JP2015166331A - Crystals of nalfurafine and method for producing the same - Google Patents
Crystals of nalfurafine and method for producing the same Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 75
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 19
- XGZZHZMWIXFATA-UEZBDDGYSA-N nalfurafine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@H]3N(C)C(=O)\C=C\C1=COC=C1)CN2CC1CC1 XGZZHZMWIXFATA-UEZBDDGYSA-N 0.000 title abstract description 53
- 229960000441 nalfurafine Drugs 0.000 title abstract description 50
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 72
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 19
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- 238000010898 silica gel chromatography Methods 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 12
- 229940011051 isopropyl acetate Drugs 0.000 claims description 10
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 10
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 7
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical compound C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 abstract description 3
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 abstract 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
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- 239000000843 powder Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- LHRMPWNUXGPPNK-OWOJBTEDSA-N (e)-3-(furan-3-yl)prop-2-enoyl chloride Chemical compound ClC(=O)\C=C\C=1C=COC=1 LHRMPWNUXGPPNK-OWOJBTEDSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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Abstract
Description
本発明は、そう痒症改善薬等の有効成分であるナルフラフィン塩酸塩の前駆体となるナルフラフィンの結晶およびその製造方法に関する。 The present invention relates to a crystal of nalfurafine serving as a precursor of nalfurafine hydrochloride, which is an active ingredient such as a pruritus remedy, and a method for producing the same.
ナルフラフィン塩酸塩は、モルヒナン誘導体である１７−シクロプロピルメチル−３,１４β−ジヒドロキシ−４,５α−エポキシ−６β−［Ｎ−メチル−トランス−３−（３−フリル）アクリルアミド］モルヒナンの塩酸塩であり、オピオイド系の医薬成分として期待されていて、実際にそう痒症改善薬として上市されている。このナルフラフィン塩酸塩の物性や製造方法は、特許文献１の実施例６８に記載されている。 Nalfurafine hydrochloride is the hydrochloride salt of morphinan derivative 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β- [N-methyl-trans-3- (3-furyl) acrylamide] morphinan. Yes, it is expected as an opioid pharmaceutical ingredient, and is actually marketed as a pruritus remedy. The physical properties and production method of this nalflavine hydrochloride are described in Example 68 of Patent Document 1.
特許文献１の実施例６８で得られるナルフラフィン塩酸塩はアモルファスであり、ナルフラフィン塩酸塩を製品化した後にｐＨが一定にならない、最大不純物であるシス体の含有率が極めて高い等の問題があった。この問題については、特許文献２において、ナルフラフィン塩酸塩を結晶として得ることにより解決されている。 The nalfurafine hydrochloride obtained in Example 68 of Patent Document 1 is amorphous, and there are problems such that the pH does not become constant after commercialization of nalfurafine hydrochloride, and the content of the cis isomer that is the maximum impurity is extremely high. . This problem is solved in Patent Document 2 by obtaining nalfrafin hydrochloride as crystals.
ところで、このナルフラフィン塩酸塩は、ナルフラフィンを前駆体とし、これを塩酸塩とするものであるが、そもそも特許文献１の実施例６８に基づいて得られるナルフラフィンは医薬原料に用いるには純度が低いものであり、これを高める必要があることは全く知られていなかった。 By the way, this nalfurafine hydrochloride is obtained by using nalfurafine as a precursor and making it a hydrochloride, but nalfurafin obtained based on Example 68 of Patent Document 1 is originally low in purity for use as a pharmaceutical raw material. It was never known that there was a need to increase this.
従って、本発明の課題は、これまで報告されていない、ナルフラフィン塩酸塩の原料となるナルフラフィンの純度を医薬原料として用いるのに問題がない純度にまで高めた結晶やその製造方法を提供することである。 Therefore, an object of the present invention is to provide a crystal that has not been reported so far, and has improved the purity of nalfurafine, which is a raw material of nalfurafine hydrochloride, to a purity that does not cause a problem when used as a pharmaceutical raw material, and a method for producing the same. is there.
本発明者は、上記課題を解決するために鋭意研究した結果、ナルフラフィンを特定の有機溶媒を用いて再結晶させることにより、ナルフラフィンの純度を医薬原料として用いるのに問題がない純度にまで高められた新たな結晶が得られることを見出した。また、本発明者は、再結晶の前に、ナルフラフィンを特定の展開溶媒を用いたシリカゲルクロマトグラフィーに付すことにより、ナルフラフィンの純度をより高めることができることを見出し、本発明を完成させた。 As a result of diligent research to solve the above-mentioned problems, the present inventor has improved the purity of nalfurafine to a level that does not cause a problem by recrystallizing nalfurafine using a specific organic solvent. It has been found that new crystals can be obtained. Further, the present inventor has found that the purity of nalfurafine can be further increased by subjecting nalfurafine to silica gel chromatography using a specific developing solvent before recrystallization, and has completed the present invention.
すなわち、本発明は、以下の（１）〜（６）である。
（１）粉末Ｘ線回折像において、回折角２θが１５.４°、２３.４°の位置（それぞれ±０.２°の誤差を含む）に強度の大きい回折ピークを与えることを特徴とするナルフラフィンの結晶
（２）ナルフラフィンを、テトラヒドロフランに溶解させた後、シクロヘキサンと混合することを特徴とする上記（１）記載の結晶の製造方法
（３）ナルフラフィンを、テトラヒドロフランに溶解させる前に、ｎ−ヘプタン、酢酸エチルおよびトリエチルアミンを体積比で５：５：０.５とした展開溶媒を用いたシリカゲルクロマトグラフィーに付すものである上記（２）記載の結晶の製造方法
（４）粉末Ｘ線回折像において、回折角２θが５.９°、１１.５°、１５.７°、１８.６°の位置（それぞれ±０.２°の誤差を含む）に強度の大きい回折ピークを与えることを特徴とするナルフラフィンの結晶
（５）ナルフラフィンを、イソプロパノールおよび／または酢酸エチルに溶解させた後、メチル−ｔ−ブチルエーテルおよび／または酢酸イソプロピルと混合することを特徴とする上記（４）記載の結晶の製造方法
（６）ナルフラフィンを、イソプロパノールおよび／または酢酸エチルに溶解させる前に、ｎ−ヘプタン、酢酸エチルおよびトリエチルアミンを体積比で５：５：０.５とした展開溶媒を用いたシリカゲルクロマトグラフィーに付すものである上記（５）記載の結晶の製造方法
That is, this invention is the following (1)-(6).
(1) In a powder X-ray diffraction image, a diffraction peak having a high intensity is given to a position where diffraction angles 2θ are 15.4 ° and 23.4 ° (each including an error of ± 0.2 °). Crystals of nalfurafine (2) The method for producing crystals according to the above (1), wherein nalfurafine is dissolved in tetrahydrofuran and then mixed with cyclohexane. (3) Before dissolving nalfurafine in tetrahydrofuran, n- (4) Powder X-ray diffractogram In this case, a diffraction peak having a high intensity is given at positions where the diffraction angle 2θ is 5.9 °, 11.5 °, 15.7 °, and 18.6 ° (each including an error of ± 0.2 °). (5) The crystal according to (4) above, wherein nalfurafine is dissolved in isopropanol and / or ethyl acetate and then mixed with methyl-t-butyl ether and / or isopropyl acetate. (6) Silica gel chromatography using a developing solvent in which n-heptane, ethyl acetate and triethylamine were in a volume ratio of 5: 5: 0.5 before nalflavine was dissolved in isopropanol and / or ethyl acetate. The method for producing a crystal according to (5), which is attached to
本発明のナルフラフィンの結晶は、純度が高く、ナルフラフィン塩酸塩等の医薬原料として用いるのに好適である。 The nalfurafine crystals of the present invention have high purity and are suitable for use as a raw material for pharmaceuticals such as nalfurafine hydrochloride.
また、本発明のナルフラフィンの結晶の製造方法は、再結晶や、必要によりシリカゲルクロマトグラフィーを行うだけであるため、操作が容易である。 In addition, the method for producing nalflaphine crystals of the present invention is easy to operate because it only involves recrystallization or, if necessary, silica gel chromatography.
本発明のナルフラフィンの結晶は、結晶Ａおよび結晶Ｂという２つの結晶形を有するが、これまでナルフラフィンの結晶形についての報告は一切ない。また、ナルフラフィンは、例えば、特許文献１の実施例６８等の記載に基づいて得ることができる。 The crystal of nalfurafine of the present invention has two crystal forms, crystal A and crystal B, but there has been no report on the crystal form of nalfurafine so far. Nalflafin can be obtained, for example, based on the description in Example 68 of Patent Document 1.
本発明のナルフラフィンの結晶のうち、結晶Ａは次の性質を有するものである。
（ａ１）粉末Ｘ線回折像において、回折角２θが１５.４°、２３.４°の位置（それぞれ±０.２°の誤差を含む）に強度の大きい回折ピークを与える。
（ｂ１）粉末Ｘ線回折像において、回折角２θが６.１°、６.９°、１１.１°、１１.６°、１３.８°、１４.２°、１７.０°、１８.７°、２０.２°、２１.６°、２７.２°、２８.５°の位置（それぞれ±０.２°の誤差を含む）に上記以外の強度の小さい回折ピークを与える。
（ｃ１）融点が２０７℃（±１℃の誤差を含む）である。
（ｄ１）ＨＰＬＣで測定されるナルフラフィンの純度が９９.９０％である。
Of the nalflavine crystals of the present invention, crystal A has the following properties.
(A1) In a powder X-ray diffraction image, a diffraction peak having a high intensity is given at a position where diffraction angles 2θ are 15.4 ° and 23.4 ° (each including an error of ± 0.2 °).
(B1) In the powder X-ray diffraction image, the diffraction angle 2θ is 6.1 °, 6.9 °, 11.1 °, 11.6 °, 13.8 °, 14.2 °, 17.0 °, 18 Diffraction peaks with small intensities other than the above are given at positions of 0.7 °, 20.2 °, 21.6 °, 27.2 °, and 28.5 ° (each including an error of ± 0.2 °).
(C1) The melting point is 207 ° C. (including an error of ± 1 ° C.).
(D1) The purity of narfrafin as measured by HPLC is 99.90%.
この結晶Ａは、例えば、ナルフラフィンをテトラヒドロフランに溶解させた後、シクロヘキサンと混合する方法により得ることができる。 This crystal A can be obtained, for example, by a method in which nalfurafine is dissolved in tetrahydrofuran and then mixed with cyclohexane.
上記において、ナルフラフィンを溶解させるテトラヒドロフランの量は特に限定されないが、例えば、ナルフラフィンの質量の２０倍〜６０倍、好ましくは４０倍である。また、ナルフラフィンを溶解させる際のテトラヒドロフランの温度は、ナルフラフィンを溶解できる温度であれば特に限定されず、例えば、１５℃以上、好ましくは２０〜３０℃である。また、この溶解の際には攪拌機等で適宜撹拌を行ってもよい。 In the above, the amount of tetrahydrofuran in which nalfurafine is dissolved is not particularly limited, but is, for example, 20 to 60 times, preferably 40 times the mass of nalfurafine. Moreover, the temperature of tetrahydrofuran at the time of melt | dissolving nalfurafine will not be specifically limited if it is a temperature which can melt | dissolve nalfurafine, For example, it is 15 degreeC or more, Preferably it is 20-30 degreeC. Moreover, you may stir suitably with a stirrer etc. in the case of this melt | dissolution.
なお、ナルフラフィンをテトラヒドロフランに溶解させる前に公知の手段で粗精製やシリカゲルクロマトグラフィーに付してもよく、特に、ｎ−ヘプタン、酢酸エチルおよびトリエチルアミンを体積比で５：５：０.５とした展開溶媒を用いたシリカゲルクロマトグラフィーに付すことが、結晶におけるナルフラフィンの純度を高める点から好ましい。また、このシリカゲルクロマトグラフィーにおいては、上記展開溶媒を用いる以外は通常の条件で行えばよい。また、シリカゲルクロマトグラフィーに付した後は、常法に従って、濃縮、乾燥等を行ってもよい。 In addition, before dissolving nalfrafin in tetrahydrofuran, it may be subjected to crude purification or silica gel chromatography by a known means, and in particular, n-heptane, ethyl acetate and triethylamine were in a volume ratio of 5: 5: 0.5. It is preferable to subject to silica gel chromatography using a developing solvent from the viewpoint of increasing the purity of nalfurafine in the crystal. Further, this silica gel chromatography may be carried out under ordinary conditions except that the developing solvent is used. Further, after being subjected to silica gel chromatography, concentration, drying, and the like may be performed according to a conventional method.
ナルフラフィンを溶解させたテトラヒドロフランは、次に、シクロヘキサンと混合する。この混合の際のシクロヘキサンの量は特に限定されないが、例えば、ナルフラフィンの質量の４０倍〜１２０倍、好ましくは８０倍である。また、ナルフラフィンを溶解させたテトラヒドロフランとシクロヘキサンの混合方法は特に限定されず、例えば、ナルフラフィンを溶解させたテトラヒドロフランを１０〜３０℃にし、これにシクロヘキサンを滴下等して混合すればよい。また、この混合の際には攪拌機等で適宜撹拌を行ってもよい。 Tetrahydrofuran in which narfrafin has been dissolved is then mixed with cyclohexane. The amount of cyclohexane at the time of mixing is not particularly limited, but is, for example, 40 to 120 times, preferably 80 times the mass of narfrafin. Moreover, the mixing method of tetrahydrofuran and cyclohexane in which nalfurafine has been dissolved is not particularly limited. For example, tetrahydrofuran in which nalfurafine is dissolved may be brought to 10 to 30 ° C., and cyclohexane may be added dropwise thereto. Moreover, you may stir suitably with a stirrer etc. in the case of this mixing.
ナルフラフィンを溶解させたテトラヒドロフランと、シクロヘキサンとを混合した後は、液温を１０〜３０℃にして５〜７０時間撹拌することにより結晶Ａが析出する。析出した結晶Ａは常法に従ってろ過、乾燥等することができる。 After the tetrahydrofuran in which nalfurafine has been dissolved and cyclohexane are mixed, the liquid temperature is set to 10 to 30 ° C. and the mixture is stirred for 5 to 70 hours to precipitate crystals A. The precipitated crystal A can be filtered, dried and the like according to a conventional method.
一方、本発明のナルフラフィンの結晶のうち、結晶Ｂは次の性質を有するものである。
（ａ２）粉末Ｘ線回折像において、回折角２θが５.９°、１１.５°、１５.７°、１８.６°の位置（それぞれ±０.２°の誤差を含む）に強度の大きい回折ピークを与える。
（ｂ２）粉末Ｘ線回折像において、回折角２θが７.９°、１６.６°、１８.９°、２０.７°、２１.４°、２２.１°、２３.９°、２６.１°、２６.５°の位置（それぞれ±０.２°の誤差を含む）に上記以外の強度の小さい回折ピークを与える。
（ｃ２）融点が２２６℃（±１℃の誤差を含む）である。
（ｄ２）ＨＰＬＣで測定されるナルフラフィンの純度が９９.９０％以上である。
On the other hand, of the nalflaphine crystals of the present invention, the crystal B has the following properties.
(A2) In the powder X-ray diffraction image, the intensity at the diffraction angles 2θ of 5.9 °, 11.5 °, 15.7 °, and 18.6 ° (each including an error of ± 0.2 °) Gives a large diffraction peak.
(B2) In the powder X-ray diffraction image, the diffraction angle 2θ is 7.9 °, 16.6 °, 18.9 °, 20.7 °, 21.4 °, 22.1 °, 23.9 °, 26 A diffraction peak with a small intensity other than the above is given at the positions of 0.1 ° and 26.5 ° (each including an error of ± 0.2 °).
(C2) The melting point is 226 ° C. (including an error of ± 1 ° C.).
(D2) The purity of narfrafin as measured by HPLC is 99.90% or more.
この結晶Ｂは、例えば、ナルフラフィンをイソプロパノールおよび／または酢酸エチルに溶解させた後、メチル−ｔ−ブチルエーテルおよび／または酢酸イソプロピルと混合する方法により得ることができる。 This crystal B can be obtained, for example, by a method in which nalfurafine is dissolved in isopropanol and / or ethyl acetate and then mixed with methyl-t-butyl ether and / or isopropyl acetate.
上記において、ナルフラフィンを溶解させるイソプロパノールおよび／または酢酸エチルの量は特に限定されないが、例えば、イソプロパノールであればナルフラフィンの質量の２０倍〜４０倍、好ましくは３０倍であり、酢酸エチルであればナルフラフィンの質量の５０倍〜９０倍、好ましくは７０倍である。また、ナルフラフィンを溶解させるイソプロパノールおよび／または酢酸エチルの温度は、ナルフラフィンを溶解できる温度であれば特に限定されず、例えば、５０〜７０℃であり、好ましくは６０℃である。また、この溶解の際には攪拌機等で適宜撹拌を行ってもよい。 In the above, the amount of isopropanol and / or ethyl acetate in which nalfurafine is dissolved is not particularly limited. For example, isopropanol is 20 to 40 times, preferably 30 times the mass of nalfurafine, and ethyl acetate is nalflaphine. The mass is 50 times to 90 times, preferably 70 times. Further, the temperature of isopropanol and / or ethyl acetate for dissolving nalfurafine is not particularly limited as long as it is a temperature capable of dissolving nalfurafine, and is, for example, 50 to 70 ° C, preferably 60 ° C. Moreover, you may stir suitably with a stirrer etc. in the case of this melt | dissolution.
なお、ナルフラフィンをイソプロパノールおよび／または酢酸エチルに溶解させる前に公知の手段で粗精製やシリカゲルクロマトグラフィーに付してもよく、特に、ｎ−ヘプタン、酢酸エチルおよびトリエチルアミンを体積比で５：５：０.５とした展開溶媒を用いたシリカゲルクロマトグラフィーに付すことが、結晶におけるナルフラフィンの純度を高める点から好ましい。また、このシリカゲルクロマトグラフィーにおいては、上記展開溶媒を用いる以外は通常の条件で行えばよい。また、シリカゲルクロマトグラフィーに付した後は、常法に従って、濃縮、乾燥等を行ってもよい。 In addition, before dissolving nalfraphine in isopropanol and / or ethyl acetate, it may be subjected to crude purification or silica gel chromatography by a known means. In particular, n-heptane, ethyl acetate and triethylamine in a volume ratio of 5: 5: It is preferable to subject to silica gel chromatography using a developing solvent of 0.5 from the viewpoint of increasing the purity of narfraphine in the crystal. Further, this silica gel chromatography may be carried out under ordinary conditions except that the developing solvent is used. Further, after being subjected to silica gel chromatography, concentration, drying, and the like may be performed according to a conventional method.
ナルフラフィンを溶解させたイソプロパノールおよび／または酢酸エチルは、次に、メチル−ｔ−ブチルエーテルおよび／または酢酸イソプロピルと混合する。この混合の際のメチル−ｔ−ブチルエーテルおよび／または酢酸イソプロピルの量は特に限定されないが、例えば、イソプロパノールに加える場合にはナルフラフィンの質量の５倍〜２０倍、好ましくは１０倍であり、酢酸エチルに加える場合にはナルフラフィンの質量の１０倍〜３０倍、好ましくは２０倍である。また、メチル−ｔ−ブチルエーテルおよび／または酢酸イソプロピルの混合方法は特に限定されず、例えば、ナルフラフィンを完全に溶解させたイソプロパノールおよび／または酢酸エチルの温度を維持したまま、これにメチル−ｔ−ブチルエーテルおよび／または酢酸イソプロピルを滴下等すればよい。また、この混合の際には攪拌機等で適宜撹拌を行ってもよい。 Isopropanol and / or ethyl acetate in which narfrafin has been dissolved is then mixed with methyl-t-butyl ether and / or isopropyl acetate. The amount of methyl-t-butyl ether and / or isopropyl acetate in this mixing is not particularly limited. For example, when added to isopropanol, it is 5 to 20 times, preferably 10 times the mass of nalfurafine. In the case of adding to the above, it is 10 to 30 times, preferably 20 times the mass of narfrafin. The method for mixing methyl-t-butyl ether and / or isopropyl acetate is not particularly limited. For example, while maintaining the temperature of isopropanol and / or ethyl acetate in which nalfraphine is completely dissolved, methyl-t-butyl ether is maintained. And / or isopropyl acetate may be added dropwise. Moreover, you may stir suitably with a stirrer etc. in the case of this mixing.
ナルフラフィンを溶解させたイソプロパノールおよび／または酢酸エチルと、メチル−ｔ−ブチルエーテルおよび／または酢酸イソプロピルとを混合した後は、液温を１０〜３０℃にして５〜７０時間撹拌することにより結晶Ｂが析出する。析出した結晶Ｂは常法に従ってろ過、乾燥等することができる。 After mixing isopropanol and / or ethyl acetate in which narfraphine is dissolved with methyl-t-butyl ether and / or isopropyl acetate, the liquid temperature is set to 10 to 30 ° C., and the mixture is stirred for 5 to 70 hours. Precipitate. The precipitated crystals B can be filtered, dried and the like according to a conventional method.
上記した結晶Ｂを得る方法のうち、好ましい態様は、ナルフラフィンをイソプロパノールに溶解させた後、メチル−ｔ−ブチルエーテルと混合する方法、ナルフラフィンを酢酸エチルに溶解させた後、メチル−ｔ−ブチルエーテルと混合する方法、ナルフラフィンを酢酸エチルに溶解させた後、酢酸イソプロピルと混合する方法である。 Among the methods for obtaining the above-mentioned crystals B, preferred embodiments are a method in which nalfurafine is dissolved in isopropanol and then mixed with methyl-t-butyl ether, and nalfurafine is dissolved in ethyl acetate and then mixed with methyl-t-butyl ether. In this method, nalflaphine is dissolved in ethyl acetate and then mixed with isopropyl acetate.
以上説明したナルフラフィンの結晶は、ナルフラフィン塩酸塩の原料として、これを含む医薬品の製造に利用することができる。具体的には、ナルフラフィンの結晶を、特許文献１や特許文献２の記載に従って、適宜溶媒中で塩酸と反応させ、ナルフラフィン塩酸塩のアモルファスや結晶を得て、これを医薬品の製造に利用すればよい。 The nalfurafine crystals described above can be used as a raw material for nalfurafine hydrochloride in the production of pharmaceuticals containing it. Specifically, if nalfurafine crystals are reacted with hydrochloric acid in an appropriate solvent as described in Patent Document 1 or Patent Document 2 to obtain amorphous or crystals of nalfurafine hydrochloride, this can be used for the production of pharmaceuticals. Good.
以下、本発明を実施例等を挙げて詳細に説明するが、本発明はこれら実施例等に何ら限定されるものではない。 EXAMPLES Hereinafter, although an Example etc. are given and this invention is demonstrated in detail, this invention is not limited to these Examples etc. at all.
参 考 例 １
ナルフラフィンの合成及び粗精製：
１７−シクロプロピルメチル−４，５α−エポキシ−３，１４β−ジヒドロキシ−６β−（Ｎ−メチルアミノ）モルヒナン・フタル酸塩２.１１ｇ（４.０４ｍｍｏｌ）を水１１ｍｌに溶解し、テトラヒドロフラン１１ｍｌと炭酸ナトリウム０.８７５ｇ（８.０８ｍｍｏｌ）を加えた後、反応系をアルゴン置換した。そこへ、テトラヒドロフラン４.０ｍｌに溶解させたトランス−３−（３−フリル）アクリロイルクロリド０.６９６ｇ（４.４４ｍｍｏｌ）を滴下して３０分撹拌後、メタノール４.０ｍｌと３Ｎの水酸化ナトリウム水溶液５.４ｍｌを加えて１時間撹拌した。反応系に酢酸エチル３５ｍｌと飽和炭酸水素ナトリウム水溶液２５ｍｌを加えて分液し、水層は酢酸エチル１０ｍｌにて再抽出した。得られた有機層は飽和食塩水２０ｍｌで洗浄後、硫酸ナトリウムにて乾燥後、濃縮してナルフラフィンの粗製物を得た。このナルフラフィンの粗製物におけるナルフラフィンの純度（以下、「ＨＰＬＣ純度」という）を以下の条件のＨＰＬＣで測定した。その結果、ＨＰＬＣ純度は７１.０７％であった。
Reference example 1
Synthesis and crude purification of narfrafin:
17-Cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxy-6β- (N-methylamino) morphinane phthalate (2.11 g, 4.04 mmol) was dissolved in water (11 ml), and tetrahydrofuran (11 ml) and carbonic acid were dissolved. After adding 0.875 g (8.08 mmol) of sodium, the reaction system was purged with argon. To this, 0.696 g (4.44 mmol) of trans-3- (3-furyl) acryloyl chloride dissolved in 4.0 ml of tetrahydrofuran was added dropwise and stirred for 30 minutes, and then 4.0 ml of methanol and 3N aqueous sodium hydroxide solution were added. 5.4 ml was added and stirred for 1 hour. To the reaction system, 35 ml of ethyl acetate and 25 ml of a saturated aqueous sodium hydrogen carbonate solution were added for liquid separation, and the aqueous layer was re-extracted with 10 ml of ethyl acetate. The obtained organic layer was washed with 20 ml of saturated brine, dried over sodium sulfate, and concentrated to obtain a crude product of nalfraphine. The purity of nalflaphine (hereinafter referred to as “HPLC purity”) in the crude product of nalflaphine was measured by HPLC under the following conditions. As a result, the HPLC purity was 71.07%.
＜測定条件＞
カラム：ＹＭＣ−ＰＡＣＫ ＰｒｏＣ１８ ＡＳ−３０２（ＹＭＣ製）
カラムサイズ：直径４.６ｍｍ、長さ１５０ｍｍ
カラム温度：４０℃
流速：１.０ｍｌ／ｍｉｎ
検出波長：２２５ｎｍ
試料溶液濃度：１.０ｍｇ／ｍｌ
試料溶媒：アセトニトリル／水＝５０／５０
注入量：１０μｌ
測定時間：５０ｍｉｎ
＜移動層＞
Ａ液：０.１％リン酸水溶液
Ｂ液：アセトニトリル
＜移動層のＢ液組成＞
０〜３０分：１０％→５０％
３０〜４０分：５０％→８０％
４０〜５０分：８０％→８０％
<Measurement conditions>
Column: YMC-PACK ProC18 AS-302 (manufactured by YMC)
Column size: 4.6mm diameter, 150mm length
Column temperature: 40 ° C
Flow rate: 1.0 ml / min
Detection wavelength: 225 nm
Sample solution concentration: 1.0 mg / ml
Sample solvent: acetonitrile / water = 50/50
Injection volume: 10 μl
Measurement time: 50 min
<Moving layer>
A liquid: 0.1% phosphoric acid aqueous solution
Liquid B: acetonitrile
<B liquid composition of moving bed>
0-30 minutes: 10% → 50%
30-40 minutes: 50% → 80%
40-50 minutes: 80% → 80%
実 施 例 １
ナルフラフィンのカラム精製：
参考例１で得られたナルフラフィンの粗製物１１.１ｇをシリカゲルカラムクロマトグラフィー（Ｗａｋｏｇｅｌ（登録商標） Ｃ−３００：和光純薬工業製）に付し、（展開溶媒：ｎ−ヘプタン、酢酸エチルおよびトリエチルアミンを体積比で５：５：０.５）、溶出画分を濃縮乾燥し、ナルフラフィン精製物を８.５０ｇ得た（ＨＰＬＣ純度：９８.３３％）。
Example 1
Nalflaphine column purification:
11.1 g of the crude nalflaphine obtained in Reference Example 1 was subjected to silica gel column chromatography (Wakogel (registered trademark) C-300: manufactured by Wako Pure Chemical Industries, Ltd.), and (developing solvent: n-heptane, ethyl acetate and Triethylamine in a volume ratio of 5: 5: 0.5), and the eluted fraction was concentrated and dried to obtain 8.50 g of a purified nalfraphine (HPLC purity: 98.33%).
実 施 例 ２
ナルフラフィン結晶Ａの製造：
実施例１で得られたナルフラフィン精製物５００ｍｇをテトラヒドロフラン２０.０ｍｌに２０℃で溶解させた後、２０℃でシクロヘキサン４０.０ｍｌを滴下した。２０℃でそのまま１２時間撹拌し、得られた結晶をろ過、乾燥し、ナルフラフィンの結晶を４２５ｍｇ得た（ＨＰＬＣ純度：９９.９６％）。
Example 2
Production of Nalflaffin Crystal A:
500 mg of the purified nalflaphine obtained in Example 1 was dissolved in 20.0 ml of tetrahydrofuran at 20 ° C., and 40.0 ml of cyclohexane was added dropwise at 20 ° C. The mixture was stirred as it was at 20 ° C. for 12 hours, and the obtained crystal was filtered and dried to obtain 425 mg of nalflaphine crystal (HPLC purity: 99.96%).
この結晶の融点をキャピラリー融点測定器（ＢＵＣＨＩ ５１０：ビュッヒ製）で測定したところ２０７℃であった。また、この結晶について粉末Ｘ線回折測定（２θ／θ）を行ったところ（図１）、回折角２θが１５.４°、２３.４°に強度の大きい（２３.４°のピークの強度を１００％とした時の相対強度が５０％以上のもの）回折ピークおよび６.１°、６.９°、１１.１°、１１.６°、１３.８°、１４.２°、１７.０°、１８.７°、２０.２°、２１.６°、２７.２°、２８.５°に強度の小さい（２３.４°のピークの強度を１００％とした時の相対強度が１０％以上５０％未満のもの）回折ピークが認められた。これらのことよりこの実施例では、ナルフラフィンの新たな結晶Ａが得られた。 The melting point of this crystal was 207 ° C. when measured with a capillary melting point measuring device (BUCHI 510: manufactured by Büch). Further, when the powder was subjected to powder X-ray diffraction measurement (2θ / θ) (FIG. 1), the diffraction angle 2θ was 15.4 ° and 23.4 °, and the intensity was high (23.4 ° peak intensity). With a relative intensity of 50% or more with respect to 100%) diffraction peak and 6.1 °, 6.9 °, 11.1 °, 11.6 °, 13.8 °, 14.2 °, 17 0.0, 18.7, 20.2, 21.6, 27.2, and 28.5 degrees with small intensity (relative intensity when the intensity of the 23.4 degree peak is 100%) Of 10% or more and less than 50%). A diffraction peak was observed. From these facts, in this example, a new crystal A of narfrafin was obtained.
実 施 例 ３
ナルフラフィン結晶Ｂの製造：
実施例１で得られたナルフラフィン精製物７５０ｍｇにイソプロパノール２２.５ｍｌを加えて加熱撹拌により完全に溶解させた後、５０〜６０℃を維持しながらメチル−ｔ−ブチルエーテル７.５０ｍｌを滴下した。これを２０℃に戻して１２時間撹拌後、得られた結晶をろ過、乾燥し、ナルフラフィンの結晶を５９２ｍｇ得た（ＨＰＬＣ純度：９９.９５％）。
Example 3
Production of Nalflaffin Crystal B:
After 22.5 ml of isopropanol was added to 750 mg of the purified nalflaphine obtained in Example 1 and completely dissolved by heating and stirring, 7.50 ml of methyl tert-butyl ether was added dropwise while maintaining 50-60 ° C. After returning to 20 ° C. and stirring for 12 hours, the obtained crystals were filtered and dried to obtain 592 mg of nalfraphine crystals (HPLC purity: 99.95%).
この結晶について融点をキャピラリー融点測定器（ＢＵＣＨＩ ５１０：ビュッヒ製）で測定したところ２２６℃であることから結晶Ａとは結晶形が異なる可能性が示された。そこでこの結晶について粉末Ｘ線回折測定（２θ／θ）を行ったところ（図２）、実施例２で得られた結晶Ａとピーク位置は一致せず、回折角２θが５.９°、１１.５°、１５.７°、１８.６°に強度の大きい（５.９°のピークの強度を１００％とした時の相対強度が５０％以上のもの）回折ピークおよび７.９°、１６.６°、１８.９°、２０.７°、２１.４°、２２.１°、２３.９°、２６.１°、２６.５°に強度の小さい（５.９°のピークの強度を１００％とした時の相対強度が１０％以上５０％未満のもの）回折ピークが認められた。これらのことよりこの実施例で得られたナルフラフィンの結晶は、結晶Ａとは異なる結晶Ｂであることがわかった。 When the melting point of this crystal was measured with a capillary melting point measuring device (BUCHI 510: manufactured by Büch), it was 226 ° C., indicating that the crystal form may be different from that of crystal A. Therefore, when powder X-ray diffraction measurement (2θ / θ) was performed on this crystal (FIG. 2), the peak position did not coincide with the crystal A obtained in Example 2, and the diffraction angle 2θ was 5.9 °, 11 .5 °, 15.7 °, 18.6 ° with high intensity (with a relative intensity of 50% or more when the intensity of the 5.9 ° peak is taken as 100%) diffraction peak and 7.9 °, Low intensity at 16.6 °, 18.9 °, 20.7 °, 21.4 °, 22.1 °, 23.9 °, 26.1 °, 26.5 ° (peak at 5.9 ° The relative intensity is 10% or more and less than 50% when the intensity is 100%.) A diffraction peak was observed. From these facts, it was found that the crystals of narfrafin obtained in this Example were crystals B different from crystals A.
実 施 例 ４
ナルフラフィン結晶Ｂの製造：
実施例１で得られたナルフラフィン精製物８.５０ｇに酢酸エチル５９５ｍｌを加えて加熱撹拌により完全に溶解させた後、５０〜６０℃を維持しながらメチル−ｔ−ブチルエーテル１７０ｍｌを滴下した。これを２０℃に戻して１２時間撹拌後、得られた結晶をろ過、乾燥し、ナルフラフィンの結晶を５.８８ｇ得た（ＨＰＬＣ純度：９９.９７％）。
Example 4
Production of Nalflaffin Crystal B:
Ethyl acetate (595 ml) was added to 8.50 g of the purified nalflaphine obtained in Example 1 and completely dissolved by heating and stirring, and then 170 ml of methyl tert-butyl ether was added dropwise while maintaining 50-60 ° C. After returning to 20 ° C. and stirring for 12 hours, the obtained crystals were filtered and dried to obtain 5.88 g of nalfraphine crystals (HPLC purity: 99.97%).
この結晶の融点をキャピラリー融点測定器（ＢＵＣＨＩ ５１０：ビュッヒ製）で測定したところ２２６℃であったため、結晶Ｂと同じ結晶形と考えられ、実際にこの結晶について粉末Ｘ線回折測定（２θ／θ）を行ったところ、実施例３で得られた結晶Ｂとピーク位置が完全に一致した。そのため、この実施例で得られた結晶は結晶Ｂであった。 The melting point of this crystal was measured with a capillary melting point measuring device (BUCHI 510: manufactured by Büch) and was found to be 226 ° C., so it was considered to be the same crystal form as crystal B. ), The peak position completely coincided with the crystal B obtained in Example 3. Therefore, the crystal obtained in this example was crystal B.
実 施 例 ５
ナルフラフィン結晶Ｂの製造：
実施例１で得られたナルフラフィン精製物５００ｍｇに酢酸エチル３５.０ｍｌを加えて加熱撹拌により完全に溶解させた後、５０〜６０℃を維持しながら酢酸イソプロピル１０.０ｍｌを滴下した。これを２０℃に戻して１２時間撹拌後、得られた結晶をろ過、乾燥し、ナルフラフィンの結晶を３７０ｍｇ得た（ＨＰＬＣ純度：９９.９５％）。
Example 5
Production of Nalflaffin Crystal B:
After 35.0 ml of ethyl acetate was added to 500 mg of the purified nalflaphine obtained in Example 1, and dissolved completely by heating and stirring, 10.0 ml of isopropyl acetate was added dropwise while maintaining 50-60 ° C. After returning to 20 ° C. and stirring for 12 hours, the obtained crystals were filtered and dried to obtain 370 mg of nalfraphine crystals (HPLC purity: 99.95%).
この結晶の融点をキャピラリー融点測定器（ＢＵＣＨＩ ５１０：ビュッヒ製）で測定したところ２２６℃であったため、結晶Ｂと同じ結晶形と考えられ、実際にこの結晶について粉末Ｘ線回折測定（２θ／θ）を行ったところ、実施例３で得られた結晶Ｂとピーク位置が完全に一致した。そのため、この実施例で得られた結晶は結晶Ｂであった。 The melting point of this crystal was measured with a capillary melting point measuring device (BUCHI 510: manufactured by Büch) and was found to be 226 ° C., so it was considered to be the same crystal form as crystal B. Actually, this crystal was subjected to powder X-ray diffraction measurement (2θ / θ ), The peak position completely coincided with the crystal B obtained in Example 3. Therefore, the crystal obtained in this example was crystal B.
比 較 例 １
ナルフラフィンの再結晶：
実施例１で得られたナルフラフィンの精製物の再結晶をメタノール、メタノールおよびメチル−ｔ−ブチルエーテル、エタノール、エタノールおよびトルエン、エタノールおよびメチル−ｔ−ブチルエーテル、アセトニトリルおよびトルエン、アセトンおよび水、メチルエチルケトンおよび酢酸エチルを溶媒として用い、２０〜６０℃の温度範囲で試みたが、結晶を得ることはできなかった。
Comparative Example 1
Nalfurafine recrystallization:
Recrystallization of the purified product of nalflaphine obtained in Example 1 was performed using methanol, methanol and methyl-t-butyl ether, ethanol, ethanol and toluene, ethanol and methyl-t-butyl ether, acetonitrile and toluene, acetone and water, methyl ethyl ketone and acetic acid. Attempts were made in the temperature range of 20 to 60 ° C. using ethyl as a solvent, but crystals could not be obtained.
本発明のナルフラフィンの結晶は、ナルフラフィンの純度が高いため、ナルフラフィン塩酸塩の原料として、これを含む医薬品の製造に利用することができる。
以 上
Since the nalfurafine crystals of the present invention have a high purity of nalfurafine, it can be used as a raw material for nalfurafine hydrochloride in the production of pharmaceuticals containing it.
that's all
Claims (6)
Before 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β- [N-methyl-trans-3- (3-furyl) acrylamide] morphinan is dissolved in isopropanol and / or ethyl acetate 6. The method for producing a crystal according to claim 5, wherein n-heptane, ethyl acetate and triethylamine are subjected to silica gel chromatography using a developing solvent in a volume ratio of 5: 5: 0.5.
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| CN115015440A (en) * | 2022-07-08 | 2022-09-06 | 江苏杜瑞制药有限公司 | Method for detecting naftifine in biological sample |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993015081A1 (en) * | 1992-01-23 | 1993-08-05 | Toray Industries, Inc. | Morphinan derivative and medicinal use |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1993015081A1 (en) * | 1992-01-23 | 1993-08-05 | Toray Industries, Inc. | Morphinan derivative and medicinal use |
Non-Patent Citations (2)
| Title |
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| NAGASE, H. ET AL., CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 46, no. 2, JPN7017004278, 1998, pages 366 - 369, ISSN: 0003830287 * |
| 芦澤 一英、他, 医薬品の多形現象と晶析の科学, JPN7015003233, 20 September 2002 (2002-09-20), pages 305 - 317, ISSN: 0003830288 * |
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|---|---|---|---|---|
| CN115015440A (en) * | 2022-07-08 | 2022-09-06 | 江苏杜瑞制药有限公司 | Method for detecting naftifine in biological sample |
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