CN101993417A - 磷酸二甲啡烷的稳定新晶型 - Google Patents
磷酸二甲啡烷的稳定新晶型 Download PDFInfo
- Publication number
- CN101993417A CN101993417A CN2009100911456A CN200910091145A CN101993417A CN 101993417 A CN101993417 A CN 101993417A CN 2009100911456 A CN2009100911456 A CN 2009100911456A CN 200910091145 A CN200910091145 A CN 200910091145A CN 101993417 A CN101993417 A CN 101993417A
- Authority
- CN
- China
- Prior art keywords
- phosphoric acid
- dimemorfan
- new crystal
- acid dimemorfan
- crystal form
- 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
- KBEZZLAAKIIPFK-NJAFHUGGSA-N dimemorfan Chemical compound C1C2=CC=C(C)C=C2[C@@]23CCN(C)[C@@H]1[C@H]2CCCC3 KBEZZLAAKIIPFK-NJAFHUGGSA-N 0.000 title claims abstract description 36
- 229960001056 dimemorfan Drugs 0.000 title claims abstract description 36
- 239000013078 crystal Substances 0.000 title claims abstract description 26
- 238000001228 spectrum Methods 0.000 claims abstract description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 70
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
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- 238000000634 powder X-ray diffraction Methods 0.000 claims description 4
- 229910017488 Cu K Inorganic materials 0.000 claims description 3
- 229910017541 Cu-K Inorganic materials 0.000 claims description 3
- 239000000843 powder Substances 0.000 abstract description 5
- 229910002483 Cu Ka Inorganic materials 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 206010011224 Cough Diseases 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 238000000034 method Methods 0.000 description 6
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
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- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
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- 229920000084 Gum arabic Polymers 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
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- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
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- 235000012211 aluminium silicate Nutrition 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
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- 229960002675 xylitol Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供磷酸二甲啡烷的稳定新晶型I，其特征在于：以度2θ表示的、使用Cu-Kα辐射的X射线粉末衍射的光谱基本上在约5.3、约13.5、约16.3、约24.5有特征峰。
Description
技术领域
本发明涉及磷酸二甲啡烷的新晶型、含有这些新晶型的药用组合物及其在制备镇咳类药物中的用途。
背景技术
磷酸二甲啡烷的化学名为(9α，13α，14α)-3，17-二甲基吗啡喃磷酸盐，结构式如下所示：
本品为非成瘾性中枢镇咳嗽药，镇咳效果略优于右美沙芬，约为可待因的2倍。优点是毒性低，安全性大，治疗剂量不抑制呼吸，没有便秘副作用。磷酸二甲啡烷已在日本上市30多年未见任何严重不良反应的报道，疗效确切，安全可靠。
文献Chem.Pharm.Bull.(1972，20，1706-1710)报道了磷酸二甲啡烷可由二甲啡烷与磷酸成盐定量得到，但未对其重结晶方法进行描述。本发明人在研究磷酸二甲啡烷重结晶工艺的过程中发现了磷酸二甲啡烷的一种新晶型，命名为晶I。
发明内容
本发明提供磷酸二甲啡烷的新晶型，命名为晶I，其以度2θ表示的、使用Cu-Kα辐射的X射线粉术衍射的光谱基本上在约5.3、约13.5、约16.3、约24.5有特征峰。
本发明中，2θ值的测定使用CuKα光源，精度为±0.2°，因此，上述“以度2θ表示的、使用Cu-Kα辐射的X射线粉末衍射的光谱基本上在约”中的“约”应定义为2θ±0.2°，代表上述所取的2θ值允许有一定合理的误差范围，其误差范围为±0.2°。
在光照、高湿、高温条件考察磷酸二甲啡烷的新晶型，测定其含量、X射线粉末衍射，结果表明磷酸二甲啡烷新晶型是稳定的。
磷酸二甲啡烷的新晶型，可以通过常规的方法制备。例如，通过加热得到饱和溶液后冷却析晶，溶剂可以是单一溶剂或混合溶剂；或者使二甲啡烷和磷酸直接在溶剂中成盐而析出。
本发明还提供新晶型的磷酸二甲啡烷为活性成分的药用组合物。
本发明磷酸二甲啡烷新晶型组合物含有生理有效量的本发明的磷酸二甲啡烷新晶型和适宜的药用辅料，所述组合物是磷酸二甲啡烷新晶型与药用辅料配制成的医学上可接受的药物制剂。
本发明的药物制剂可以是任何可药用的口服剂型，这些剂型包括片剂、胶囊剂、口服液、糖浆剂、颗粒剂、丸剂、散剂等。
本发明的口服固体药物制剂可含有常用的药用辅料，诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和湿润剂，必要时可对片剂进行包衣。适用的填充剂包括纤维素、甘露糖醇、乳糖和其它类似的填充剂。适宜的崩解剂包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物，例如羟基乙酸淀粉钠。适宜的润滑剂，例如硬脂酸镁。适宜的药物可接受的湿润剂包括十二烷基硫酸钠。可通过混合，填充，压片等常用的方法制备固体口服组合物。进行反复混合可使活性物质分布在整个使用大量填充剂的那些组合物中。
口服液体制剂的形式例如可以是水性或油性悬浮液、溶液、乳剂、糖浆剂或酏剂，或者可以是一种在使用前可用水或其它适宜的载体复配的干燥产品。这种液体制剂可含有常规的添加剂，诸如悬浮剂，例如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪，乳化剂，例如卵磷脂、脱水山梨醇一油酸酯或阿拉伯胶；非水性载体(它们可以包括食用油)，例如杏仁油、分馏椰子油、诸如甘油的酯的油性酯、丙二醇或乙醇；防腐剂，例如对羟基苯甲酯或对羟基苯甲酸丙酯或山梨酸，并且如果需要，可含有常规的香味剂或着色剂。
以上制剂中所用药用辅料选自：甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素C、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍尘物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、土温80、琼脂、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β一环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
本发明的药物制剂可以通过药剂学常规技术制备。
具体实施方式
下面的实施例将对本发明做进一步的解释，但是本发明并不仅仅局限于这些实施例，这些实施例不以任何方式限制本发明的范围。本领域的技术人员在权利要求的范围内所作出的某些改变和调整也应认为属于本发明的范围。
实施例1
将21.8g二甲啡烷水浴加热溶于60ml丙酮中，搅拌下滴加9.8ml85％磷酸，滴毕后室温下搅拌2h，过滤，适量丙酮洗涤二次，50℃减压干燥，得白色固体27g，即磷酸二甲啡烷晶I。
1H-NMR(CD3OD，ppm)：2.198～2.223(d，1H)，2.306(s，3H)，2.865(s，3H)，3.530(s，1H)，7.022～7.038(d，1H)，7.095～7.110(d，1H)，7.159(s，1H)。ESI-MS：256.2。
实施例2
取17.3g磷酸二甲啡烷，加入400ml甲醇，加热回流使溶解，趁热过滤，滤液室温放置使其完全析晶。过滤，50℃减压干燥，得12.4g磷酸二甲啡烷晶I。
实施例3
按下述方法制备每片含10mg磷酸二甲啡烷新晶型的片剂：
处方：磷酸二甲啡烷10g，微晶纤维素(PH-102)44g，乳糖35g，交联羧甲基纤维素钠0.5g，硬脂酸镁0.5g，制成1000片。
方法：将主药粉碎过80目筛，其它辅料过60目筛，混合均匀，半成品检验，测定含量，确定平均片重；压片，包薄膜衣。
实施例4磷酸二甲啡烷新晶型物理特性的测定
通过X-射线衍射方法将新晶型的磷酸二甲啡烷粉末置于粉末衍射仪上，以4度/分的扫描速率在2.6～40度2θ角之间进行扫描，使用Cu-Ka 40Kv～100mAX射线辐射，以2θ角度和晶面间距(d值)表示的新晶型的磷酸二甲啡烷的X-射线粉末衍射应在约5.3、约13.5、约16.3、约24.5有特征峰，如附图1是X-射线衍射图所示。
实施例5磷酸二甲啡烷新晶型稳定性考察
取同一批次的磷酸二甲啡烷新晶型，取适量装于三个培养皿中，分别置于下述条件(4500lx±500lx光照、45℃高温、92.5％高湿度)下考察其晶型稳定性，测定结果如下表所示。
实施例6.对小鼠咳嗽的影响
小鼠45只随机分3组，磷酸二甲啡烷新晶型组A、磷酸二甲啡烷对照组B、及生理盐水对照组C。A、B组药物均需先溶解于生理盐水中，按10mL/kg灌胃给予。，小鼠灌胃给药后1h置于倒置的500ml烧杯内，放入0.3ml氨水的棉球，立即观察和记录小鼠咳嗽潜伏期和3分钟内咳嗽次数。结果表明A组和B组药物对氨水致小鼠咳嗽均具有显著止咳作用，与对照组比较有显著差异(P＜0.01)，A组的治疗作用优于B组(P＜0.05)，可见磷酸二甲啡烷新晶型疗效确定稳定。见表1。
表1对小鼠咳嗽的抑制作用
Claims (4)
1.磷酸二甲啡烷的一种稳定新晶型，其特征在于：以度2θ表示的、使用Cu-Kα辐射的X射线粉末衍射的光谱基本上在约5.3、约13.5、约16.3、约24.5有特征峰。
2.含有权利要求1所述的磷酸二甲啡烷稳定新晶型的药用组合物。
3.权利要求2所述的药用组合物由磷酸二甲啡烷稳定新晶型和合适的药用辅料组成。
4.权利要求2所述的药用组合物在制备镇咳类药物中的用途。
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| CN102241630A (zh) * | 2011-05-20 | 2011-11-16 | 杭州保灵集团有限公司 | 一种镇咳嗽药磷酸二甲啡烷的制备方法 |
| CN102746227A (zh) * | 2012-07-09 | 2012-10-24 | 浙江保灵药业有限公司 | 一种磷酸二甲啡烷晶型ⅱ及制备方法和药物组合物 |
| CN103169681A (zh) * | 2013-03-29 | 2013-06-26 | 山东罗欣药业股份有限公司 | 磷酸二甲啡烷片组合物及其制备方法 |
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| CA919668A (en) * | 1970-06-20 | 1973-01-23 | Murakami Masuo | Morphinan derivatives |
| CN101278933A (zh) * | 2008-05-14 | 2008-10-08 | 北京润德康医药技术有限公司 | 一种含有二甲啡烷的药物组合物及其制备方法 |
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| CN102241630A (zh) * | 2011-05-20 | 2011-11-16 | 杭州保灵集团有限公司 | 一种镇咳嗽药磷酸二甲啡烷的制备方法 |
| CN102746227A (zh) * | 2012-07-09 | 2012-10-24 | 浙江保灵药业有限公司 | 一种磷酸二甲啡烷晶型ⅱ及制备方法和药物组合物 |
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| CN105596312B (zh) * | 2016-01-08 | 2018-06-26 | 珠海联邦制药股份有限公司 | 一种磷酸二甲啡烷胶囊组合物及其制备方法 |
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