CN1190955A - 结晶[R-(R',R')]－2－(4－氟苯基)－β,δ－二羟基－5－(1－甲基乙基)－3－苯基－4－[(苯氨基)羰基 - Google Patents

结晶[R-(R',R')]－2－(4－氟苯基)－β,δ－二羟基－5－(1－甲基乙基)－3－苯基－4－[(苯氨基)羰基 Download PDF

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CN1190955A
CN1190955A CN96195564A CN96195564A CN1190955A CN 1190955 A CN1190955 A CN 1190955A CN 96195564 A CN96195564 A CN 96195564A CN 96195564 A CN96195564 A CN 96195564A CN 1190955 A CN1190955 A CN 1190955A
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atorvastatin
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C·A·布芮格斯
R·A·杰宁斯
R·A·韦德
原泽喜久子
市川茂
箕原一光
中川新佐
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Varner-lambert Co., Ltd.
Pfizer Corp
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    • C—CHEMISTRY; METALLURGY
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

命名为Ⅰ型、Ⅱ型和Ⅳ型的新型结晶形式[R－(R*,R*)]－2－(4－氟苯基)－β,δ－二羟基－5－(1－甲基乙基)－3－苯基－4－[(苯氨基)羰基]－1H－吡咯－1－庚酸半钙盐,其特征在于有所述的X－射线粉末衍射和/或固态NMR,以及描述了制备方法及其药物组合物,该组合物用作治疗高血脂症和高胆固醇症的药剂。

Description

结晶[R-(R*，R*)]-2-(4-氟苯基)-β，δ-二羟基 -5-(1-甲基乙基)-3-苯基-4-[(苯氨基)羰基] -1H-吡咯-1-庚酸半钙盐(ATORVASTATIN)
本发明涉及新型的结晶形式atorvastatin，其化学名称为[R-(R*，R*)]-2-(4-氟苯基)-β，δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯氨基)羰基]-1H-吡咯-1-庚酸半钙盐，它们用作药剂；涉及它们的制备和分离方法；涉及含有这些化合物和药物上可接受的载体的药物组合物；以及涉及药物治疗方法。本发明的新型结晶化合物用作酶3-羟基-3-甲基戊二酰基-辅酶A还原酶(HMG-CoA还原酶)的抑制剂，因此是适用的低血脂剂和低胆固醇剂。
US 4681893公开了某些反-6-[2-(3-或4-羧酰胺基取代的吡咯-1-基)烷基]-4-羟基-吡喃-2-酮，包括反-(±)-5-(4-氟苯基)-2-(1-甲基乙基)-N，4-二苯基-1-[(2-四氢-4-羟基-6-氧代-2H-吡喃-2-基)乙基]-1H-吡咯-3-羧酰胺，该专利在这里作为参考并入。
US 5273995公开了有反-5-(4-氟苯基)-2-(1-甲基乙基)-N，4-二苯基-1-[(2-四氢-4-羟基-6-氧代-2H-吡喃-2-基)乙基]-1H-吡咯-3-羧酰胺的R型开环酸的对映体，即[R-(R*，R*)]-2-(4-氟苯基)-β，δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯氨基)羰基]-1H-吡咯-1-庚酸，该专利在这里作为参考并入。
US 5003080、5097045、5103024、5124482、5149837、5155251、5216174、5245047、5248793、5280126、5397792和5342952公开了制备atorvastatin的各种方法和关键的中间体，这些专利在这里作为参考并入。
atorvastatin以其钙盐被制备，即[R-(R*，R*)]-2-(4-氟苯基)-β，δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯氨基)羰基]-1H-吡咯-1-庚酸钙盐(2∶1)。钙盐是希望的，因为它能使atorvastatin很容易配制成如口服用的片剂、胶囊、锭剂、粉剂等。此外，仍有需要制备纯的和结晶形式的atorvastatin，以便能制备满足严格的药物要求和规格的配方。
此外，生产atorvastatin的方法需要是一种适合于大规模生产的方法。另外，希望产物为易于过滤和干燥的形式。最后，在经济上希望产品是长期稳定的，从而不需要特殊的贮存条件。
在上述美国专利中的方法公开了无定形atorvastatin，它不适合大规模生产中的过滤和干燥，还必需使它免受热、光、氧和水汽的作用。
我们现在吃惊地和意想不到地发现，atorvastatin可以结晶形式来制备。因此，本发明提供称为I型、II型和IV型的新型结晶形式的atorvastatin。I型atorvastatin由比以前的无定形产品更小的颗粒和更均匀的粒度分布的atorvastatin组成，它具有更有利过滤和干燥的特性。此外，I型atorvastatin比无定形产品更纯和更稳定。
因此，本发明涉及结晶I型atorvastatin及其水合物，其特征是，有按2θ、d-面间距、相对强度大于20％的相对强度表示的以下X-射线粉末衍射图，它是在研磨2分钟后在Siemens D-500衍射仪上测量的，使用CuKα射线测量：2θ               d                研磨2分钟样品的相
                               对强度(＞20％)9.150             9.6565           42.609.470             9.3311           41.9410.266            8.6098           55.6710.560            8.3705           29.3311.853            7.4601           41.7412.195            7.2518           24.6217.075            5.1887           60.1219.485            4.5520           73.5921.626            4.1059           100.0021.960            4.0442           49.4422.748            3.9059           45.8523.335            3.8088           44.7223.734            3.7457           63.0424.438            3.6394           21.1028.915            3.0853           23.4229.234            3.0524           23.36
此外，本发明还涉及I型结晶atorvastatin及其水合物，其特征在于，有以下的固态13C核磁共振谱，其中化学位移以ppm表示，在Bruker AX-250克谱仪上测量：规定(7KHz)                         化学位移C12或C25                           182.8C12或C25                           178.4C16                                166.7(宽)和159.3芳族碳C2-C5，C13-C18，C19-C24，C27-C32   137.0
                               134.9
                               131.1
                               129.5
                               127.6
                               123.5
                               120.9
                               118.2
                               113.8C8，C10                            73.1
                               70.5
                               68.1
                               64.9亚甲基碳C6，C7，C9，C11                    47.4
                               41.9
                               40.2C33                                26.4
                               25.2C34                                21.3
在本发明第一方面的优选实施方案中，I型结晶atorvastatin为三水合物。
第二方面，本发明涉及II型结晶atrovastatin及其水合物，其特征在于，有按2θ、d-面间距、相对强度大于20％的相对强度表示的以下X-射线粉末衍射图，它是在研磨2分钟后在SiemensD-500衍射仪上的测量的，使用CuKα射线测量：2θ               d                研磨2分钟样品的相对强
                               度(＞20％)5.582             15.8180          42.007.384             11.9620          38.638.533             10.3534          100.009.040             9.7741           92.0612.440(宽)        7.1094           30.6915.771(宽)        5.6146           38.7817.120-17.360(宽) 5.1750-5.1040    63.66-55.1119.490            4.5507           56.6420.502            4.3283           67.2022.706-23.159(宽) 3.9129-3.8375    49.20-48.0025.697(宽)        3.4639           38.9329.504            3.0250           37.86
此外，本发明的第二方面涉及II型结晶atorvastatin及其水合物，其特征在于，有以下固态13C核磁共振谱，其中化学位移以ppm表示，在Bruker AX-250光谱仪上测量：规定                               化学位移自旋边带                           209.1自旋边带                           206.8C12或C25                           181(宽)C12或C25                           163(宽)C16                                161(宽)芳族碳C2-C5，C13-C18，C19-C24，C27-C32   140.5
                               134.8
                               133.3
                               129.0
                               122.9
                               121.4
                               120.3
                               119.0
                               117.1
                               115.7
                               114.7C8，C10                            70.6
                               69.0
                               68.0
                               67.3自旋边带                           49.4自旋边带                           48.9亚甲基碳C6，C7，C9，C11                    43.4
                               42.3
                               41.7
                               40.2C33                                27.5C34                                22.8(宽)
第三方面，本发明涉及IV型结晶atorvastatin及其水合物，其特征在于，有按2θ、d-面间距和相对强度大于15％的相对强度表示的X-射线粉末衍射图，在Siemens D-500衍射仪上测量的，用CuKα射线。2θ               d                相对强度(＞15％)4.889             18.605           38.455.424             16.2804          20.125.940             14.8660          17.297.997             11.0465          100.009.680             9.1295           67.3110.416            8.4859           20.0012.355            7.1584           19.1517.662            5.0175           18.5718.367            4.8265           23.5019.200            4.6189           18.1419.569            4.5327           54.7921.723            4.0879           17.9923.021            3.8602           28.8923.651            3.7587           33.3924.143            3.6832           17.23
此外，本发明的第四方面涉及IV型结晶atorvastatin及其水合物，其特征在于，有以下固态13C核磁共振谱，其中化学位移以ppm表示，在Bruker AX-250光谱仪上测量：规定                               化学位移C12或C25                           186.4
                               184.9C12或C25                           181.4
                               179.3C16                                166.1(宽)和
                               159.0(宽)芳族碳C2-C5，C13-C18，C19-C24，C27-C32   138.1(宽)
                               134.7
                               129.2
                               127.1
                               122.7
                               119.8
                               115.7C8，C10                            71.5
                               67.9
                               66.3
                               63.5亚甲基碳C6，C7，C9，C11                    46.1
                               43.4
                               42.1
                               40.0C33                                25.9C34                                20.3
                               19.4
                               17.9
作为HMG-CoA的抑制剂，新型的结晶形式atorvastatin是适用的低血脂剂和低胆固醇剂。
本发明的另一实施方案是一种药物组合物，用于在上述治疗方法中，按单位剂量形式，提供有效数量I型、II型或IV型结晶atorvastatin。最后，本发明涉及生产I型、II型或IV型atorvastatin的方法。
用以下非限制性实施例，参考附图1-6进一步说明本发明，
附图简述如下：
图1
研磨2分钟的I型atorvastatin的衍射图(Y轴＝0至最大强度3767.50数/秒(cps))。
图2
研磨2分钟的II型atorvastatin的衍射图(Y轴＝0至最大强度1500cps)。
图3
IV型atorvastatin的衍射图(Y轴＝0至最大强度8212.5cps)。
图4
用I型atorvastatin星号标记的带自旋边带的固态13C核磁共振谱。
图5
用II型atorvastatin星号标记的带自旋边带的固态13C核磁共振谱。
图6
用IV型atorvastatin星号标记的带自旋边带的固态13C核磁共振谱。
I型、II型或IV型结晶atorvastatin可用其X-射线粉末衍射图和/或用其固态核磁共振谱(NMR)表征。
I型、II型或IV型atorvastatin用其X-射线粉末衍射图表征。因此，I型、II型和VI型atorvastatin的X-射线衍射图在Siemens D-500衍射仪上测量，使用CuKα射线测量。
设备为Siemens D-500 Diffractometer-Kristalloflex，有IBM-相容界面，软件为DIFFRACAT(SOCABIM1986，1992)。
CuKα射线(20毫安，40千伏，λ＝1.5406埃，狭缝I和II1度)在电子上用Kevex Psi Peltier冷却的硅[硅(锂)]检测器(狭缝III1度和IV0.15度)。
每天用硅标校准X-射线管。
连续θ/2θ联动扫描：2θ范围：4.00度至40.00度，扫描速率为6度/分，每步0.4秒/0.04度。从小瓶中轻轻敲出样品，并入铝架中零背景石英中。样品宽度为13-15毫米。
样品在室温下贮存和操作。
研磨用来使这里所示的衍射图的强度偏差减小。但是，如果研磨使衍射图发生明显变化或使样品的无定形物含量增加，那么就使用未研磨样的衍射图。研磨在小型玛瑙研钵和研杵中进行。在研磨过程中固定研钵，并给研杵轻轻加压力。
在进行X-射线衍射分析以前，将经研磨的II型atorvastatin通过230目筛进行筛分。
表1列出I型结晶atorvastatin的所有相对强度大于20％的衍射线的2θ、d-面间距和相对强度。表1还列出在研磨2分钟后测量的衍射图中相同衍射线的相对强度。研磨2分钟的样品的强度为更有代表性的衍射图，没有优先的取向性。还应指出，计算机得到的未四舍五入的数字列入该表。
         表1I型atorvastatin相对强度大于
         20％的所有衍射线的强度和峰位置2θ               d                相  对  强  度  相  对  强  度
                               (＞20％)        (＞20％)*
                               未研磨          研磨2分钟9.150             9.6565           37.42           42.609.470             9.3311           46.81           41.9410.266            8.6098           75.61           55.6710.560            8.3705           24.03           29.3311.853            7.4601           55.16           41.7412.195            7.2518           20.03           24.6217.075            5.1887           25.95           60.1219.485            4.5520           89.93           73.5921.626            4.1059           100.00          100.0021.960            4.0442           58.64           49.4422.748            3.9059           36.95           45.8523.335            3.8088           31.76           44.7223.734            3.7457           87.55           63.0424.438            3.6394           23.14           21.1028.915            3.0853           21.59           23.4229.234            3.0524           20.45           23.36
*第二列相对强度给出研磨2分钟后原有衍射图上的衍射线的相对强度。
表2列出结晶II型atorvastatin的研磨/筛分样相对强度大于20％的所有衍射线的2θ、d-面间距和相对强度。还应指出，计算机得到的未四舍五入的数字列入该表。
       表2II型atorvastatin相对强度大于
      20％的所有衍射线的强度的和峰位置2θ               d                相对强度(＞20％)5.582             15.8180          42.007.384             11.9620          38.638.533             10.3534          100.009.040             9.7741           92.0612.440(宽)        7.1094           30.6915.771(宽)        5.6146           38.7817.120-17.360(宽) 5.1750-5.1040    63.66-55.1119.490            4.5507           56.6420.502            4.3283           67.2022.706-23.159(宽) 3.9129-3.8375    49.20-48.0025.697(宽)        3.4639           38.9329.504            3.0250           37.86
表3列出IV型结晶atorvastatin的未研磨样相对强度大于15％的所有衍射线的2θ、d-面间距和相对强度。还应该指出，计算机得到的未四舍五入的数字列入该表。
表3IV型atorvastatin相对强度大于
15％的所有衍射线的强度和峰位置2θ               d                相对强度(＞15％)4.889             18.605           38.455.424             16.2804          20.125.940             14.8660          17.297.997             11.0465          100.009.680             9.1295           67.3110.416            8.4859           20.0012.355            7.1584           19.1517.662            5.0175           18.5718.367            4.8265           23.5019.200            4.6189           18.1419.569            4.5327           54.7921.723            4.0879           17.9923.021            3.8602           28.8923.651            3.7587           33.3924.143            3.6832           17.23
固态核磁响应(NMR)
用Bruker AX-250，250兆赫NMR光谱仪进行所有固态13CNMR测量。在约5千赫下用高功率质子去偶和带魔角自旋(MAS)的横向极化(cp)得到高分辨谱图。通过测定边带，用KBr的Br信号来调节魔角，如Frye和Maciel所述(Frye J.S.andMaciel G.E.，J.Mag Res.，1982；48：125)。大约300-450毫克装入设计成小罐的转子中的样品用于每一实验。化学位移参考外标四(三甲基甲硅烷基)硅烷(甲基信号3.50ppm处)(Muntean J.V.and Stock L.M.，J.Mag.Res.，1988；76：54)。
表4列出I型结晶atorvastatin的固态NMR谱。
表4I型atorvastatin的碳原子规定和化学位移规定(7KHz)                         化学位移C12或C25                           182.8C12或C25                           178.4C16                                166.7(宽)和
                               159.3芳族碳C2-C5，C13-C18，C19-C24，C27-C32   137.0
                               134.9
                               131.1
                               129.5
                               127.6
                               123.5
                               120.9
                               118.2
                               113.8
                               73.1C8，C10                            70.5
                               68.1
                               64.9亚甲基碳C6，C7，C9，C11                    47.4
                               41.9
                               40.2C33                                26.4
                               25.2C34                                21.3
表5列出结晶II型atorvastatin的固态NMR谱
表5II型atorvastatin的碳原子规定和化学位移规定                               化学位移自旋边带                           209.1自旋边带                           206.8C12或C25                           181(宽)C12或C25                           163(宽)C16                                161(宽)芳族碳C2-C5，C13-C18，C19-C24，C27-C32   140.5
                               134.8
                               133.3
                               129.0
                               122.9
                               121.4
                               120.3
                               119.0
                               117.1
                               115.7
                               114.7
                               70.6
                               69.0C8，C10                            68.0
                               67.3自旋边带                           49.4自旋边带                           48.9亚甲基碳C6，C7，C9，C11                    43.4
                               42.3
                               41.7
                               40.2C33                                27.5C34                                22.8(宽)
表6列出结晶IV型atorvastatin的固态NMR谱。
表6IV型atorvastatin的碳原子规定和化学位移规定                               化学位移C12或C25                           186.4
                               184.9C12或C25                           181.4
                               179.3C16                                166.1(宽)和
                               159.0(宽)芳族碳C2-C5，C13-C18，C19-C24，C27-C32   138.1(宽)
                               134.7
                               129.2
                               127.1
                               122.7
                               119.8
                               115.7C8，C10                            71.5
                               67.9
                               66.3
                               63.5亚甲基碳C6，C7，C9，C11                    46.1
                               43.4
                               42.1
                               40.0C33                                25.9C34                                20.3
                               19.4
                               17.9
本发明的I型、II型和IV型结晶atorvastatin可以无水形式以及水合形式存在。通常，水合形式与非水合形式是等价的，包括在本发明的范围内。I型结晶atorvastatin含有约1至8摩尔水。优选的是，I型atorvastatin含有3摩尔水。
本发明提供了一种制备I型结晶atorvastatin的方法，该法包括在生成I型结晶atorvastatin的条件下使atorvastatin从溶剂的溶液中结晶。
生成I型结晶atorvastatin的准确条件可按经验确定，它只能给出许多适合于实施的方法。
例如，I型结晶atorvastatin可通过在受控的条件下晶化来制备。特别是，它既可从相应在的碱盐如碱金属盐如锂盐、钾盐、钠盐等，氨或胺盐的水溶液来制备；优选的是，钠盐加钙盐，如乙酸钙等，或者通过将无定形atorvastatin悬浮在水中来制备。通常，优选使用羟基共溶剂如低碳烷醇，如甲醇等。
当制备所需的I型结晶atorvastatin的原料是相应的钠盐溶液时，一优选的制备方法包括优选在至多约70℃的升温下，如在约45-60℃下、优选在约47至52℃下，用乙酸钙水溶液处理钠盐水溶液，水中含有不小于约5％(体积)甲醇、优选约5至33％(体积)甲醇、特别优选约10至15％(体积)甲醇。使用乙酸钙是优选的，通常1摩尔乙酸钙比2摩尔atorvastatin钠盐。在这些条件下，钙盐生成及晶化优选在升温下进行，如在上述的温度范围内进行。已发现，少量的甲基叔丁基醚(MTBE)如约7％(重量)含在起始的溶液中可能是有利的。常发现，为了始终生成I型结晶atorvastatin，将I型结晶atorvastatin“晶种”加到晶化溶液中是希望的。
当原料是无定形atorvastatin或无定形atorvastatin和I型结晶atorvastatin的组合时，可通过以下步骤制得所需的I型结晶atorvastatin将固体悬浮在含有至多约40％(体积)如约0至20％(体积)、特别优选约5至15％(体积)共溶剂的水中，共溶剂如甲醇、乙醇、2-丙醇、丙酮等，一直到完全转化成所需的形式；随后进行过滤。常常发现，为了确保完全转化成I型结晶atorvastatin，将I型结晶atorvastatin“晶种”加到悬浮液中是希望的。另一方面，可在升温下，如在至多约75℃下，特别优选在约65至70℃下加热主要由无定形atorvastatin组成的含水滤饼，一直到生成大量I型结晶atorvastatin为止，随后如上所述可将无定形/I型结晶结混物浆化。
I型结晶atorvastatin比无定形atorvastatin容易分离得多，冷却后可从晶化介质中过滤出来，并洗涤和干燥。例如，50毫升I型结晶atorvastatin浆液的过滤可在10秒内完成。类似数量的无定形atorvastatin的过滤需1小时。
本发明还提供一种制备II型结晶atorvastatin的方法，该法包括将atorvastatin在生成II型结晶atorvastatin的条件下悬浮在溶剂中。
生成II型结晶atorvastatin的准确条件可按经验来确定，只能给出适合于实施的方法。
例如，当原料为无定形atorvastatin、无定形和I型结晶atorvastatin或I型结晶atorvastatin时，可用以下步骤制得所需的II型结晶atorvastatin：将固体悬浮在含有约40至约50％水的甲醇中，一直到完全转化成所需的结晶形式；随后进行过滤。
本发明还提供一种制备IV型结晶atorvastatin的方法，该法包括在生成IV型结晶atorvastatin的条件下使atorvastatin从其溶剂的溶液中晶化。
生成IV型结晶atorvastatin的准确条件可按经验确定，只可给出一种适合实施的方法。
例如，当原料为I型结晶atorvastatin时，可通过将固体溶于甲醇中，随后使IV型结晶沉淀来制得所需的IV型结晶atorvastatin。
本发明的化合物可以各种口服和肠胃外的剂量形式制备和给药。例如，本发明的化合物可用注射的方法给药，也就是静脉内、肌肉内、皮内、皮下、十二指肠内或腹腔内给药。同样，本发明的化合物也可用吸入法如鼻内吸入法给药。此外，本发明的化合物可经由皮肤给药。显然，对于熟悉本专业的技术人员来说，以下剂量形式可包括本发明的化合物或相应的药物上可接受的盐作为有效组分。
对于由本发明的化合物制备药物组合物来说，药物上可接受的载体可为固体或液体。固体形式的制剂包括粉剂、片剂、丸剂、胶囊、扁囊剂、栓剂和可分散的颗粒。固体载体可为一种或多种可作为稀释剂、香料、增溶剂、润滑剂、悬浮剂、粘合剂、防腐剂、片剂崩塌剂或包囊材料的物质。
在粉剂中，载体为细分散的固体，它与细分散的有效组分混合。
在片剂中，有效组分与有必要的粘合性质的载体按适合的比例混合，并压制成所需的形状和尺寸。
粉剂和片剂优选含有2或10至约70％有效化合物。适合的载体为碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精、淀粉、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可油等。术语“制剂”打算包括有效化合物与作为载体提供胶囊的包囊材料的配方，其中有其他载体或没有其他载体，有效化合物被载体包裹，从而与它结合在一起。类似地，也包括扁囊剂和锭剂。片剂、粉剂、胶囊、丸剂、扁囊剂和锭剂都可作为适合口服给药的固体剂量形式。
为了制备栓剂，低熔点蜡如脂肪酸甘油酯或可可油的混合物首先被熔融，然后将有效组分均匀地分散在其中，如用搅拌的方法。然后将熔融的均匀混合物倒入方便定尺寸的模子中，冷却，从而固化。
液体形式的制剂包括溶液、悬浮液、滞留灌肠剂和乳液，如水溶液或水丙二醇溶液。对于肠胃外注射来说，液体制剂可配制成含水聚乙二醇溶液。
适合于口服的含水溶液可用以下步骤制备：将有效组分溶于水中；按需要加入适合的着色剂、香料、稳定剂和稠化剂。
适合于口服的含水悬浮液可通过将细分散的有效组分分散在有粘性材料的水中来制备，粘性材料如天然的或合成的胶、树脂、甲基纤维素、羧甲基纤维素钠和其他大家熟悉的悬浮剂。
也包括这样的固体形式制剂，它为在使用前不久制成口服给药的液体形式制剂。这样的液体形式包括溶液、悬浮液和乳液。除有效组分外，这些制剂还可含有着色剂、香料、稳定剂、缓冲剂、人造的和天然的甜味剂、分散剂、稠化剂、增溶剂等。
药物制剂优选为单位剂量形式。在这样的形式中，将制剂细分成含有适量有效组分的单位剂量。单位剂量形式可为包装的制剂，含有分立量制剂的小包，如包装的片剂、胶囊和在小瓶或安瓿中的粉剂。同样，单位剂量形式可为胶囊、扁囊剂或锭剂本身，或者它可为适当数目的任何包装形式。
在单位剂量制剂中有效组分的量可根据特定的应用场合以及有效组分的效力变化或在0.5至100毫克、优选2.5至80毫克之间调节。如果需要，组合物也可含有其他相容的治疗剂。
在用作低血脂剂和/或低胆固醇剂治疗中，在本发明药物方法中使用的I型、II型和IV型结晶atorvastatin最初每天以约2.5至约80毫克剂量给药。每天的剂量为约2.5至约20毫克是优选的。但是，剂量可视患者的需要、治疗疾病的严重性和所用的化合物而变化。对于特定的情况，适合的剂量的确定是在本专业范围内。通常，开始用较小剂量治疗，它小于该化合物的最佳剂量。此后，剂量以小的增量不断增加，一直到达到这种情况下的最佳效果为止。为了方便起见，每天的总剂量可分成几份在一天中分几次给药。
以下非限制性的实施例用来说明发明人优选的制备本发明化合物的方法。
实施例1
[R-(R*，R*)]-2-(4-氟苯基)-β，δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯氨基)羰基]-1H-吡咯-1-庚酸半钙盐(I型atorvastatin)
方法A
在48-58℃下，将(2R-反)-5-(4-氟苯基)-2-(1-甲基乙基)-N，4-二苯基-1-[2-(四氢-4-羟基-6-氧代-2H-吡喃-2-基)乙基]-1H-吡咯-3-羧酰胺(atorvastatin内脂)(US 5273995)(75公斤)、甲基叔丁基醚(MTBE)(308公斤)和甲醇(190升)的混合物与氢氧化钠水溶液(5.72公斤氢氧化钠在950升水中)反应40-60分钟，生成开环的钠盐。冷却到25-35℃后，废弃有机层，用MTBE(230公斤)再次萃取水层。废弃有机层，并将MTBE饱和的钠盐水溶液加热到47-52℃。将乙酸钙半水合物(11.94公斤)溶于水(410升)的溶液在至少30分钟内加到该溶液中。在加入乙酸钙溶液后不久，用I型结晶atorvastatin的浆液(1.1公斤atorvastatin在11升水和5升甲醇中)给混合物加晶种。然后将混合物在51-57℃下加热至少10分钟，再冷却到15-40℃。过滤混合物，用水(300升)和甲醇(150升)的溶液，然后用水(450升)洗涤。将固体在60-70℃、真空下干燥3-4天，得到I型结晶atorvastatin(72.2公斤)。
方法B
将无定形atorvastatin(9克)和I型结晶atorvastatin(1克)在约40℃下，在水(170毫升)和甲醇(30毫升)的混合物中搅拌17小时。过滤混合物，用水洗涤，在70℃、减压下干燥，得到I型结晶atorvastatin(9.7克)。
实施例2
[R-(R*，R*)]-2-(4-氟苯基)-β，δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯氨基)羰基]-1H-吡咯-1-庚酸半钙盐(II型atorvastatin)
将无定形atorvastatin和I型结晶atorvastatin的混合物(100克)悬浮在甲醇(1200毫升)和水(800毫升)的混合物中，并搅拌3天。过滤该物质，在70℃、减压下干燥，得到II型结晶atorvastatin。
实施例3
[R-(R*，R*)]-2-(4-氟苯基)-β，δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯氨基)羰基]-1H-吡咯-1-庚酸半钙盐(IV型atorvastatin)
在50-55℃下，将(2R-反)-5-(4-氟苯基)-2-(1-甲基乙基)-N，4-二苯基-1-[2-(四氢-4-羟基-6-氧代-2H-吡喃-2-基)乙基]-1H-吡咯-3-羧酰胺(atorvastatin内酯)(US 5273995)(12公斤)、MTBE(50公斤)和甲醇(30升)的混合物与氢氧化钠水溶液(1.83公斤氢氧化钠于150升水中)反应30-45分钟，生成开环的钠盐。冷至20-25℃后，废弃有机层，并用MTBE(37公斤)再次萃取水层。废弃水层，并将钠盐的水溶液加热到70-80℃，并用蒸馏法除去残留的MTBE。然后将溶液冷至60-70℃。将乙酸钙半水合物(1.91公斤)溶于水/甲醇(72升水+16升甲醇)中的溶液加到该溶液中。在乙酸钙溶液加入后不久，用I型结晶atorvastatin(180克)给混合物加晶种。将混合物在65-75℃下加热至少5分钟，然后冷至50-55℃。过滤混合物，并在55-65℃下浆化在甲醇(约200升)中，然后冷至25-30℃并过滤。将固体在66-70℃、真空下干燥，得到IV型结晶atorvastatin(分离出约3公斤)。

Claims (29)

1.I型结晶atorvastatin及其水合物，其特征在于，有以下研磨2分钟后测量的根据2θ、d-面间距和大于20％的相对强度表示的X-射线粉末衍射图，使用CuKα射线测量：2θ               d                研磨2分钟样品的相
                               对强度(＞20％)9.150             9.6565           42.609.470             9.3311           41.9410.266            8.6098           55.6710.560            8.3705           29.3311.853            7.4601           41.7412.195            7.2518           24.6217.075            5.1887           60.1219.485            4.5520           73.5921.626            4.1059           100.0021.960            4.0442           49.4422.748            3.9059           45.8523.335            3.8088           44.7223.734            3.7457           63.0424.438            3.6394           21.1028.915            3.0853           23.4229.234            3.0524           23.36
2.I型结晶atorvastatin及其水合物，其特征在于，有以下固态13C核磁共振谱，其中化学位移以ppm表示：规定(7KHz)                         化学位移C12或C25                           182.8C12或C25                           178.4C16                                166.7(宽)和159.3芳族碳C2-C5，C13-C18，C19-C24，C27-C32   137.0
                               134.9
                               131.1
                               129.5
                               127.6
                               123.5
                               120.9
                               118.2
                               113.8C8，C10                            73.1
                               70.5
                               68.1
                               64.9亚甲基碳C6，C7，C9，C11                    47.4
                               41.9
                               40.2C33                                26.4
                               25.2C34                                21.3
3.根据权利要求1的I型结晶atorvastatin，其中水合物为三水合物。
4.II型结晶atorvastatin及其水合物，其特征在于，有以下研磨2分钟后测量的根据2θ、d-面间距和大于20％的相对强度表示的X-射线粉末衍射图，用CuKα射线测量：2θ              d                 研磨2分钟样品的相对强
                               度(＞20％)5.582           15.8180            42.007.384             11.9620          38.638.533             10.3534          100.009.040             9.7741           92.0612.440(宽)        7.1094           30.6915.771(宽)        5.6146           38.7817.120-17.360(宽) 5.1750-5.1040    63.66-55.1119.490            4.5507           56.6420.502            4.3283           67.2022.706-23.159(宽) 3.9129-3.8375    49.20-48.0025.697(宽)        3.4639           38.9329.504            3.0250           37.86
5.II型结晶atrovastatin及其水合物，其特征在于，有以下固态13C核磁共振谱，其中化学位移以ppm表示：规定                               化学位移自旋边带                           209.1自旋边带                           206.8C12或C25                           181(宽)C12或C25                           163(宽)C16                                161(宽)芳族碳C2-C5，C13-C18，C19-C24，C27-C32   140.5
                               134.8
                               133.3
                               129.0
                               122.9
                               121.4
                               120.3
                               119.0
                               117.1
                               115.7
                               114.7C8，C10                            70.6
                               69.0
                               68.0
                               67.3自旋边带                           49.4自旋边带                           48.9亚甲基碳C6，C7，C9，C11                    43.4
                               42.3
                               41.7
                               40.2C33                                27.5C34                                22.8(宽)
6.IV型结晶atorvastatin及其水合物，其特征在于，有以下研磨2分钟后测量的根据2θ、d面间距和大于20％的相对强度表示的X-射线粉末衍射图，用CuKα射线测量：2θ                d               相对强度(＞15％)4.889              18.605          38.455.424              16.2804         20.125.940              14.8660         17.297.997              11.0465         100.009.680              9.1295          67.3110.416             8.4859          20.0012.355             7.1584          19.1517.662             5.0175          18.5718.367             4.8265          23.5019.200             4.6189          18.1419.569            4.5327           54.7921.723            4.0879           17.9923.021            3.8602           28.8923.651            3.7587           33.3924.143            3.6832           17.23
7.IV型结晶atorvastatin及其水合物，其特征在于，有以下固态13C核磁共振谱，其中化学位移以ppm表示：规定                               化学位移C12或C25                           186.4
                               184.9C12或C25                           181.4
                               179.3C16                                166.1(宽)和
                               159.0(宽)芳族碳C2-C5，C13-C18，C19-C24，C27-C32   138.1(宽)
                               134.7
                               129.2
                               127.1
                               122.7
                               119.8
                               115.7C8，C10                            71.5
                               67.9
                               66.3
                               63.5亚甲基碳C6，C7，C9，C11                    46.1
                               43.4
                               42.1
                               40.0C33                                25.9C34                                20.3
                               19.4
                               17.9
8.一种片剂形式的药物组合物，它含有与至少一种药物上可接受的赋形剂、稀释剂或载体混合的权利要求1规定的I型结晶atorvastatin。
9.一种胶囊形式的药物组合物，它含有与至少一种药物上可接受的赋形剂-稀释剂或载体混合的权利要求1规定的I型结晶atorvastatin。
10.一种粉剂形式的药物组合物，它含有与至少一种药物上可接受的赋形剂、稀释剂或载体混合的权利要求1规定的I型结晶atorvastatin。
11.一种锭剂形式的药物组合物，它含有与至少一种药物上可接受的赋形剂、稀释剂或载体混合的权利要求1规定的I型结晶atorvastatin。
12.一种栓剂形式的药物组合物，它含有与至少一种药物上可接受的赋形剂、稀释剂或载体混合的权利要求1规定的I型结晶atorvastatin。
13.一种滞留灌肠剂形式的药物组合物，它含有与至少一种药物上可接受的赋形剂、稀释剂或载体混合的权利要求1规定的I型结晶atorvastatin。
14.一种治疗高血脂症和高胆固醇症的方法，该法包括以单位剂量形式将治疗上有效量的权利要求1的化合物给药给患病者。
15.一种制备I型结晶atorvastatin的方法，该法包括：步骤(a)用钙盐处理[R-(R*，R*)]-2-(4-氟苯基)-β，δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯氨基)羰基]-1H-吡咯-1-庚酸的碱性盐水溶液；以及步骤(b)分离I型结晶atorvastatin。
16.根据权利要求15的方法，其中步骤(a)将I型结晶atorvastatin的晶种在用钙盐处理[R-(R*，R*)]-2-(4-氟苯基)-β，δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯氨基)羰基]-1H-吡咯-1-庚酸的碱性盐水溶液过程中或过程后加入。
17.根据权利要求15的方法，其中步骤(a)水溶液含有羟基共溶剂和甲基叔丁基醚。
18.根据权利要求17的方法，其中步骤(a)羟基共溶剂为甲醇。
19.根据权利要求15的方法，其中步骤(a)钙盐为乙酸钙。
20.根据权利要求15的方法，其中步骤(b)I型结晶atorvastatin进一步干燥。
21.根据权利要求20的方法，其中步骤(b)I型结晶atorvastatin在减压下进一步干燥。
22.根据权利要求15的方法，其中步骤(a)碱性盐选自碱金属盐、铵盐和胺盐。
23.根据权利要求22的方法，其中步骤(a)碱性盐为钠盐。
24.根据权利要求15的方法，其中使用2摩尔碱性盐比1摩尔钙盐。
25.一种制备I型结晶atorvastatin的方法，该法包括：步骤(a)将无定形atorvastatin和I型结晶atorvastatin的混合物悬浮在含有共溶剂的水中；以及步骤(b)分离I型结晶atorvastatin。
26.根据权利要求25的方法，其中步骤(a)共溶剂选自甲醇、乙醇、2-丙醇和丙酮。
27.根据权利要求26的方法，其中步骤(a)共溶剂为甲醇。
28.根据权利要求25的方法，其中步骤(b)I型结晶atorvastatin进一步干燥。
29.根据权利要求28的方法，其中步骤(b)I型结晶atorvastatin在减压下进一步干燥。
CN96195564A 1995-07-17 1996-07-08 结晶[R－(R*,R*)]－2－(4－氟苯基)－β,δ－二羟基－5－(1－甲基乙基)－3－苯基－4－[(苯氨基)羰基]－1H－吡咯－1－庚酸半钙盐 Expired - Lifetime CN1087288C (zh)

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