phase used for the mobile phase of high performance liquid chromatography is not limited to water, but may contain 10% or less of an organic solvent, but contains 10% or less of methanol with respect to the entire aqueous phase.
  • the aqueous phase is preferred, more preferably 5% or less of methanol is contained, 2% or less of methanol is further preferably contained, and 0.1 to 1% of methanol is contained Particularly preferred.
  • acetic acid or a salt thereof citric acid or a salt thereof, tartaric acid or a salt thereof, phosphoric acid or a salt thereof can be added.
  • acetic acid or a salt thereof include acetic acid and sodium acetate.
  • Citric acid or a salt thereof includes citric acid, monosodium citrate, disodium citrate and trisodium citrate.
  • tartaric acid or its salt tartaric acid, sodium tartrate, phosphoric acid or its salt include phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate.
  • a phosphate is preferable, and sodium dihydrogenphosphate is more preferable, in view of the properties of the measurement substance, the shape of the peak obtained in the measurement, and the reproducibility of the measurement.
  • sodium dihydrogenphosphate is more preferable, in view of the properties of the measurement substance, the shape of the peak obtained in the measurement, and the reproducibility of the measurement.
  • the concentration of the buffer that can be used in the present invention can be appropriately adjusted as long as the buffer does not precipitate during measurement of high performance liquid chromatography.
  • it is 1 to 50 mM, more preferably 5 to 40 mM, still more preferably 10 to 30 mM, and particularly preferably 18 to 20 mM.
  • the ratio of the organic phase to the whole mobile phase at the retention time of the analogues 1, 2, 3, 4, 5 and trifluridine is preferably 1 to 14% by volume, more preferably 2 to 10% by volume And 3 to 7% by volume are particularly preferred.
  • the present invention is characterized by including the gradient conditions of step 1 and step 2.
  • Step 1 The ratio of the organic phase to the total mobile phase is 1 to 14% by volume.
  • Step 2 After step 1, apply a gradient to further increase the ratio of organic phase to total mobile phase.
  • the mobile phase may be in a gradient or in an isocratic state, but an isocratic state is preferred.
  • the ratio of the organic phase to the whole mobile phase in step 1 may be 1 to 14% by volume, preferably 2 to 10% by volume, and particularly preferably 3 to 7% by volume.
  • “the ratio of the organic phase to the whole mobile phase in step 1 is X to Y volume%” means that the ratio is in the range of X to Y volume% during step 1.
  • the start of step 1 is within 5 minutes of injecting the sample into high performance liquid chromatography, preferably within 3 minutes, more preferably within 1 minute, and particularly preferably simultaneously with the injection.
  • step 1 is 13 to 30 minutes after injecting the sample into high performance liquid chromatography. Taking into consideration that trifluridine does not overlap with the depressions in the baseline and ghost peaks, the end of step 1 is preferably 15-28 minutes after the injection, and particularly preferably 17-25 minutes.
  • the measurement time in step 1 is not particularly limited as long as it is in the range of the above start and end, but it is preferably 15 to 28 minutes, and more preferably 17 to 25 minutes.
  • the upper limit of the flow rate of the mobile phase in step 1 may be that which is usually used in high performance liquid chromatography, but the flow rate is preferably 2.5 mL / min or less in consideration of separation of the retention time of each related substance. 2.0 mL / min or less is more preferable, 1.5 mL / min or less is more preferable, 1.3 mL / min or less is still more preferable, and 1.1 mL / min or less is particularly preferable. Further, the range of the flow rate of the mobile phase in step 1 is not particularly limited, but is preferably 0.5 to 2.5 mL / min, more preferably 0.5 to 2.0 mL / min, and more preferably 0.7 to 1. 5 mL / min is more preferable, 0.8 to 1.3 mL / min is even more preferable, and 0.9 to 1.1 mL / min is particularly preferable.
  • step 1 one or more trifluridine analogues selected from the group consisting of analogues 1, 2, 3, 4 and 5 can be detected.
  • analogues 1, 2, 3, 4 and 5 can be detected in step 1.
  • Step 1 when at least one of Related Substances 1, 2, 3, 4 and 5 is detected in Step 1, Related Substances 1, 2, 3,
  • the difference between the maximum value and the minimum value of the ratio of the organic phase to the entire mobile phase at each retention time of each of those detected in step 1 among 4 and 5 is 5% by volume or less of the total mobile phase Preferably, it is 1% by volume or less.
  • step 2 the mobile phase is subjected to a gradient to increase the proportion of the organic phase. If gradients were applied in step 1, step 2 applies gradients to increase the proportion of the organic phase. In the case of isocratic state in step 1, step 2 applies a gradient to increase the proportion of the organic phase.
  • the ratio of the organic phase to the whole mobile phase at the end of Step 2 is 25 to 70% by volume, more preferably 30 to 65% by volume, and particularly preferably 35 to 60% by volume.
  • the end of step 2 means the point at which the application of the gradient of step 2 is stopped and the ratio of the organic phase to the whole mobile phase is started to be reduced.
  • the start of step 2 is not particularly limited as long as it starts within 3 minutes after the end of step 1, but 1 minute or less is preferable, and the end of step 1 and its time are more preferable.
  • Step 2 is not particularly limited as long as it is after the retention time of Related Substance 6, but it is 35 to 65 minutes after injecting the sample into high performance liquid chromatography, and more preferably 40 to 60 minutes. .
  • the measurement time in step 2 is not particularly limited as long as the retention time of the related substance 6 can be measured, but 10 to 50 minutes is preferable, and 15 to 45 minutes is more preferable.
  • the gradient in step 2 is not particularly limited as long as it increases the ratio of the organic phase to the total mobile phase, but increases the ratio of the organic phase to the total mobile phase in one minute by 0.9% or more It is more preferable to increase by 1.0% by volume or more per minute, and it is particularly preferable to increase 2.0% by volume or more by 1 minute.
  • the upper limit of the increase in the ratio of the organic phase to the entire mobile phase is not particularly limited, but for example, 10% by volume or less is preferable, and 5.0% by volume or less is more preferable.
  • the change in the ratio of the organic phase to the whole mobile phase during the measurement time of step 2 (the difference between the maximum value and the minimum value among the ratios of the organic phase to the whole mobile phase in the measurement time) Of the whole mobile phase is preferably 30% by volume or more, and more preferably 50% by volume or more.
  • the upper limit of the change in the ratio of the organic phase to the total mobile phase during the measurement time of step 2 is not particularly limited, but preferably 80% by volume or less of the total mobile phase, for example 70% by volume or less Particularly preferred.
  • the flow rate of the mobile phase in step 2 may be any flow rate commonly used in high performance liquid chromatography, but the flow rate is preferably 2.5 mL / min or less, considering the separation of the retention time of each related substance. 0 mL / min or less is more preferable, and 1.5 mL / min or less is more preferable.
  • the range of the flow rate of the mobile phase in step 2 is not particularly limited, but is preferably 0.5 to 2.5 mL / min, more preferably 0.5 to 2.0 mL / min, and more preferably 1.0 to 1. 5 mL / min is more preferable. From the viewpoint of shortening the overall measurement time, it is also possible to gradually increase the flow rate after the start of step 2, and the flow rate at the end of step 2 is 1.0 to 1.5 of the flow rate at the end of step 1 Double is preferred.
  • step 2 the related substance 6 can be detected.
  • an ion pairing reagent in addition to the above additives, an ion pairing reagent can be added.
  • the ion pairing reagent include sodium pentane sulfonate, sodium hexane sulfonate, sodium heptane sulfonate, sodium octane sulfonate, an alkyl sulfonic acid such as sodium dodecane sulfonate or a salt thereof (preferably sodium alkyl sulfonate), sodium dodecyl sulfate And the like (alkyl sodium sulfate), tetraethylammonium hydroxide, tetrabutylammonium hydroxide, tetrabutylammonium chloride, quaternary ammonium salts such as tetrabutylammonium bromide, trihexylamine, trioctylamine And other tertiary amines can be used.
  • the pH of the mobile phase (typically, the aqueous phase) in the present invention can be appropriately adjusted by the above-mentioned additives and the like, but is preferably 2.0 to 5.0.
  • the detection wavelength that can be used in the method of the present invention can be 208 to 280 nm, preferably 208 to 240 nm, more preferably 208 to 212 nm, in consideration of the properties of each related substance.
  • the temperature of the mobile phase in the column that can be used in the method of the present invention can be set as appropriate.
  • the temperature is preferably kept constant, more preferably 25 to 50 ° C., still more preferably 35 to 45 ° C., particularly preferably 40 to 50 ° C. It is 44 ° C.
  • a preheat mixer etc. can be used in order to keep the said temperature constant.
  • the injection amount, the temperature in the column, and the like can be appropriately changed.
  • analogues 1 to 5 can be synthesized by known methods, or can be obtained as commercial products.
  • the related substance 6 can be synthesized from triflulysine or a commercially available compound according to a known method, or can be synthesized according to the method described later.
  • the high-performance liquid chromatography retention time, mass spectrum, and photodiode array (PDA) of the analogues thus obtained are compared with those of the analogues detected according to the present invention to identify the analogues. can do.
  • these analogues can be quantitatively measured by any method of using an external standard or a method of using an internal standard.
  • analogues can also be detected from trifluridine or salts thereof by the method of the present invention.
  • one or more of the analogues 1 to 6 can be used as a standard product for quality control, preferably three or more of the analogues 1 to 6, and more preferably the analogues It is four or more of 1 to 6, particularly preferably analogues 2, 3, 5 and 6.
  • the trifluridine used in such standard products and the related substances derived therefrom become highly pure. Therefore, each related substance separated under the conditions of the high performance liquid chromatography can be used as a standard. Therefore, the present invention can be reworded as a method for producing the related substance, which is characterized in that it is isolated from a combination drug containing trifluridine or a salt thereof.
  • the related substances include the above-mentioned related substances 1 to 6, and preferably the related substances 2, 3, 5, and 6.
  • the quality control method provided by the present invention is a method for quality control of a compounding agent containing trifluridine or a salt thereof, which comprises the step of carrying out the above-mentioned method of the present invention.
  • the quality control method of the present invention for example, when the content (mass) of the above-mentioned analogue (for example, any one or more of analogues 1 to 6) is not more than a predetermined amount, the combination agent is It can be evaluated that the criteria for
  • the present invention also provides a method for producing a combination drug containing trifluridine or a salt thereof, which comprises the steps of carrying out the above-mentioned method of the present invention.
  • the production method of the present invention performs, for example, the step of producing trifluridine or a salt thereof, the obtained trifluridine or a salt thereof, and the quality control of the compounding agent containing the above method (preferably containing triflulidine or a salt thereof) ) Can be included.
  • the present invention includes the related substances 2, 3, 5 or 6 used for quality control of a pharmaceutical composition containing trifluridine or a salt thereof, and further, an impurity of a pharmaceutical composition containing trifluridine or a salt thereof It contains related substances 2, 3, 5 or 6 for use as a standard in detection.
  • a method of producing analogues 2, 3, 5 or 6 characterized in that it is isolated from a pharmaceutical composition containing trifluridine or a salt thereof is also included in the present invention.
  • the method comprises the conditions of the following Step 1 and Step 2 for detecting at least one trifluridine-derived analogue selected from the group consisting of analogues 1 to 6.
  • Step 1 The ratio of the organic phase to the total mobile phase is 1 to 14% by volume.
  • Step 2 After step 1, apply a gradient to further increase the proportion of the organic phase.
  • the method includes the conditions of step 1 and step 2 below.
  • Step 1 Detect at least one trifluridine-derived analogue selected from the group consisting of analogues 1 to 5, and the ratio of the organic phase to the whole mobile phase is 1 to 14% by volume, in an isocratic state is there.
  • Step 2 After step 1, detect related substance 6 by applying a gradient to further increase the proportion of the organic phase.
  • the method includes the conditions of step 1 and step 2 below.
  • Step 1 The ratio of the organic phase to the total mobile phase is 2 to 10% by volume, is isocratic, and detects Related Substances 1 to 5.
  • Step 2 After step 1, detect related substance 6 by applying a gradient to further increase the ratio of the organic phase to the total mobile phase.
  • Step 1 The ratio of the organic phase to the total mobile phase is 2 to 10% by volume, is isocratic, and detects Related Substances 1 to 5.
  • Step 2 Apply a gradient to further increase the ratio of the organic phase to the total mobile phase after Step 1, and the ratio of the organic phase to the total mobile phase at the end of Step 2 is 25 to 70% by volume, Detect related substance 6
  • the method includes the conditions of the following steps 1 and 2 in which the organic phase in the mobile phase contains acetonitrile, the water phase contains water, and the mobile phase contains phosphate.
  • Step 1 The ratio of the organic phase to the total mobile phase is 2 to 10% by volume, is isocratic, and detects Related Substances 1 to 5.
  • Step 2 Apply a gradient that increases the ratio of the organic phase to the total mobile phase by 0.9% or more per minute after step 1, and the ratio of the organic phase to the total mobile phase at the end of step 2 is 30 It is up to 65% by volume, and the related substance 6 is detected.
  • the method includes the conditions of the following steps 1 and 2 in which the organic phase in the mobile phase contains acetonitrile, the water phase contains water, and the mobile phase contains phosphate.
  • Step 1 The ratio of the organic phase to the total mobile phase is 2 to 10% by volume, is isocratic, and detects Related Substances 1 to 5.
  • Step 2 Apply a gradient that increases the ratio of the organic phase to the total mobile phase by 0.9% or more per minute after step 1, and the ratio of the organic phase to the total mobile phase at the end of step 2 is 30 It is up to 65% by volume, and the related substance 6 is detected.
  • the method includes the conditions of the following steps 1 and 2 in which the organic phase in the mobile phase contains acetonitrile, the water phase contains water, and the mobile phase contains phosphate.
  • Step 1 The ratio of the organic phase to the total mobile phase is 3 to 7% by volume, is isocratic, and detects Related Substances 1 to 5.
  • Step 2 After step 1, apply a gradient that increases the ratio of the organic phase to the total mobile phase by 0.9% by volume or more, and the ratio of the organic phase to the total mobile phase at the end of step 2 is 35 Up to 60% by volume, the related substance 6 is detected.
  • the method includes the conditions of the following steps 1 and 2 in which the organic phase in the mobile phase contains acetonitrile, the water phase contains water, and the mobile phase contains sodium phosphorous dihydrogen.
  • Step 1 The ratio of the organic phase to the whole mobile phase is 3 to 7% by volume, is isocratic, the measurement time is 15 to 28 minutes, and the related substances 1 to 5 are detected.
  • Step 2 After step 1, apply a gradient that increases the ratio of the organic phase to the whole mobile phase by 0.9% by volume or more per minute, and the organic phase to the whole mobile phase at the end of step 2 The ratio is 35 to 60% by volume, the measurement time is 10 to 50 minutes, and the related substance 6 is detected.
  • the method includes the conditions of the following steps 1 and 2 in which the organic phase in the mobile phase contains acetonitrile, the water phase contains water, and the mobile phase contains sodium phosphorous dihydrogen.
  • Step 1 The ratio of the organic phase to the whole mobile phase is 3 to 7% by volume, is isocratic, the measurement time is 15 to 28 minutes, and the related substances 1 to 5 are detected.
  • Step 2 After step 1, apply a gradient that increases the ratio of the organic phase to the total mobile phase by 0.9% by volume or more, and the ratio of the organic phase to the total mobile phase at the end of step 2 is 35 It is ⁇ 60% by volume, the measurement time is 10 to 50 minutes, and the flow rate at the end of step 2 is 1.0 to 1.5 times the flow rate of step 1, and the related substance 6 is detected.
  • Step 1 the organic phase in the mobile phase contains acetonitrile, the water phase contains water, and the mobile phase contains methanol and sodium phosphorous dihydrogen.
  • Step 1 The ratio of the organic phase to the whole mobile phase is 3 to 7% by volume, is isocratic, the measurement time is 15 to 28 minutes, and the related substances 1 to 5 are detected.
  • Step 2 After step 1, apply a gradient that increases the ratio of the organic phase to the total mobile phase by 0.9% by volume or more, and the ratio of the organic phase to the total mobile phase at the end of step 2 is 35 It is ⁇ 60% by volume, the measurement time is 10 to 50 minutes, and the flow rate at the end of step 2 is 1.0 to 1.5 times the flow rate of step 1, and the related substance 6 is detected.
  • the sample to be measured by high performance liquid chromatography was prepared as follows.
  • the solution was dissolved in a solution having the same composition as the mobile phase used in each measurement condition so that the concentration of trifluridine was about 0.8 mg / mL, and a properly diluted solution was used as a sample.
  • “%” indication in each mobile phase means volume%.
  • Example 1-1 Column: Hydrosphere C18, manufactured by YMC (3 ⁇ m) Flow rate: 1.0 mL / min Mobile phase A: 0.05 mol / L aqueous sodium dihydrogenphosphate aqueous solution Mobile phase B: acetonitrile Gradient: The mobile phase A and the mobile phase B were changed as follows to control the concentration gradient. 0 to 18 minutes: A 95% B 5%, 18 to 55 minutes: A 95 to 60% B 5% to 40%, 55 to 55.1 minutes A 60% to 95% B 40% to 5%, 55.1 or later A 95% B 5%.
  • Example 1-2 Gradient Concentration gradient control was performed by changing mobile phase A and mobile phase B as follows. 0 to 18 minutes: A 95% B 5%, 18 to 48 minutes: A 95 to 60% B 5% to 40%, 48 to 48.1 minutes A 60% to 95% B 40% to 5%, 48.1 or later A 95% B 5%.
  • the column, flow rate, mobile phase A and mobile phase B are the same as in Example 1.
  • Example 1-3 Concentration gradient control was performed by changing mobile phase A and mobile phase B as follows. 0 to 20 minutes: A 95% B 5%, 20 to 50 minutes: A 95 to 60% B 5% to 40%, 50 to 50.1 minutes A 60% to 95% B 40% to 5%, 50.1 or later A 95% B 5%.
  • the column, flow rate, mobile phase A and mobile phase B are the same as in Example 1.
  • Example 1-3-1 Gradient The concentration gradient was controlled by changing the mobile phase A and the mobile phase B as follows. 0 to 15 minutes: A 95% B 5%, 15 to 45 minutes: A 95 to 60% B 5% to 40%, 45 to 45.1 minutes A 60% to 95% B 40% to 5%, 45.1 or later A 95% B 5%.
  • the column, flow rate, mobile phase A and mobile phase B are the same as in Example 1.
  • the flow rate, the mobile phase A and the mobile phase B are the same as in Example 1-3.
  • Example 1-3-2 Column: Inertsil ODS-4 GL Science (3 ⁇ m) The flow rate, the mobile phase A and the mobile phase B, and the gradient are the same as in Example 1-3-1.
  • Example 1-3-3 Column: YMC-Pack Pro C18 RS (3 ⁇ m) The flow rate, the mobile phase A and the mobile phase B, and the gradient are the same as in Example 1-3-1.
  • Example 1-3-4 Column: YMC-Pack Pro C18 (3 ⁇ m) The flow rate, the mobile phase A and the mobile phase B, and the gradient are the same as in Example 1-3-1.
  • Example 2-1 Column: Hydrosphere C18, manufactured by YMC (5 ⁇ m) Flow rate: 0 to 21 minutes 1.0 mL / min, 21 to 46 minutes 1.0 ⁇ 1.3 mL / min, 46 to 46.1 minutes 1.3 ⁇ 1.0 mL / min, 46.1 minutes or later 1.0 mL / Min
  • Mobile phase A 3.0 g of sodium dihydrogen phosphate dihydrate was dissolved in 1000 mL of water, adjusted to pH 2.2 by adding phosphoric acid, and then 10 mL of methanol was added.
  • Mobile phase B acetonitrile gradient: Mobile phase A and mobile phase B were changed as follows to control concentration gradient. 0 to 21 minutes: A 96% B 4%, 21 to 46 minutes: A 96 to 45% B 4 to 55%, 46 to 46.1 minutes A 45 to 96% B 55 to 4%, 46.1 or more A 96% B 4%.
  • the retention time of trifluridine was 17.4 minutes. Further, the retention time of Related Substance 1 is 3.1 minutes, the retention time of Related Substance 2 is 5.6 minutes, the retention time of Related Substance 3 is 4.1 minutes, the retention time of Related Substance 4 is 7.9 minutes, The retention time of Related Substance 5 was 8.8 minutes, and the retention time of Related Substance 6 was 42.9 minutes.
  • the detected analogues were compounds showing structures of analogues 1 to 6 because their retention times were identical to those of the analogues purchased or synthesized separately.
  • Example 2-2 Column: Unison UK-C18, manufactured by Intact (5 ⁇ m) Other conditions are the same as in Example 2-1.
  • Example 2-3 Mobile phase A: 3.0 g of sodium dihydrogen phosphate dihydrate was dissolved in 1000 mL of water, adjusted to pH 2.2 with phosphoric acid, and then 9 mL of methanol was added. Other conditions are the same as in Example 2-1.
  • Example 2-4 Flow rate: 0 to 21 minutes 0.95 mL / min, 21 to 46 minutes 0.95 to 1.25 mL / min, 46 to 46.1 minutes 1.25 to 0.95 mL / min, 46.1 minutes to 0.95 mL / Min Other conditions are the same as in Example 2-1.
  • Example 2-5 Concentration gradient control was performed by changing mobile phase A and mobile phase B as follows. 0 to 21 minutes: A 95.8% B 4.2%, 21 to 46 minutes: A 95.8 ⁇ 43% B 4.2 ⁇ 57%, 46 to 46.1 minutes A43 ⁇ 95.8% B57 ⁇ 4.2%, 46.1 or later A 95.8% B 4.2%. Other conditions are the same as in Example 2-1.
  • Example 3 Column: Inertsil ODS-2, manufactured by GL Science (5 ⁇ m) Flow rate: 1.0 mL / min Mobile phase A: 0.05 mol / L sodium dihydrogenphosphate aqueous solution Mobile phase B: acetonitrile Gradient: The mobile phase A and the mobile phase B were changed as follows to control the concentration gradient. 0 to 2 minutes: A 85% B 15%, 2 to 7 minutes: A 85 to 60% B 15 to 40%, 7 minutes or more A 60% B 40%.
  • Example 2 Column: Inertsil ODS-2, manufactured by GL Science (5 ⁇ m) Flow rate: 1.0 mL / min Mobile phase A: water Mobile phase B: acetonitrile gradient: A60% B40% isocratic state.

Landscapes

  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de détection d'un analogue qui est dérivé de la trifluridine, le procédé comprenant une étape consistant à soumettre un échantillon qui comprend de la trifluridine ou un sel de celle-ci à une chromatographie liquide à grande vitesse qui utilise une phase mobile qui comprend une phase organique et une phase aqueuse. L'étape de soumission de l'échantillon à la chromatographie liquide à grande vitesse comprend une étape 1 et une étape 2 qui satisfont les conditions suivantes. Étape 1 : la fraction de phase organique de la phase mobile est de 1 à 14 % en volume. Étape 2 : après l'étape 1, un gradient est appliqué pour augmenter la fraction de phase organique de la phase mobile.
PCT/JP2019/000010 2018-01-05 2019-01-04 Procédé de détection d'un analogue dérivé de la trifluridine WO2019135405A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP19736109.0A EP3736568B1 (fr) 2018-01-05 2019-01-04 Procédé de détection d'un analogue dérivé de la trifluridine
JP2019563983A JP7257969B2 (ja) 2018-01-05 2019-01-04 トリフルリジン由来の類縁物質の検出方法

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP2018000881 2018-01-05
JP2018-000881 2018-01-05
US16/040,734 US10816517B2 (en) 2018-01-05 2018-07-20 Method for detecting trifluridine-related substance by high-performance liquid chromatography
US16/040,734 2018-07-20
CN201810821041.5 2018-07-24
CN201810821041.5A CN110007010A (zh) 2018-01-05 2018-07-24 源自曲氟尿苷的类似物质的检测方法

Publications (1)

Publication Number Publication Date
WO2019135405A1 true WO2019135405A1 (fr) 2019-07-11

Family

ID=67144225

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2019/000010 WO2019135405A1 (fr) 2018-01-05 2019-01-04 Procédé de détection d'un analogue dérivé de la trifluridine

Country Status (1)

Country Link
WO (1) WO2019135405A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10809237B2 (en) 2018-01-05 2020-10-20 Taiho Pharmaceutical Co., Ltd. Method for detecting trifluridine-related substance by high-performance liquid chromatography
US10866219B2 (en) 2017-12-22 2020-12-15 Taiho Pharmaceutical Co., Ltd. Method for detecting trifluridine- and/or tipiracil-related substance
CN117871740A (zh) * 2024-03-11 2024-04-12 炉霍雪域俄色有限责任公司 俄色果原浆液相色谱品质检测方法

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6110565A (ja) * 1984-06-26 1986-01-18 Takeda Chem Ind Ltd ウラシル−５−カルボン酸エステル類の製造法
WO1996030346A1 (fr) 1995-03-29 1996-10-03 Taiho Pharmaceutical Co., Ltd. Derives d'uracile, agents de potentialisation d'effet antitumoral et agent antitumoral renfermant ces derives
WO2006080327A1 (fr) 2005-01-26 2006-08-03 Taiho Pharmaceutical Co., Ltd. MÉDICAMENTS ANTICANCÉREUX CONTENANT DE LA α,α,α-TRIFLUOROTHYMIDINE ET UN INHIBITEUR DE LA THYMIDINE PHOSPHORYLASE
JP4437786B2 (ja) 2003-11-11 2010-03-24 三井化学株式会社 ペントース−５−リン酸エステルの製造方法。
JP4441313B2 (ja) 2004-04-02 2010-03-31 三井化学株式会社 ２’−デオキシ−５−パーフルオロアルキルウリジンの製造法
JP4603274B2 (ja) 2004-02-24 2010-12-22 三井化学株式会社 ２’−デオキシ−５−トリフルオロメチルウリジンの製造方法
WO2013122134A1 (fr) 2012-02-15 2013-08-22 大鵬薬品工業株式会社 Composition pharmaceutique orale
WO2013122135A1 (fr) 2012-02-15 2013-08-22 大鵬薬品工業株式会社 Composition pharmaceutique orale
CN105198947A (zh) 2014-06-27 2015-12-30 江苏奥赛康药业股份有限公司 一种Trifluridine化合物及其药物组合物
CN105461772A (zh) 2015-11-23 2016-04-06 国药一心制药有限公司 一种曲氟尿苷中间体及曲氟尿苷的制备方法
CN106749194A (zh) 2017-01-23 2017-05-31 齐鲁天和惠世制药有限公司 一种替匹嘧啶的制备方法

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6110565A (ja) * 1984-06-26 1986-01-18 Takeda Chem Ind Ltd ウラシル−５−カルボン酸エステル類の製造法
WO1996030346A1 (fr) 1995-03-29 1996-10-03 Taiho Pharmaceutical Co., Ltd. Derives d'uracile, agents de potentialisation d'effet antitumoral et agent antitumoral renfermant ces derives
JP4437786B2 (ja) 2003-11-11 2010-03-24 三井化学株式会社 ペントース−５−リン酸エステルの製造方法。
JP4603274B2 (ja) 2004-02-24 2010-12-22 三井化学株式会社 ２’−デオキシ−５−トリフルオロメチルウリジンの製造方法
JP4441313B2 (ja) 2004-04-02 2010-03-31 三井化学株式会社 ２’−デオキシ−５−パーフルオロアルキルウリジンの製造法
WO2006080327A1 (fr) 2005-01-26 2006-08-03 Taiho Pharmaceutical Co., Ltd. MÉDICAMENTS ANTICANCÉREUX CONTENANT DE LA α,α,α-TRIFLUOROTHYMIDINE ET UN INHIBITEUR DE LA THYMIDINE PHOSPHORYLASE
WO2013122134A1 (fr) 2012-02-15 2013-08-22 大鵬薬品工業株式会社 Composition pharmaceutique orale
WO2013122135A1 (fr) 2012-02-15 2013-08-22 大鵬薬品工業株式会社 Composition pharmaceutique orale
CN105198947A (zh) 2014-06-27 2015-12-30 江苏奥赛康药业股份有限公司 一种Trifluridine化合物及其药物组合物
CN105461772A (zh) 2015-11-23 2016-04-06 国药一心制药有限公司 一种曲氟尿苷中间体及曲氟尿苷的制备方法
CN106749194A (zh) 2017-01-23 2017-05-31 齐鲁天和惠世制药有限公司 一种替匹嘧啶的制备方法

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
A. FRESCO-TABOADA ET AL., CATALYSIS TODAY, vol. 259, 2015, pages 197 - 204
B. PAW ET AL., PHARMAZIE, vol. 7, 1997, pages 551 - 552
BALANSARD, G.: "Determination of ophthalmic therapeutic trifluorothymidine and its degradation product by reversed-phase high-performance liquid chromatography", JOURNAL OF CHROMATOGRAPHY, vol. 348, no. 1, 1985, pages 299 - 303, XP026483215 *
COULIER, L. ET AL.: "Simultaneous Quantitative Analysis of Metabolites Using lon-Pair Liquid Chromatography.Electrospray Ionization Mass Spectrometry", ANALYTICAL CHEMISTRY, vol. 78, no. 18, 2006, pages 6573 - 6582, XP008139074 *
D.V. MOISEEV ET AL., PHARMACEUTICAL CHEMISTRY JOURNAL, vol. 41, no. 1, 2007, pages 25 - 33
G. BALANSARD ET AL., JOURNAL OF CHROMATOGRAPHY, vol. 348, 1985, pages 299 - 303
HAGINOYA, N. ET AL.: "Nucleosides and Nucleotides. 160. Synthesis of Oligodeoxyribonucleotides Containing 5-( N -Aminoalkyl)carbamoyl-2‘-deoxyuridines by a New Postsynthetic Modification Method and Their Thermal Stability and Nuclease-Resistance Properties", BIOCONJUGATE CHEMISTRY, vol. 8, no. 3, 1997, pages 271 - 280, XP055619645 *
HORSCH, PH ET AL.: "Influence of radiation sterilization on the stability of trifluorothymidine", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 222, no. 2, 17 July 2001 (2001-07-17), pages 205 - 215, XP002407461 *
JONES, M. F.: "The stability of trifluorothymidine: hydrolysis in buffered aqueous solutions", JOURNAL OF PHARMACY AND PHARMACOLOGY, vol. 33, no. 5, 1981, pages 274 - 278, XP009522080, ISSN: 0022-3573, DOI: 10.1111/j.2042-7158.1981.tb13780.x *
K. JOGI ET AL., INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND CHEMISTRY, vol. 7, 2017, pages 63 - 70
K. SAKAMOTO ET AL., INTERNATIONAL JOURNAL OF ONCOLOGY, vol. 46, 2015, pages 2327 - 2334
LEE, M. G.: "A high pressure liquid chromatographic method for the determination of trifluorothymidine degradation in aqueous solution", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 5, no. 1, 1980, pages 19 - 24, XP023832068 *
M. RIEGEL ET AL., JOURNAL OF CHROMATOGRAPHY, vol. 568, 1991, pages 467 - 474
M.S.H. RIZWAN ET AL., INTERNATIONAL JOURNAL OF INNOVATIVE PHARMACEUTICAL SCIENCES AND RESEARCH, vol. 5, 2017, pages 32 - 42
N. TANAKA ET AL., ONCOLOGY REPORTS, vol. 32, 2014, pages 2319 - 2326
P. HORSCH ET AL., INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 222, 2001, pages 205 - 215
S. GODAY ET AL.: "Natural and Social Sciences", INTERNATIONAL JOURNAL OF RESEARCH IN APPLIED, vol. 5, 2017, pages 93 - 104
See also references of EP3736568A4 *
T. BRIGGLE ET AL., JOURNAL OF CHROMATOGRAPHY, vol. 381, 1986, pages 343 - 355
T. KAWAUCHI ET AL., JOURNAL OF CHROMATOGRAPHY, vol. 751, 2001, pages 325 - 330

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10866219B2 (en) 2017-12-22 2020-12-15 Taiho Pharmaceutical Co., Ltd. Method for detecting trifluridine- and/or tipiracil-related substance
US10809237B2 (en) 2018-01-05 2020-10-20 Taiho Pharmaceutical Co., Ltd. Method for detecting trifluridine-related substance by high-performance liquid chromatography
US10816517B2 (en) 2018-01-05 2020-10-27 Taiho Pharmaceutical Co., Ltd. Method for detecting trifluridine-related substance by high-performance liquid chromatography
CN117871740A (zh) * 2024-03-11 2024-04-12 炉霍雪域俄色有限责任公司 俄色果原浆液相色谱品质检测方法
CN117871740B (zh) * 2024-03-11 2024-05-10 炉霍雪域俄色有限责任公司 俄色果原浆液相色谱品质检测方法

Similar Documents

Publication Publication Date Title
JP7257969B2 (ja) トリフルリジン由来の類縁物質の検出方法
WO2019124544A1 (fr) Procédé de détection d'analogues dérivés de trifluridine et/ou de tipiracil
WO2019135405A1 (fr) Procédé de détection d'un analogue dérivé de la trifluridine
US8440677B2 (en) Atropisomers of 2-purinyl-3-tolyl-quinazolinone derivatives and methods of use
CN108473408A (zh) 壳二孢氯素衍生物及其作为ampk激活剂的用途
Wan et al. A stereospecific HPLC method and its application in determination of pharmacokinetics profile of two enantiomers of naringenin in rats
JP7466642B2 (ja) レンバチニブメシル酸塩結晶形ｘｉ及びその調製方法
JP7257968B2 (ja) トリフルリジン及び／又はチピラシル由来の類縁物質の検出方法
CN102636600B (zh) 一种测定盐酸帕洛诺司琼组合物中光学异构体的方法
CN110007010A (zh) 源自曲氟尿苷的类似物质的检测方法
CN114432249B (zh) 一种青蒿素/青蒿素衍生物固体分散体及其制备方法和应用
CN104771369A (zh) 一种磷酸氟达拉滨冻干粉针剂
CN107870211A (zh) 一种分离测定盐酸帕洛诺司琼的液相色谱方法
Hu et al. Effects of Tween-80 on the dissolution properties of Daidzein solid dispersion in vitro
Hamsa et al. Analytical profile of cinacalcet hydrochloride: A review
CN104688694B (zh) 一种含有硫酸氢氯吡格雷的药物组合物
CN105085614B (zh) 一种链丝菌素甲磺酸钠及其制备方法和用途
CN114306342B (zh) 一种注射用伊马替尼盐的药物组合物及其制备方法
CN114028348B (zh) 一种枸橼酸西地那非口腔崩解片及其制备方法
Srinivasan et al. Method development and validation of tenofovir disoproxil fumerate and emtricitabine in combined tablet dosage form by UV-spectrophotometry and RP-HPLC
CN114200066A (zh) 一种安立生坦有关物质分离检测方法
IT202000027678A1 (it) Dispersioni solide amorfe di cabozantinib-(s)-malato e processi per la loro preparazione
CN117705964A (zh) 一种盐酸达泊西汀及其制剂的分析方法
Moes et al. Pharmaceutical and clinical development of a new oral solid dispersion formulation of paclitaxel
TR201810257A2 (tr) Stabi̇l lurasi̇don tablet formülasyonlari

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19736109

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2019563983

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2019736109

Country of ref document: EP

Effective date: 20200805