CN101291911A - 拉奎尼莫晶体及其制备方法 - Google Patents
拉奎尼莫晶体及其制备方法 Download PDFInfo
- Publication number
- CN101291911A CN101291911A CNA2006800392016A CN200680039201A CN101291911A CN 101291911 A CN101291911 A CN 101291911A CN A2006800392016 A CNA2006800392016 A CN A2006800392016A CN 200680039201 A CN200680039201 A CN 200680039201A CN 101291911 A CN101291911 A CN 101291911A
- Authority
- CN
- China
- Prior art keywords
- sodium
- mixture
- laquinimod
- laquinimod sodium
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- GKWPCEFFIHSJOE-UHFFFAOYSA-N laquinimod Chemical compound OC=1C2=C(Cl)C=CC=C2N(C)C(=O)C=1C(=O)N(CC)C1=CC=CC=C1 GKWPCEFFIHSJOE-UHFFFAOYSA-N 0.000 title claims abstract description 141
- 229960004577 laquinimod Drugs 0.000 title claims abstract description 140
- 238000000034 method Methods 0.000 title claims abstract description 66
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- 238000002360 preparation method Methods 0.000 claims abstract description 37
- 239000012535 impurity Substances 0.000 claims abstract description 13
- 239000011734 sodium Substances 0.000 claims description 122
- 229910052708 sodium Inorganic materials 0.000 claims description 122
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 63
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- 238000001953 recrystallisation Methods 0.000 claims description 34
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- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims description 2
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
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- 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
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4704—2-Quinolinones, e.g. carbostyril
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
公开了制备拉奎尼莫钠的一个方法,该方法在盐形成步骤后去除杂质,因此产生的晶体具有较高的纯度,并且具有改进的晶体特性。
Description
技术领域
本申请主张美国临时申请号60/728657(1005年10月19日归档)的权益,其整个内容结合再此作为参考。
本申请参考各种出版物、已公开的专利申请和已公开的专利。为了更完整地叙述本发明的现有技术状况,这些公开的出版物完整地结合在此作为参考。
发明背景
拉奎尼莫(Laquinimod)是一种化合物,在急性实验性自免疫脑脊椎炎(aEAE)模型中表现有效(美国专利6077851)。其化学名为N-乙基-N-苯基-1,2-二氢-4-羟基-5-氯-1-甲基-2-氧代喹啉-3-甲酰胺,其化学登记号为248281-84-7。拉奎尼莫(Laquinimod)的合成方法及其钠盐的制备在美国专利6077851中有公开。拉奎尼莫(Laquinimod)的另一种合成方法公开在美国专利6875869中。
在公开于美国专利6077851的拉奎尼莫钠的制备方法中,将拉奎尼莫悬浮在乙醇中,加入5M氢氧化钠溶液。搅拌后,过滤产生的沉淀,用乙醇洗涤,然后干燥。在美国专利6077851中用来制备拉奎尼莫钠的方法一般称为浆料到浆料盐形成方法。
在拉奎尼莫钠的浆料到浆料盐形成方法中,拉奎尼莫钠是不溶解在溶液中的。因此,任何存在于拉奎尼莫钠悬浮液中的固体杂质无法用过滤去除。
本申请人发现,拉奎尼莫钠的浆料到浆料盐形成方法通常产生掺杂了其他化合物和/或金属的产品。在此公开的方法就是要解决这个问题。
发明内容
在此公开的是一个制备拉奎尼莫钠(Laquinimod sodium)的方法,该方法在盐形成步骤之后除去所含的杂质,因此形成高纯度的晶体,该晶体具有改良的晶体特性。
本发明提供结晶的拉奎尼莫钠颗粒的混合物,其中拉奎尼莫钠颗粒的体积总量的10%或更多具有大于40微米的粒度。
本发明还提供结晶的拉奎尼莫钠颗粒的混合物,其轻叩密度(tapped density)至少是0.6g/mL.
本发明还提供一种组合物,其含有拉奎尼莫钠和不超过2ppm的重金属(按组合物中拉奎尼莫钠的总量计算)。
本发明还提供拉奎尼莫钠的重结晶方法,包含a)将拉奎尼莫钠溶解在水中,形成水溶液;b)浓缩水溶液,形成浓缩溶液;c)向溶液中加入与水可混溶的反溶剂(water-miscible anti-solvent),形成拉奎尼莫钠结晶;d)分离出拉奎尼莫钠晶体。
本发明还提供制备含有拉奎尼莫钠的药用组合物的方法,包含:
a)制备批量拉奎尼莫钠;b)测定在步骤a)的批量中是否存在不溶解的物质,方法是将该步骤的样品在室温下与去离子水混合(混合比例为至少110毫克样品对1.0毫升水),然后检查所形成的混合物中是否有不溶解的物质;c)如果在步骤b)中测定的不溶解物质的量低于预定量,则将批量a)与至少一种药学上可接受的载体混合。
附图说明
图1:从实施例14在重结晶前按照实施例1制备的拉奎尼莫钠的扫描电镜图
图2:实施例15的重结晶晶体的扫描电镜图
图3:实施例16的重结晶晶体的扫描电镜图
具体实施方式
本发明提供结晶的拉奎尼莫钠颗粒的混合物,其中拉奎尼莫钠颗粒的体积总量的10%或更多具有大于40微米的粒度。
在混合物一个实施方式中,拉奎尼莫钠颗粒的体积总量的50%或更多具有大于15微米的粒度。
在另一个实施方式中,混合物的轻叩密度(tapped density)至少是0.6g/mL,至少0.5g/mL,或至少0.4g/mL.
在另一个实施方式中,混合物的堆积密度(bulk density)至少是0.4g/mL,至少0.3g/mL,或至少0.2g/mL.
在另一个实施方式中,混合物的轻叩密度(tapped density)小于0.8g/mL,或小于0.7g/mL.
在另一个实施方式中,混合物包含不高于2ppm重金属。该重金属可以是铁、镍或铬。
在另一个实施方式中,混合物含有不高于2ppm铁,不高于1.5ppm铁,或不高于1ppm铁。
在另一个实施方式中,混合物含有不高于0.2ppm镍,不高于0.15ppm镍,或不高于0.1ppm镍。
在另一个实施方式中,混合物含有不高于0.3ppm铬,不高于0.25ppm铬,不高于0.2ppm铬,不高于0.15ppm铬,或不高于0.1铬。
本发明还提供一种药物组合物,包含任何一中所公开的混合物和一种药学上可接受的载体。该药物组合物可以是药片或胶囊的形式。
本发明还提供一种药物组合物,包含拉奎尼莫钠和不高于2ppm重金属(按组合物中拉奎尼莫钠的总量计算)。重金属可以是铁、镍或铬。
在另一个实施方式中,组合物的铁含量不超过2ppm,不超过1.5ppm,或不超过1ppm.
在另一个实施方式中,组合物的镍含量不超过0.2ppm,不超过0.15ppm,或不超过0.1ppm.
在另一个实施方式中,组合物的铬含量不超过0.3ppm,不超过0.25ppm,不超过0.2ppm,不超过0.15ppm,或不超过0.1ppm.
在另一个实施方式中,组合物是结晶的形式。结晶形式的组合物可以是任何所公开的实施方式的形式。
本发明还提供拉奎尼莫钠的重结晶方法,包含a)将拉奎尼莫钠溶解在水中,形成水溶液;b)浓缩水溶液,形成浓缩溶液;c)向浓缩溶液中加入与水混溶的反溶剂(water-miscible anti-solvent),形成拉奎尼莫钠结晶;d)分离出拉奎尼莫钠晶体。
在该方法的一个实施方式中,步骤a)通过加热水溶液到40-80℃进行。
在该方法的另一个实施方式中,浓缩的溶液包含1-4毫升水/克拉奎尼莫钠。
在该方法的另一个实施方式中,浓缩的溶液包含1-2毫升水/克拉奎尼莫钠。
在另一个本方法的实施方式中,反溶剂是包括乙醇、异丙醇、和丙酮的一种溶剂,或多于一种溶剂的混合物。
在另本方法的一个实施方式中,反溶剂是丙酮。
在本方法的另一个实施方式中,反溶剂的加入量是3-15毫升/克拉奎尼莫钠。
在本方法的另一个实施方式中,步骤c)后接着将溶液冷却到10℃以下的温度。
在本方法的另一个实施方式中,步骤b)后面接着用拉奎尼莫钠作为晶种加入浓缩溶液中。
本发明还提供用所公开的任何一个方法制备的拉奎尼莫钠。
制备包含拉奎尼莫钠的药物组合物的方法包含:a)制备批量的拉奎尼莫钠;b)测定在步骤a)的批量中是否存在不溶解的物质,方法是将该步骤a)的样品在室温下与去离子水混合(混合比例为至少110毫克样品对1.0毫升水),然后检查所形成的混合物中是否有不溶解的物质;c)如果在步骤b)中测定的不溶解物质的量低于预定量,则将批量a)与至少一种药学上可接受的载体混合。
在本方法的另一个实施方式中,如果步骤b)测定的混合物中的不溶解物质不是在预定量以下存在,则本方法还包含如下步骤;d)将步骤a)的批量溶解在水中,形成水溶液;e)过滤步骤d)的水溶液,以便将不溶解物质的量降低到预定量以下;f)浓缩步骤e)的水溶液,形成浓缩溶液;g)将与水不混溶的反溶剂加入步骤f)的浓缩溶液,形成拉奎尼莫钠晶体;h)分离步骤g)的拉奎尼莫钠。
在此使用的“药学上可接受的”组分是指适合用于人和/或动物而无不适当的副作用并具有合理的利益/风险比的组分(副作用包括例如毒性、刺激性、以及过敏反应)。
因此,“药学上可接受的载体”是药学上可接受的溶剂、悬浮剂或介质,用来将所述的化合物输送给人或动物。根据所计划的给药方式选择载体。脂质体也是药用载体。
单位剂量可包含单一化合物或多种化合物的混合物。可制备单位剂量用于口服剂型,如药片、胶囊、药丸、粉剂、和颗粒剂。
药物物质可与合适的药用稀释剂、填充剂、赋形剂、或载体(总称为药学上可接受的载体)混合给药。载体的选择是根据给药方式和常规的药学实践来选择。单位剂型应是适合口服的形式。药物物质可以单独给药,但通常能够与药学上可接受的载体混合,并以药片、胶囊、脂质体或聚集的粉末的形式共同给药。合适的固体载体包括乳糖、蔗糖、明胶和琼脂。胶囊或药片容易配制,并可制造得容易吞咽或咀嚼;其他固体形式包括颗粒、和松散的粉末。药片可含有黏合剂、润滑剂、稀释剂、崩解剂、着色剂、调味剂、流动促进剂和融化剂。
可用来配制本发明口服剂型的具体技术、药学上可接受的载体和赋形剂叙述在,例如,公开的美国专利申请2005/0192315。例如,本发明的口服剂型可包含碱性反应组分,为了保持pH在8以上,所述组分最好占配方的1-20重量%。
在本发明中用来置备剂型的一般技术和组合物在以下文献中叙述:7 ModernPharmaceutics,Chapters 9 and 10(Banker & Rhodes,Editors,1979);PharmaceuticalDosage Forms:Tablets(Lieberman et al.,1981);Ansel,Introduction toPharmaceutical Dosage Forms 2nd Edition(1976);Remington’s PharmaceuticalSciences,17th ed.(Mack Publishing Company,Easton,Pa.,1985);Advances inPharmaceutical Sciences(David Ganderton,Trevor Jones,Eds.,1992);Advances inPharmaceutical Sciences VoI 7.(David Ganderton,Trevor Jones,James McGinity,Eds.,1995);Aqueous Polymeric Coatings for Pharmaceutical DosageForms(Drugsand the Pharmaceutical Sciences,Series 36(James McGinity,Ed.,1989);Pharmaceutical ParticulateCarriers:Therapeutic Applications:Drugs andthePharmaceutical Sciences,VoI 61(Alain Rolland,Ed.,1993);Drug Delivery tothe Gastrointestinal Tract(Ellis HorwoodBooks in the Biological Sciences.Seriesin Pharmaceutical Technology;J.G.Hardy,S.S.Davis,Clive G.Wilson,Eds.);Modern Pharmaceutics Drugs and the Pharmaceutical Sciences,VoI 40(Gilbert S.Banker,Christopher T.Rhodes,Eds.).
药片可含有黏合剂、润滑剂、崩解剂、着色剂、调味剂、流动促进剂、和融化剂。例如,用于口服的片剂或胶囊的单位剂型,活性药物组分可与口服的无毒的药学上可接受的惰性载体结合(如乳糖、明胶、琼脂、淀粉、蔗糖、葡萄糖、甲基纤维素、磷酸二钙、硫酸钙、甘露醇、山梨糖醇、微晶纤维素等)。合适的黏合剂包括淀粉、明胶、天然的糖如葡萄糖或β-乳糖、玉米淀粉、天然或合成的树胶(如阿拉伯胶、黄蓍胶)或海藻酸钠、聚维酮、羧甲基纤维素、聚乙二醇、腊等。这些剂型中的润滑剂包括油酸钠、硬脂酸钠、苯甲酸钠、乙酸钠、氯化钠、硬脂酸、富马酸硬脂基酯钠、滑石粉等。崩解剂但不限于淀粉、甲基纤维素、琼脂、膨润土、黄原树胶、交联羧甲基纤维素钠、淀粉乙醇酸酯钠等。
在此使用的“反溶剂”,在其中拉奎尼莫钠在室温(20-25C)是微溶的,极微溶的,实际上是不溶的,或不溶的。术语“溶解度”按照美国药典XXV定义如下。
术语 | 溶解1份溶质所需溶剂的份数 |
微溶极微溶实际上不溶不溶 | 100-10001000-1000010000及以上10000及以上 |
在此使用的“密度”是一种量度,定义为每单位体积中的物质质量。
在此使用的“堆积密度”或“BD”是指一种疏松的、未经过压缩的物质的密度的量度,其中物质的体积包括颗粒之间所包存的空气。
在此使用的“轻叩密度”或”TD”是指已经被轻叩或振动,因此通过消除或尽量减少在颗粒之间包存的空气,使物质的体积最小化的物质的密度的量度。
不纯的结晶化合物的纯化通常通过从合适的溶剂或溶剂混合物中重结晶而实施(见Vogel’s Textbook of Practical Organic Chemistry.5th edition.Longman Scientific& Technical,1989.)。重结晶过程一般包含以下步骤:a)将不纯的结晶化合物溶解在接近沸点的合适的溶剂中;b)过滤热的溶液以除去不溶解的物质或灰尘;c)让热溶液冷却,使溶解的物质结晶出来;d)使结晶和上层的溶液分开。
但是,当使用在拉奎尼莫钠时,标准的重结晶技术伴随着低产率或零产率。如实施例1-10所示,企图重结晶拉奎尼莫钠总是导致很差的产率(如果还有产率的话)。本发明提供工业上可重复的重结晶方法,该方法可高产率得到拉奎尼莫钠。
本发明方法使用拉奎尼莫钠在其中实际上是不溶解的反溶剂。此外,本发明方法在加入反溶剂之前先浓缩拉奎尼莫钠水溶液。
用本发明方法制造的拉奎尼莫钠比先前技术所公开的拉奎尼莫钠的纯度要高。美国专利No.6,875,869公开了一个高产率低杂质的基料化合物拉奎尼莫的制备方法。但是,该专利的方法只用来合成基料化合物而不是其盐。因此还是需要用浆料到浆料盐形成方法来形成钠盐。先前公开的该浆料到浆料盐形成方法不能有效地除去原料中的任何杂质。
本发明的重结晶的第二个优点是对环境的友善性,因为它使用水作为基本的溶剂。
本发明重结晶方法的第三个优点是拉奎尼莫钠晶体的密度比先前技术的拉奎尼莫钠晶体的密度要高。低轻叩密度对药物物质的某些重要品质(如可压缩性,即压力下减少粉末体积的能力,和紧密性,即粉末压缩成具有一定强度和硬度的药片的能力)是十分有害的。具有低轻叩密度的晶体其流动性也很差,这导致在最终的剂型中(特别是在片剂中)的内容物缺乏均匀性。(见Rudnic et al.Chpt.45,Remington’s PharmaceuticalSciences,20th Edition,Lippincott Williams & Wilkins,Baltimore,MD.(2000))。内容物均匀性的问题在在药片中的药物活性组分含量低的片剂中特别重要。
本发明重结晶方法的第四个优点是产生的拉奎尼莫钠晶体具有高的粒度。大的拉奎尼莫钠颗粒在制备药物组合物时更容易加工。小颗粒常常伴随像灰尘一样的性质,它会干扰要区组合物的制备。而且,一些例子显示,小粒度引起的表面积的增加会导致化学稳定性的降低。(见Felmeister,A.Chpt 88,Remington’s Pharmaceutical Sciences,15thEdition,Mack Publishing Company,Easton,PA(1975)).
详细实验
粉末密度测定
堆积(松散)密度(Bulk Density)
1.混合粉末;
2.在0.01克灵敏度天平上称量一个50毫升空量筒的皮重;
3.使量筒保持45度角,不加压缩地将粉末转移到量筒中,达到40-50毫升的没有轻叩的表观体积;
4.迅速将装有样品的量筒扶正到垂直位置,以便使体积取平便于读取;
5.读出表观体积(Va)到最接近的刻度单位;
6.将装有样品的量筒称重;
7.按照公式BD=M/Va计算松散密度(单位:克/毫升);
8.重复进行步骤1-7,报告重复实验的平均值。
轻叩密度(Tapped Density)
1.把用在测定堆积密度的同样的量筒放在Quantachrome Dual Autotap仪器中;
2.进行1250次轻叩;
3.读取轻叩体积(Vf)到最接近的刻度单位;
4.按照公式TD=M/Vf计算轻叩密度(单位克/毫升);
5.重复进行步骤1-4,报告平均值。
粒度测定(Determination of Particle Size)
使用Mastersizer S模型,通过Malvern激光散射测定粒度分布。激光散射取决于这样的事实:光的散射角与粒度成反比。测定颗粒的性质并解释为球形的量度(球形是唯一的可用一个唯一的数字描述的形状)。此外,激光散射基于体积术语计算粒度分布,因此无需颗粒计数就可以测定粒度。Mastersizer S模型使用单一技术和单一范围设定来测量颗粒。
D(0.1)是粒度(单位:微米),低于该粒度可发现10%体积的颗粒分布。D(0.5)是粒度(单位:微米),低于该粒度可发现50%体积的颗粒分布。D(0.9)是粒度(单位:微米),低于该粒度可发现90%体积的颗粒分布。
重金属测定(Determination of Heavy Metals)
使用感应耦联等离子体原子发射光谱计测定金属含量,使用感应耦联等离子体原子发射光谱计(″ICP-AES″)系统,Spectro(Kleve,Germany).制造。样品吸收在65%硝酸中,用钪作为内标。
说明:在以下实施例中,所用溶剂的体积按照拉奎尼莫钠的起始重量计算。产率按重量百分数计算。
纯度确定(Determination of Purity)
拉奎尼莫钠和极性杂质/分解产物用等度(isocratic)反相高效液相色谱(RP-HPLC)测定,使用ODS-3V柱,流动相由pH7乙酸铵缓冲液(80%)和乙腈(20%)组成。在240nm测定紫外吸收。
实施例1(拉奎尼莫钠的制备方法)
拉奎尼莫酸按照美国专利No.6,875,869的方法制备:5-氯-1,2-二氢-4-羟基-1-甲基-2-氧代-喹啉-3-羧酸甲酯(3.0克),N-乙基苯胺(2当量,2-2.88毫升),和庚烷(60毫升)一起加热,挥发性物质(主要是庚烷和生成的甲醇(32毫升)在6小时又35分钟期间蒸馏出来)。在冷却到室温后,过滤结晶悬浮液,晶体用庚烷洗涤,真空干燥,得到拉奎尼莫酸(3.94g,98%),为灰百色晶体。
用美国专利No.6,077,851实施例2的方法将拉奎尼莫酸转化为拉奎尼莫钠:用灭菌水将50重量%的氢氧化钠溶液(10.0克)稀释到总体积位5毫升,制备5M氢氧化钠。将N-乙基N-苯基-1,2-二氢-4-羟基-5-氯-1-甲基-2-氧代-喹啉-3-羧羧酰胺(10.0克)悬浮在乙醇(150毫升)中,将先前制备的5M氢氧化钠溶液加入到pH8-12(5.6毫升)。反应混合物在室温搅拌30分钟。过滤生成的沉淀,迅速用乙醇洗涤2次(2×150毫升)。沉淀放在P2O5上方真空干燥,得到标题化合物(9.5可)。该方法称为“浆料到浆料方法”。
实施例2
在50℃将按实施例1制备的拉奎尼莫钠加到6.1体积的水中。加入氢氧化钠(NaOH)将pH调节到12.5,搅拌混合物,直到完全溶解。加入50.0体积的乙醇。将溶液冷却到2℃,但是没有产生晶体。
实施例3
在50℃将按实施例1制备的拉奎尼莫钠加到6.1体积的水中。加入NaOH将pH调节到12.5,搅拌混合物,直到完全溶解。加入100.0体积的乙醇。将溶液冷却到-18℃,但是没有产生晶体。
实施例4
在50℃将按实施例1制备的拉奎尼莫钠加到6.1体积的水中。加入NaOH将pH调节到12.5,搅拌混合物,直到完全溶解。加入50.0体积的乙醇。将溶液冷却到-18℃,但是没有产生晶体。
实施例5
在50℃将按实施例1制备的拉奎尼莫钠加到6.1体积的水中。加入NaOH将pH调节到12.5,搅拌混合物,直到完全溶解。加入50.0体积的乙醇。加入HCl将pH调节到5.0以酸化溶液。将溶液冷却到4℃,产生了晶体。过滤结晶的化合物,用20毫升乙醇-水(1∶1)洗涤,在50℃真空干燥到恒重,测定的结果是拉奎尼莫酸,产率为56.2%。
实施例2-5的讨论
在实施例2-5中,试图通过将拉奎尼莫钠溶解在小量水中,加入反溶剂乙醇来重结晶。虽然拉奎尼莫钠在乙醇中的溶解度低(拉奎尼莫钠在室温微溶在乙醇中),但是,即使加入大量乙醇(多到100毫升),拉奎尼莫钠还是没有发生结晶。
实施例6
在76℃将按实施例1制备的拉奎尼莫钠加到9.9体积的水中。加入NaOH将pH调节到10.5-11,搅拌混合物,直到完全溶解。将溶液冷却到3℃,但是没有产生晶体。
实施例7
在76℃将按实施例1制备的拉奎尼莫钠加到9.9体积的水中。加入NaOH将pH调节到10.5-11,搅拌混合物,直到完全溶解。加入30.6体积的异丙醇。将溶液冷却到5℃,但是没有产生晶体。
实施例2-7的讨论
实施例6表明,单单冷却拉奎尼莫钠的水溶液不能发生结晶。实施例7表明,加入异丙醇反溶剂(拉奎尼莫钠在室温极微溶于异丙醇)到拉奎尼莫钠的水溶液中不能发生结晶。
实施例2-7表明,重结晶的标准方法用于拉奎尼莫的重结晶是无效的,因为或者不发生结晶或者产率低。
实施例8
将实施例的溶液真空蒸发浓缩到3.8毫升。有少量晶体从溶液中结晶出来。混合物在7℃冷区过夜。过滤混合物,固体晶体用20毫升异丙醇洗涤,在50℃真空干燥到恒重。测定产率为11.2%。
实施例9
收集实施例8的滤液,室温加入8.2体积(相对于实施例7中的起始的拉奎尼莫钠)异丙醇到滤液中。加过异丙醇的滤液冷却到7℃,固体晶体从滤液中结晶出来。晶体用10毫升异丙醇洗涤,50℃真空干燥到恒重。测定的产率为29.8%(基于实施例7中的起始的拉奎尼莫钠)。
实施例10
将按照实施例1制备的拉奎尼莫钠加到9.9体积76℃的水中。加入NaOH调节pH到10.5-11,搅拌混合物,直到完全溶解。加入91体积丙酮。溶液冷却到5℃,看到少量的固体晶体。固体用丙酮洗涤,过滤,在50℃真空干燥到恒重。测定的产率为10.2%。
实施例11
将按照实施例1制备的拉奎尼莫钠加到9.9体积76℃的水中。加入NaOH调节pH到10.5-11,搅拌混合物,直到完全溶解。用旋转蒸发仪把溶液浓缩到1.4体积。
将8.0体积丙酮加到溶液中,发生了结晶。混合物冷却到7℃g过夜。过滤固体,在50℃真空干燥到恒重。该固体经测定为拉奎尼莫钠,产率为90.3%。
实施例10和11的讨论
实施例10表明即使加入大量丙酮(拉奎尼莫钠在室温是实际上不溶于丙酮的)到未浓缩的拉奎尼莫钠水溶液中,也只能得到低产率的结晶拉奎尼莫钠。
另一方面,实施例11表明,如果拉奎尼莫钠的水溶液先被浓缩,然后加入反溶剂,拉奎尼莫钠晶体的产率是高的。在此例子中,为了得到高产率,并不需要加入大量反溶剂。
实施例12
将按照实施例1制备的拉奎尼莫钠加到11.1体积78℃的水中。加入NaOH调节pH到12,搅拌混合物,直到完全溶解。用旋转蒸发仪将溶液浓缩到1.9体积。把溶液转移到温热的反应器中(夹套温度50℃),慢慢加入9.5体积丙酮,发生了结晶。混合物冷却到3℃,在反应器中混合1.5小时。过滤固体,用丙酮洗涤,在50℃真空干燥到恒重。测定是拉奎尼莫钠,产率为79.5%。
实施例13(不用晶种的重结晶)
将按实施例1的方法通过加大规模制备的46.7克拉奎尼莫钠(批量A)和500毫升去离子水加入到实验室玻璃反应器中。搅拌混合物并加热到50℃直到固体完全溶解。通过滤纸过滤溶液,滤纸用10毫升水洗涤,把洗涤液和滤液合并。
将得到的溶液加入到装有真空蒸馏系统的实验室反应器中。通过真空(35-38mbar)蒸馏浓缩溶液到112毫升的体积。蒸发后将压力调节到大气压力,套温升高到50℃,在2小时内把295克丙酮加入溶液中。在加入丙酮的过程中看到固体结晶出现。将溶液冷却到2℃并在此温度搅拌12小时。过滤分出固体产物,用丙酮洗涤2次,在35-40℃真空干燥到恒重。得到35.7克,产率76.4%。
将按照实施例1制备的原料(批量A)和干燥的重结晶产物取样并分析粒度分布、粉末密度、和化学纯度。结构列在表1中。
表1:拉奎尼莫钠的性质和纯度,实施例13
质量参数 | 按实施例1(批量A)制备的拉奎尼莫钠 | 重结晶产物 | |
Malvern粒度分布微米 | d(0.1)d(0.5)d(0.9) | 1.57.123.2 | 13.351.1105.1 |
粉末密度(克/毫升) | BDTD | 0.1660.347 | 0.4980.758 |
由IPC测定的重金属(ppm) | FeNiCr | 70.60,7 | <2<0.50.3 |
颜色 | 灰 | 灰白 | |
由HPLC测定的纯度(面积%) | 杂质,1RT=5.49 | 0.06 | 未检出 |
HPLC=高效液相色谱 RT=保留时间
实施例13的方法伴随着高产率,是工业上可重现的。
实施例13表明,重结晶方法提高了拉奎尼莫钠的纯度,在重结晶以后不再能检出峰1杂质峰,并且颜色也改变了。此外,重金属Fe,Ni,Cr的量也降低了。
此外,拉奎尼莫钠的粉末密度提高了,颗粒的粒度也得到提高。
实施例14(自发结晶的拉奎尼莫钠重结晶---在水中成核)
将按实施例1的方法通过加大规模制备的71.4克拉奎尼莫钠(批量B)和750毫升去离子水加入到实验室玻璃反应器中。搅拌混合物并加热到60℃直到固体完全溶解。通过滤纸过滤溶液,滤纸用36毫升水洗涤,把洗涤液和滤液合并。
将得到的溶液加入到装有真空蒸馏系统的实验室反应器中。通过真空(37-38mbar)蒸馏浓缩溶液到153毫升的体积。蒸发后将压力调节到大气压力,套温升高到50℃,溶液搅拌25分钟。在此阶段看到固体的自发结晶。然后在2小时内把450.5克丙酮加入溶液中。将溶液冷却到2℃并在此温度搅拌12小时。过滤分出固体产物,用丙酮洗涤2次,在35-40℃真空干燥到恒重。得到64.2克,产率89.9%。
将按照实施例1制备的原料(批量B)和干燥的重结晶产物取样并分析粒度分布、粉末密度、和化学纯度。结构列在表2中。
表2:拉奎尼莫钠的性质和纯度,实施例14
实施例15(用晶种结晶的重结晶方法---受控的水中成核)
将按实施例1的方法通过加大规模制备的25.0克拉奎尼莫钠(批量C)和260毫升去离子水加入到实验室玻璃反应器中。搅拌混合物并加热到60℃直到固体完全溶解。通过滤纸过滤溶液,滤纸用15毫升水洗涤,把洗涤液和滤液合并。将得到的溶液加入到装有真空蒸馏系统的实验室反应器中。通过真空(20-25mbar)蒸馏浓缩溶液到60.0克重量的残留物。蒸发完成后,将残留物放入预先加热到50℃(套温)的实验室玻璃反应器中。混合物用0.2克固体拉奎尼莫钠晶种,搅拌1小时,观察到了结晶。在2小时内加入157.7克丙酮。混合物冷却到2℃,搅拌12小时。过滤分出固体产物,用丙酮洗涤2次,在35-40℃真空干燥到恒重。得到22.6克,产率90.4%。
将按照实施例1制备的原料(批量C)和干燥的重结晶产物取样并分析粒度分布、粉末密度、和化学纯度。结构列在表3中。
表3:拉奎尼莫钠的性质和纯度
实施例14和15的讨论
实施例14和15伴随着高产率,是工业上可再现的。
实施例14和15表明,重结晶方法提高了拉奎尼莫钠的纯度,在重结晶以后不再能检出杂质峰。此外,重金属Fe,Ni,Cr的量也降低了。在实施例14和15重结晶后得到的晶体比重结晶以前的要大。
实施例16(无晶种的结晶---在丙酮存在下成核)
将水(532毫升)和拉奎尼莫钠(52.3克)加入到实验室玻璃反应器(0.5L)中。悬浮液加热到70-73℃直到固体完全溶解。热溶液冷却到50℃,然后通过0.2微米滤纸过滤,滤纸用10毫升水洗涤,把洗涤液和滤液合并。将得到的溶液在30-5-mbar真空下搅拌,在1升反应器中蒸发浓缩到112毫升,同时保持套温在60℃,放映器温度在35-40℃。在蒸发刚完成并调节压力后,在2小时内将丙酮(417毫升)加入蒸发残留物,同时套温保持在50℃。在2小时内将结晶混合物冷却到2℃,在此温度保持5-10小时。过滤分出固体产物,用50毫升丙酮洗涤2次,湿物质在干燥器中在30-40℃真空干燥,得到47.6克,干燥物质的产率为90.6%。结果列在表4:
表4.拉奎尼莫钠的性质,实施例16
质量参数 | 按实施例1(批量B)制备的拉奎尼莫钠 | 重结晶产物 | |
Malvern粒度分布微米 | d(0.1)d(0.5)d(0.9) | 2.110.835.3 | 15.765.5156.4 |
颜色 | 白 | 白 |
由重结晶方法产生的晶体比原料晶体要大。
实施例17(含有不溶解杂质的粗品拉奎尼莫钠的重结晶)
按照实施例1方法规模的方法制备的拉奎尼莫钠(批量D)的55毫克样品在室温与0.5毫升去离子水混合。样品不完全溶解在水中。
该批量的样品的重结晶纯化进行如下:
水(391毫升)和拉奎尼莫钠(实施例1批量D)(39.1克)加入实验室玻璃反应器(0.5L)中。通过升高套温到73℃加热悬浮液。20分钟后溶液还没有澄清。再升高套温到75℃加热悬浮液,还是没有得到澄清的溶液。将热溶液冷却到50℃,用布氏漏斗通过实验室滤纸过滤。有0.3克固体残留物留在滤纸上。将固体残留物的样品用来试验杂质含量。滤纸用47毫升水洗涤,将洗涤液与滤液合并。通过降低套温到25℃使得到的溶液冷却,然后真空(P<45mmHg)浓缩该溶液,同时在此过程中通过将套温升高到65℃来加热。蒸发完成后,通过将套温降低到50℃来冷却残留物(82.1ml,93.2g,d=1.135g/ml)并且振动10分钟。然后该批量用固体拉奎尼莫作为晶种加入,在保持套温50℃的同时搅拌1小时。然后在50℃在2小时内将丙酮(316.7mL,250.2g)加入结晶混合物中。在4小时内将得到的悬浮液冷却到2℃,在该温度再保持11小时。形成的固体过滤收集,用31.3克丙酮洗涤2次。湿物质在30-40℃在干燥器中真空干燥,得到31.7克(81.1%)干燥的结晶拉奎尼莫钠。在重结晶前和重结晶后通过ICP分析粗拉奎尼莫钠的杂质含量。
表5拉奎尼莫钠的杂质含量(单位ppm)
杂质 | 按实施例1(批量D)制备的拉奎尼莫钠 | 重结晶产物 | 固体残留物 |
Al | 14.0 | 5.6 | 411 |
Ca | 165 | 65 | 860 |
Cr | 2.6 | <0.5 | 99 |
Cu | 2.8 | 1.3 | 64 |
Fe | 31.5 | 5.8 | 1544 |
Ni | 5.5 | <0.5 | 69 |
S | 466 | <1 | 193 |
Zn | 20.5 | 7.5 | 352 |
实施例17的讨论
即使粗拉奎尼莫钠在重结晶之前有高的不溶解的杂质含量,重结晶方法也能降低杂质含量。固体残留物中的高杂质含量表明,为了降低杂质含量,拉奎尼莫钠水溶液的过滤是很重要的。因此,希望能将不溶解物质的量降低到预定不会产生不良影响(如拉奎尼莫配方的稳定性)的预定量。
Claims (40)
1.一重结晶的拉奎尼莫钠颗粒的混合物,其中拉奎尼莫钠颗粒体积总量的10%或更多所具有的粒度大于40微米。
2.如权利要求1所述的混合物,其中拉奎尼莫钠颗粒体积总量的50%或更多所具有的粒度大于15微米。
3.如权利要求1或2所述的混合物,具有至少为0.6g/mL.的轻叩密度。
4.如权利要求1-3的任何一个所述的混合物,具有至少为0.4g/mL的松散密度。
5.如权利要求1-4的任何一个所述的混合物,具有少于为0.8g/mL.的轻叩密度。
6.如权利要求1-5的任何一个所述的混合物,包含不高于2ppm的重金属。
7.如权利要求6所述的混合物,其中的重金属为铁、镍、或铬。
8.如权利要求7所述的混合物,包含不高于2ppm的铁。
9.如权利要求7所述的混合物,包含不高于0.2ppm的镍。
10.如权利要求7所述的混合物,包含不高于0.3ppm的铬。
11.一种结晶的拉奎尼莫钠颗粒的混合物,具有至少为0.6g/mL的轻叩密度。
12.如权利要求11所述的混合物,具有至少为0.4g/mL的松散密度。
13.如权利要求11或12所述的混合物,具有少于为0.8g/mL的轻叩密度。
14.如权利要求11到13任一所述的混合物,包含不高于2ppm的重金属。
15.如权利要求14所述的混合物,其中的重金属为铁、镍、或铬。
16.如权利要求15所述的混合物,包含不高于2ppm的铁。
17.如权利要求15所述的混合物,包含不高于0.2ppm的镍。
18.如权利要求15所述的混合物,包含不高于0.3ppm的铬。
19.一种药物组合物,包含如权利要求1-18所述的任何一个所述的混合物和一种药学上可接受的载体。
20.如权利要求19所述的药物组合物,其形式是药片或胶囊。
21.一种组合物,包含拉奎尼莫钠和不高于2ppm的重金属,以在组合物中拉奎尼莫钠的总量为基础计算。
22.如权利要求21所述的混合物,其中的重金属为铁、镍、或铬。
23.如权利要求22所述的组合物,其中铁的含量不高于2ppm.
24.如权利要求22所述的组合物,其中镍的含量不高于0.2ppm.
25.如权利要求22所述的组合物,其中铬的含量不高于0.3ppm.
26.如权利要求21-25的任何一个所述的组合物,是结晶的形式。
27.如权利要求21-26的任何一个所述的组合物,还包含一种药学上可接受的载体。
28.如权利要求27所述的组合物,是药片或胶囊的形式。
29.拉奎尼莫钠重结晶的一种方法,包含:a)将拉奎尼莫钠溶解在水中,形成水溶液;b)过滤水溶液,以除去固体杂质;c)浓缩水溶液,形成浓缩的溶液;d)加入与水可混溶的反溶剂到浓缩溶液中,形成拉奎尼莫钠晶体;e)分离拉奎尼莫钠晶体。
30.如权利要求29所述的方法,其中步骤a)通过将水溶液加热到40-80℃的温度来完成。
31.如权利要求29-30所述的方法,其中浓缩溶液包含1-4毫升水/克拉奎尼莫钠。
32.如权利要求31所述的方法,其中浓缩溶液包含1-2毫升水/克拉奎尼莫钠。
33.如权利要求29-32所述的方法,其中的反溶剂是以下的一种溶剂或是多种溶剂的混合物:乙醇、异丙醇、丙酮。
34.如权利要求33所述的方法,其中反溶剂是丙酮。
35.如权利要求29-34所述的方法,其中的反溶剂的加入量是3-15毫升/克拉奎尼莫钠。
36.如权利要求29-35所述的方法,其中步骤c)接着是冷却溶液到低于10℃的温度。
37.如权利要求29-36所述的方法,其中步骤b)接着是用拉奎尼莫钠晶种加入浓缩溶液。
38.通过权利要求29-37的任何一个制备的拉奎尼莫钠。
39.制备包含拉奎尼莫钠的药物组合物的方法,包含:a)制备批量的拉奎尼莫钠;b)测定在步骤a)的批量中是否存在不溶解的物质,方法是将该步骤a)的样品在室温下与去离子水混合(混合比例为至少110毫克样品对1.0毫升水),然后检查所形成的混合物中是否有不溶解的物质;c)如果在步骤b)中测定的不溶解物质的量低于预定量,则将批量a)与至少一种药学上可接受的载体混合。
40.如权利要求39所述的方法,其中如果步骤b)混合物中测定的不溶解物质的量不是低于预定量,则方法还包含:d)将步骤a)批量溶解在水中,形成水溶液;e)过滤步骤d)的水溶液,将不溶解物质的量降低到预定量以下;f)浓缩步骤e)水溶液,形成浓缩溶液;g)将水可混溶的反溶剂加入步骤f)的浓缩溶液,形成拉奎尼莫钠晶体;h)分离步骤g)的拉奎尼莫钠晶体。
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AU2011338647A1 (en) * | 2010-12-07 | 2013-07-04 | Teva Pharmaceutical Industries Ltd. | Use of laquinimod for reducing fatigue, improving functional status, and improving quality of life in multiple sclerosis patients |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103626701A (zh) * | 2012-08-28 | 2014-03-12 | 天津药物研究院 | 一种制备喹啉衍生物的方法 |
CN103626702A (zh) * | 2012-08-30 | 2014-03-12 | 天津药物研究院 | 一种制备喹啉酮衍生物的方法 |
CN105051013A (zh) * | 2013-03-14 | 2015-11-11 | 泰华制药工业有限公司 | 拉喹莫德钠晶体及其改进的制造方法 |
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