CN1061348C - 一种喹啉羧酸盐酸盐的新结晶型体及其制法和药物制剂 - Google Patents
一种喹啉羧酸盐酸盐的新结晶型体及其制法和药物制剂 Download PDFInfo
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Abstract
本发明涉及1-环丙基-7([S，S]-2，8-二氮杂双环-[4.3.0]壬-8-基)-6-氟-1，4-二氢-8-甲氧基-4-氧代-3-喹啉羧酸盐酸盐(CDCH)的新的一水合物，其制备方法以及含有该一水合物作为活性化合物的药物制剂。
Description
本发明涉及1-环丙基-7-([S,S]-2,8-二氮杂双环[4,3,0]壬-8-基)-6-氟-1,4-二氢-8-甲氧基-4-氧代-3-喹啉羧酸盐酸盐(CDCH)的新的一水合物，其制备方法，以及含此一水化合物作为活性化合物的药物制剂。
CDCH是具有广谱抗菌作用的用于人类和动物的化学治疗剂。该活性化合物也可用于材料的防腐作用。CDCH显示出低毒性。对肠杆菌科特别有效，尤其是对对抗生素有抗性的菌株：金色链霉菌，铜绿色极毛杆菌，肠球菌faecalis和大肠杆菌。在EP-A-550 903和EP-A-591808中作为内铵盐(betain)介绍过CDCH。
无水形式的CDCH是迄今所知的仅有的一种结晶型体。然而，这一结晶型体在制备各种形式药物时不是完全令人满意的。CDCH是吸湿性的，在不利的贮存条件下和在将活性化合物制成药物形式的加工过程中它吸收水。这有损于剂量的准确度和制剂的质量。当CDCH以悬浮液形式或在环境湿度下贮存时引起的其无水形式的结晶构造的变化是CDCH物理不稳定性的原因所在。所以，采用一种尽可能稳定的结晶形式对于制备含CDCH的药物形式是非常重要的。
现已发现，可以将CDCH转变为一种新的含水结晶型体，与已知的无水形式相比，它的不同之处在于稳定性增加，特别是在湿度高的条件下贮存期间，并且特别适合于制备稳定的药物制剂。
在从含水介质中制备一水合物期间，活性化合物以严重失去光泽的针状形式结晶出来。令人惊奇的是，在特定结晶条件下，采用一种受控方式，可以改变这种结晶特性。如此形成的棱晶代表了本发明的较好的实施方案，这是因为它不失去光泽，并且比针状一水合物显著地更具有自由流动性。这在制备药物时具有所期望的优点。通过使用非吸湿性、自由流动的活性化合物，在制备药物时，可以达到满意的剂量准确度，这增加了安全性，因而对病人来说减少危险性。
因此，本发明涉及式Ⅰ所示CDCH的新的一水合物及其制备方法，
其特征在于，用足以彻底混合并形成一水合物的水在低于80℃的温度下处理无水的结晶状CDCH，直到吸收化学计量的结晶水并且使结晶完全转化，将所得晶体分离并干燥至一水合物的恒定重量，以便除去存在的被吸附的水。为了避免生成无水型体，干燥过程中的湿度应当不低于30％相对湿度。由水含量高于10％的含水介质中结晶出针状一水合物。
以棱晶体结晶的较好的一水合物型体可通过下述方法制得；将无水结晶状CDCH悬浮于乙醇/水混合物中，特别优选最多含10％水的乙醇/水混合物，例如，通过搅拌悬浮液或者摇动、旋动、转动反应容器等方法，保证使其中所含固体与加入的水彻底混合，直到已经吸收了所需量的结晶水，并且晶体完全转化。如果乙醇/水混合物中最大水含量是10％，则该一水合物以棱晶形式结晶出来。
只要水的量足以形成化学计量的一水合物，并且足以使所用的CDCH与水彻底混合，对于形成针状一水合物的情况，可以采用任意量的水，这是因为在晶体转化过程中发生的结晶水的吸收导致一水合物生成，并且不会得到进一步的水合物。合适的水量应限制在既能发生彻底混合，又没有或只有低的溶解度损失。一水合物分离优选在室温下进行，但也可以在更高温度下进行，如30℃至60℃，或在更低温度下进行，如5℃至20℃。从无水型体制备一水合物型体也可在相对湿度大于30％的湿度条件下成功地发生。但是，这一方法不适于制备以棱晶形式结晶的优选的一水合物。
一水合物的晶体可通过常规方法，例如过滤、滗析、离心等，从过量溶剂中分离出来。分离出的一水合物晶体最好在室温或在较高温度(至多50℃)下、在相对湿度至少为30％的条件下进行干燥。
本发明的CDCH一水合物具有特异的红外光谱(图1)，显示出在OH价振动区域(3600-3100cm-1)的结晶水的特异吸收带，这在无水结晶型体中是不存在的。在其他频率范围它与无水CDCH也不相同，这样可以得出结论，在两种型体的晶格中分子具有完全不同的排列。
水含量测定证实了化学计量的CDCH一水合物的存在。用几个一水合物样品进行热重量分析测得的重量损失是1摩尔水(3.9％，图2)。在大气压力下由DSC(差示扫描量热法)记录的一水合物的差示热分析图(图3)，与热重量分析法测量结果一致，由其宽的吸热峰(表示所分析的一水合物的晶格发生重排、CDCH和水发生解离以及解离的结晶水蒸发时的热函)表明释放出水来。无水型体和一水合物的X-射线衍射图和13C-NMR谱、喇曼光谱以及FIR谱表明其特异性差别(图4-7，表2-5)：于是，例如13C-NMR谱在168.1ppm处有一个特征峰，X-射线衍射图在2θ=26.7处有一条线。
DSC和TGA的差示热分析图是用Perkin-Elmer公司的热分析器(DSC7和TGA7)得到的，X-射线衍射图是用Stoe透射衍射计记录的。IR、FIR和喇曼光谱是用Bruker公司的傅里叶-IR光谱仪IFS66(IR)、IFS66v(FIR)和IFS88(喇曼)记录的。13C-固体-NMR谱是用Bruker MSL 300记录的。显微照片是用Leitz公司Laborlux S显微镜拍摄的。
在贮存期间，本发明的CDCH一水合物和无水结晶型体相比显示出较高的物理稳定性，因此更适合于制备各种形式的药物。以棱晶形式结晶出来的优选的一水合物进一步赋予CDCH以优良的细流和流动性能，这在制备药物制剂时是很有好处的(图8)。因此，本发明又涉及含有本发明CDCH一水合物的液体和固体药物制剂，例如悬浮液，乳液，片剂，包衣片剂，包衣片核，栓剂，硬或软明胶胶囊剂等。口服用的水悬液和片剂优选包含本发明的一水合物，特别优选其棱晶形式。
在这些药物制剂中，CDCH可以作为仅有的活性化合物存在，或者可以和其他抗菌活性物质结合。
药物制剂可以包含本发明的CDCH一水合物本身，或者包含其与几种其他活性化合物的混合物，或者与药物中常用的助剂和添加剂如片剂粘合剂、填充剂、防腐剂、片剂崩解剂、流动性调节剂、增塑剂、润湿剂、分散剂、乳化剂、溶剂、调味剂等一起加工，制得口服、胃肠外或直肠用药。
以已知方式制得药物制剂，例如，用混合、搅拌、悬浮、分散、乳化等手段将活性化合物与药物助剂混合或混入，然后将这些组分加工成适于口服、胃肠外或直肠给药的药物剂型。
CDCH晶体(针状，棱晶)的制备
实施例1(棱晶)
将1克无水CDCH溶于150毫升无水乙醇，将溶液过滤。在60℃加热该溶液，直至溶剂完全蒸发。沉淀出的晶体在室温/环境湿度下干燥。
实施例2(棱晶)
将0.1克无水CDCH溶于10毫升乙醇(10％水含量)中。在60℃加热该溶液，直至溶剂完全蒸发。沉淀出的晶体在室温/环境湿度下干燥。
实施例3(棱晶)
将4克无水CDCH溶于300毫升乙醇(96％)中。在60℃和120毫巴下用旋转蒸发器蒸除溶剂。晶体在真空干燥室内于80毫巴和105℃下干燥2小时，然后暴露于环境湿度下。
实施例4(针状)
将0.3克无水CDCH溶于6毫升水∶乙醇(1∶1)中。在70℃加热该溶液，直至溶剂完全蒸发。沉淀出的晶体在室温下和真空中干燥，然后在室温/85％相对湿度下静置过夜。
实施例5(针状)
将0.1克无水CDCH溶于5毫升甲醇中。该溶液在室温下静置，直至溶剂完全蒸发。将晶体在真空中和室温下干燥，然后在室温/85％相对湿度下静置过夜。
实施例6(针状)
将0.1克无水CDCH溶于5毫升水中。该溶液在室温下静置，直至溶剂完全蒸发。晶体在室温和真空中干燥，然后在室温/85％相对湿度下静置过夜。
实施例7
将25.1克CDCH一水合物(棱晶)、3.3克Avicel PH 101和1.7克玉米淀粉在高剪切混合器中混合，然后用13克水进行造粒。锉磨(4毫米)之后，将颗粒于微型流化床干燥器中(入口空气温度80℃)干燥，通过0.8毫米筛。然后与0.19克Ac-Di-Sol和0.01克硬脂酸镁混合。混合物用单冲杆压片机(片型5.5r9，片重68.5毫克)压片。
实施例8
将196.6克微粉化CDCH一水合物(针晶)与88克Avicel在高剪切混合器中混合(粉状混合物)。将3.6克PVP 25溶于97.2克水中(造粒液体)。将粉状混合物与造粒液体一起造粒。锉磨(3毫米)之后，将颗粒于干燥器中(入口空气温度90℃)干燥，通过1毫米筛。然后与1.8克Ac-Di-Sol和0.1克硬脂酸镁混合。混合物用旋转压片机(片型5.5r9，片重83.4毫克)压片。
表1：红外光谱
| 无水形式[cm-1] | 水合物[cm-1] |
| 722804834938957994104811861319135413721453151316221709242725242700292934693527 | 722804835875938994104510821163118413191352137213941432145615171624170924272456252426342925269827452893292534723530 |
表2：X-射线衍射谱
| 无水形式[2θ] | 水合物[2θ] |
| 5.88.610.311.613.614.515.015.817.317.518.318.919.319.620.621.522.522.823.023.824.224.725.026.327.027.427.828.229.429.730.030.331.331.834.535.337.1 | 5.88.510.111.613.414.514.815.617.017.217.417.517.918.619.119.620.421.121.822.723.023.624.124.526.526.727.027.327.527.828.528.929.229.731.431.932.332.634.235.135.536.837.5 |
表3:13C固体NMR谱
| 无水形式[ppm] | 水合物[ppm] |
| 8.512.314.118.220.022.835.239.746.549.552.355.959.262.665.8105.4108.1116.9117.5134.7136.0137.3140.1142.6150.1152.6165.3166.0175.5 | 7.78.39.010.812.118.219.822.934.940.247.049.550.152.655.956.859.464.166.8105.0107.1116.3117.4135.2136.1137.4140.8143.5149.3150.9168.1175.5 |
表4：喇曼光谱
| 无水形式[cm-1] | 水合物[cm-1] |
| 1101472432783884254965437238339641031119112671305132013541376143314912891292229572991302030543069308230883110 | 10914824327830942549654372483396210311191130513211352137614331490155416191711283528882923294229582977299030193056306930893106 |
表5:FIR光谱
| 无水形式[cm-1] | 水合物[cm-1] |
| 137165187219230248279289311342370386396412423436456474494 | 95111139145163185220230277313340369388399412423436459476494 |
Claims (8)
1．下式所示的CDCH一水合物，
其13C-NNR谱中在168.1ppm处具有特征峰，并且其X-射线衍射图中在2θ=26.7处有一谱带。
2．权利要求1所述的化合物，其晶型为棱晶。
3．权利要求1的CDCH一水合物的制备方法，其特征在于无水CDCH用至少足以彻底混合并发生水合作用的水处理，直至吸收了化学计量的结晶水，并且晶体完全转化，分离所得到的一水合物晶体，以及除去吸附的水。
4．权利要求3所述的方法，其特征在于将无水CDCH在含水介质中的悬浮液进行搅拌，直至水合作用和晶体转化作用完成。
5．权利要求3所述的方法，其特征在于将无水CDCH或针状CDCH一水合物溶于其中水含量按化学计量是足够的、但又限于至多10％的介质中，然后除去溶剂，以制备棱晶状一水合物。
6．权利要求3所述的方法，其特征在于将无水CDCH暴露于湿气中，直至晶体定量地转化。
7．含有权利要求1和2所述化合物的抗菌组合物。
8．权利要求1和2所述化合物在制备药物中的应用。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19546249.1 | 1995-12-12 | ||
| DE19546249A DE19546249A1 (de) | 1995-12-12 | 1995-12-12 | Neue Kristallmodifikation des 1-Cyclopropyl-7-([S,S]-2,8-diazabicyclo[4,3,0]non-8-yl)-6-fluor-1,4-dihydro-8-methoxy-4-oxo-3-chinolincarbonsäure Hydrochlorid (CDCH), Verfahren zu dessen Herstellung und diese enthaltende pharmazeutische Zubereitungen |
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| CN1160052A CN1160052A (zh) | 1997-09-24 |
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| PT1017392E (pt) * | 1997-09-25 | 2002-10-31 | Bayer Ag | Formulacao de medicamento com libertacao controlada do principio activo |
| DE19751948A1 (de) | 1997-11-24 | 1999-05-27 | Bayer Ag | Verfahren zur Herstellung von 8-Methoxy-Chinoloncarbonsäuren |
| US6716830B2 (en) * | 1998-09-30 | 2004-04-06 | Alcon, Inc. | Ophthalmic antibiotic compositions containing moxifloxacin |
| US6509327B1 (en) | 1998-09-30 | 2003-01-21 | Alcon Manufacturing, Ltd. | Compositions and methods for treating otic, ophthalmic and nasal infections |
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| EP0550903A1 (de) * | 1992-01-10 | 1993-07-14 | Bayer Ag | Chinolon- und Naphthyridon-Carbonsäurederivate als antibakterielles Mittel |
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| EP0550903A1 (de) * | 1992-01-10 | 1993-07-14 | Bayer Ag | Chinolon- und Naphthyridon-Carbonsäurederivate als antibakterielles Mittel |
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