CN1087288C - 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 - 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]－1H－吡咯－1－庚酸半钙盐 Download PDF

Info

Publication number
CN1087288C
CN1087288C CN96195564A CN96195564A CN1087288C CN 1087288 C CN1087288 C CN 1087288C CN 96195564 A CN96195564 A CN 96195564A CN 96195564 A CN96195564 A CN 96195564A CN 1087288 C CN1087288 C CN 1087288C
Authority
CN
China
Prior art keywords
type crystallization
atorvastatin
crystallization atorvastatin
atorvastatin hydrate
type
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.)
Expired - Lifetime
Application number
CN96195564A
Other languages
English (en)
Other versions
CN1190955A (zh
Inventor
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
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Varner-lambert Co., Ltd.
Pfizer Corp
Original Assignee
Warner Lambert Co LLC
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=21696090&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN1087288(C) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of CN1190955A publication Critical patent/CN1190955A/zh
Application granted granted Critical
Publication of CN1087288C publication Critical patent/CN1087288C/zh
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • 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
本发明涉及新型的结晶形式阿托伐他汀(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。
US4681893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。
US5273995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。
US5003080、5097045、5103024、5124482、5149837、5155251、5216174、5245047、5248793、5280126、5397792和5342952公开了制备阿托伐他汀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。
阿托伐他汀以其钙盐被制备，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，因为它能使阿托伐他汀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阿托伐他汀，以便能制备满足严格的药物要求和规格的配方。
此外，生产阿托伐他汀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阿托伐他汀，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，阿托伐他汀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阿托伐他汀。I型阿托伐他汀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阿托伐他汀组成，它具有更有利过滤和干燥的特性。此外，I型阿托伐他汀比无定形产品更纯和更稳定。
因此，本发明涉及结晶I型阿托伐他汀及其水合物，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型结晶阿托伐他汀及其水合物，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型结晶阿托伐他汀为三水合物。
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           42.00
7.384               11.9620           38.63
8.533               10.3534           100.00
9.040               9.7741            92.06
12.440(宽)          7.1094            30.69
15.771(宽)          5.6146            38.78
17.120-17.360(宽)   5.1750-5.1040     63.66-55.11
19.490              4.5507            56.64
20.502              4.3283            67.20
22.706-23.159(宽)   3.9129-3.8375     49.20-48.00
25.697(宽)          3.4639            38.93
29.504              3.0250            37.86
此外，本发明的第二方面涉及II型结晶阿托伐他汀及其水合物，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型结晶阿托伐他汀及其水合物，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型结晶阿托伐他汀及其水合物，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，新型的结晶形式阿托伐他汀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型结晶阿托伐他汀。最后，本发明涉及生产I型、II型或IV型阿托伐他汀的方法。
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型阿托伐他汀的衍射图(Y轴＝0至最大强度3767.50数/秒(cps))。
图2
研磨2分钟的II型阿托伐他汀的衍射图(Y轴＝0至最大强度1500cps)。
图3
IV型阿托伐他汀的衍射图(Y轴＝0至最大强度8212.5cps)。
图4
用I型阿托伐他汀星号标记的带自旋边带的固态13C核磁共振谱。
图5
用II型阿托伐他汀星号标记的带自旋边带的固态13C核磁共振谱。
图6
用IV型阿托伐他汀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型结晶阿托伐他汀可用其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型阿托伐他汀用其X-射线粉末衍射图表征。因此，I型、II型和VI型阿托伐他汀的X-射线衍射图在SiemensD-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DIFFRAC AT(SOCABIM 1986，1992)。
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III 1度和IV 0.15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型阿托伐他汀通过230目筛进行筛分。
表1列出I型结晶阿托伐他汀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型阿托伐他汀相对强度大于
          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型阿托伐他汀的研磨/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型阿托伐他汀相对强度大于
          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型结晶阿托伐他汀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型阿托伐他汀相对强度大于
          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.and MacielG.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.andStock L.M.，J.Mag.Res.，1988；76：54)。
表4列出I型结晶阿托伐他汀的固态NMR谱。
Figure C9619556400171
表4I型阿托伐他汀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                                  66.7(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型阿托伐他汀的固态NMR谱
表5II型阿托伐他汀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型阿托伐他汀的固态NMR谱。
表6IV型阿托伐他汀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型结晶阿托伐他汀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型结晶阿托伐他汀含有约1至8摩尔水。优选的是，I型阿托伐他汀含有3摩尔水。
本发明提供了一种制备I型结晶阿托伐他汀的方法，该法包括在生成I型结晶阿托伐他汀的条件下使阿托伐他汀从溶剂的溶液中结晶。
本发明提供了制备I型结晶阿托伐他汀水合物的方法，该法包括一种制备I型结晶阿托伐他汀水合物的方法，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型结晶阿托伐他汀水合物。
生成I型结晶阿托伐他汀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型结晶阿托伐他汀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，或者通过将无定形阿托伐他汀悬浮在水中来制备。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型结晶阿托伐他汀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摩尔阿托伐他汀钠盐。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型结晶阿托伐他汀，将I型结晶阿托伐他汀“晶种”加到晶化溶液中是希望的。
当原料是无定形阿托伐他汀或无定形阿托伐他汀和I型结晶阿托伐他汀的组合时，可通过以下步骤制得所需的I型结晶阿托伐他汀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型结晶阿托伐他汀，将I型结晶阿托伐他汀“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阿托伐他汀组成的含水滤饼，一直到生成大量I型结晶阿托伐他汀为止，随后如上所述可将无定形/I型结晶结混物浆化。
I型结晶阿托伐他汀比无定形阿托伐他汀容易分离得多，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型结晶阿托伐他汀浆液的过滤可在10秒内完成。类似数量的无定形阿托伐他汀的过滤需1小时。
本发明还提供一种制备II型结晶阿托伐他汀的方法，该法包括将阿托伐他汀在生成II型结晶阿托伐他汀的条件下悬浮在溶剂中。
生成II型结晶阿托伐他汀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，当原料为无定形阿托伐他汀、无定形和I型结晶阿托伐他汀或I型结晶阿托伐他汀时，可用以下步骤制得所需的II型结晶阿托伐他汀：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型结晶阿托伐他汀的方法，该法包括在生成IV型结晶阿托伐他汀的条件下使阿托伐他汀从其溶剂的溶液中晶化。
生成IV型结晶阿托伐他汀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型结晶阿托伐他汀时，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型结晶阿托伐他汀。
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。
对于滞留灌肠剂，其含有至少一种药物上可接受的赋形剂、稀释剂或载体及I型结晶阿托伐他汀水合物。
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型结晶阿托伐他汀最初每天以约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型阿托伐他汀)
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(阿托伐他汀内脂)(US5273995)(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型结晶阿托伐他汀的浆液(1.1公斤阿托伐他汀在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型结晶阿托伐他汀(72.2公斤)。
方法B
将无定形阿托伐他汀(9克)和I型结晶阿托伐他汀(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型结晶阿托伐他汀(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型阿托伐他汀)
将无定形阿托伐他汀和I型结晶阿托伐他汀的混合物(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型结晶阿托伐他汀。
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型阿托伐他汀)
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(阿托伐他汀内酯)(US5273995)(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型结晶阿托伐他汀(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型结晶阿托伐他汀(分离出约3公斤)。

Claims (24)

1.含1-8摩尔水的I型结晶阿托伐他汀水合物，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.权利要求1的I型结晶阿托伐他汀水合物，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型结晶阿托伐他汀水合物，其中I型结晶阿托伐他汀水合物为三水合物。
4.一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1-3任一要求的I型结晶阿托伐他汀水合物。
5.一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1-3任一要求规定的I型结晶阿托伐他汀水合物。
6.一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1-3任一要求的I型结晶阿托伐他汀水合物。
7.一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1-3任一要求的I型结晶阿托伐他汀水合物。
8.一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1-3任一要求规定的I型结晶阿托伐他汀水合物。
9.一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1-3任一要求的I型结晶阿托伐他汀水合物。
10.一种制备含1-8摩尔水的I型结晶阿托伐他汀水合物的方法，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型结晶阿托伐他汀水合物。
11.根据权利要求10的方法，其中步骤(a)将I型结晶阿托伐他汀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。
12.根据权利要求10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。
13.根据权利要求12的方法，其中步骤(a)羟基共溶剂为甲醇。
14.根据权利要求10的方法，其中步骤(a)钙盐为乙酸钙。
15.根据权利要求10的方法，其中步骤(b)I型结晶阿托伐他汀水合物进一步干燥。
16.根据权利要求15的方法，其中步骤(b)I型结晶阿托伐他汀水合物在减压下进一步干燥。
17.根据权利要求10的方法，其中步骤(a)碱性盐选自碱金属盐、铵盐和胺盐。
18.根据权利要求17的方法，其中步骤(a)碱性盐为钠盐。
19.根据权利要求10的方法，其中使用2摩尔碱性盐比1摩尔钙盐。
20.一种制备含1-8摩尔水的I型结晶阿托伐他汀水合物的方法，该法包括：步骤(a)将无定形阿托伐他汀和I型结晶阿托伐他汀的混合物悬浮在含有共溶剂的水中；以及步骤(b)分离I型结晶阿托伐他汀水合物。
21.根据权利要求20的方法，其中步骤(a)共溶剂选自甲醇、乙醇、2-丙醇和丙酮。
22.根据权利要求21的方法，其中步骤(a)共溶剂为甲醇。
23.根据权利要求20的方法，其中步骤(b)I型结晶阿托伐他汀水合物进一步干燥。
24.根据权利要求23的方法，其中步骤(b)I型结晶阿托伐他汀水合物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)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US145295P 1995-07-17 1995-07-17
US60/001,452 1995-07-17

Publications (2)

Publication Number Publication Date
CN1190955A CN1190955A (zh) 1998-08-19
CN1087288C true CN1087288C (zh) 2002-07-10

Family

ID=21696090

Family Applications (1)

Application Number Title Priority Date Filing Date
CN96195564A Expired - Lifetime CN1087288C (zh) 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

Country Status (38)

Country Link
US (1) US5969156A (zh)
EP (2) EP0848705B1 (zh)
JP (4) JP3296564B2 (zh)
KR (2) KR100431038B1 (zh)
CN (1) CN1087288C (zh)
AR (2) AR003459A1 (zh)
AT (3) ATE208375T1 (zh)
AU (1) AU725424B2 (zh)
BG (1) BG63630B1 (zh)
BR (1) BR9609872A (zh)
CA (1) CA2220018C (zh)
CO (1) CO4700443A1 (zh)
CY (1) CY2358B1 (zh)
CZ (3) CZ294740B6 (zh)
DE (2) DE69616808T2 (zh)
DK (2) DK1148049T3 (zh)
EA (1) EA000474B1 (zh)
EE (1) EE03606B1 (zh)
ES (2) ES2167587T3 (zh)
GE (1) GEP20002029B (zh)
HK (1) HK1018052A1 (zh)
HR (1) HRP960339B1 (zh)
HU (1) HU223599B1 (zh)
IL (7) IL122118A (zh)
MX (1) MX9709099A (zh)
NO (1) NO309898B1 (zh)
NZ (1) NZ312907A (zh)
PE (1) PE1898A1 (zh)
PL (1) PL193479B1 (zh)
PT (2) PT1148049E (zh)
RO (1) RO120070B1 (zh)
SI (2) SI0848705T1 (zh)
SK (1) SK284202B6 (zh)
TW (1) TW486467B (zh)
UA (1) UA51661C2 (zh)
UY (2) UY24285A1 (zh)
WO (1) WO1997003959A1 (zh)
ZA (1) ZA966044B (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108558726A (zh) * 2018-03-14 2018-09-21 湖北广济药业股份有限公司 一种高纯度阿托伐他汀钙的制备方法
CN110776451A (zh) * 2020-01-02 2020-02-11 湖南迪诺制药股份有限公司 一种i晶型阿托伐他汀钙的制备方法

Families Citing this family (154)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FI94339C (fi) * 1989-07-21 1995-08-25 Warner Lambert Co Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi
KR100431038B1 (ko) * 1995-07-17 2004-05-12 워너-램버트 캄파니 엘엘씨 결정질[ｒ-(ｒ*,ｒ*)]-2-(4-플루오로페닐)-베타,델타-디히드록시-5-(1-메틸에틸)-3-페닐-4-[(페닐아미노)카르보닐]-1ｈ-피롤-1-헵탄산 헤미 칼슘염 (아토르바스타틴)
HRP960312B1 (en) 1995-07-17 2001-10-31 Warner Lambert Co NOVEL PROCESS FOR THE PRODUCTION OF AMORPHOUS /R-(R*, R*)/-2-(4-FLUOROPHENYL)-"beta", "delta"-DIHYDROXY-5-PHENYL-4-/(PHENYLAMINO)CARBONYL/-1H-PYRROLE -1-HEPTANOIC ACID CALCIUM SALT (2 : 1)
US6087511A (en) * 1996-07-16 2000-07-11 Warner-Lambert Company Process for the production of amorphous [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl )-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid) calcium salt (2:1)
US6569461B1 (en) 1999-03-08 2003-05-27 Merck & Co., Inc. Dihydroxy open-acid and salts of HMG-CoA reductase inhibitors
IN191236B (zh) 1999-05-25 2003-10-11 Ranbaxy Lab Ltd
JP2003514798A (ja) * 1999-11-17 2003-04-22 テバ ファーマシューティカル インダストリーズ リミティド アトルバスタチンカルシウムの多形
US7411075B1 (en) 2000-11-16 2008-08-12 Teva Pharmaceutical Industries Ltd. Polymorphic form of atorvastatin calcium
SI20425A (sl) 1999-12-10 2001-06-30 LEK tovarna farmacevtskih in kemi�nih izdelkov d.d. Priprava amorfnega atorvastatina
JP2003517038A (ja) * 1999-12-17 2003-05-20 ワーナー・ランバート・リサーチ・アンド・ディベロップメント・アイルランド・リミテッド 結晶質アトルバスタチン三水和物半カルシウム塩の工場規模での製造方法
IL149088A0 (en) 1999-12-17 2002-11-10 Warner Lambert Res & Dev Ie A process for producing crystalline atorvastatin calcium
GB0003305D0 (en) 2000-02-15 2000-04-05 Zeneca Ltd Pyrimidine derivatives
US6258767B1 (en) * 2000-04-26 2001-07-10 Colgate-Palmolive Co. Spherical compacted unit dose softener
US6806290B2 (en) 2000-06-09 2004-10-19 Lek Pharmaceuticals D.D. Stabilized pharmaceutically effective composition and pharmaceutical formulation comprising the same
SK16982002A3 (sk) 2000-06-09 2003-04-01 Lek Pharmaceuticals D. D. Stabilizovaná farmaceuticky účinná kompozícia a liečivý prípravok túto kompozíciu obsahujúci
SK6592003A3 (en) * 2000-11-03 2004-01-08 Teva Pharma Atorvastatin hemi-calcium form VII
US6777552B2 (en) 2001-08-16 2004-08-17 Teva Pharmaceutical Industries, Ltd. Processes for preparing calcium salt forms of statins
IL156055A0 (en) * 2000-11-30 2003-12-23 Teva Pharma Novel crystal forms of atorvastatin hemi calcium and processes for their preparation as well as novel processes for preparing other forms
US7501450B2 (en) 2000-11-30 2009-03-10 Teva Pharaceutical Industries Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
ES2691680T3 (es) * 2000-12-18 2018-11-28 Cubist Pharmaceuticals Llc Daptomicina en forma cristalina y su preparación
US20060014674A1 (en) * 2000-12-18 2006-01-19 Dennis Keith Methods for preparing purified lipopeptides
CA2623599A1 (en) * 2000-12-27 2002-07-04 Paul Adrian Van Der Schaaf Crystalline forms of atorvastatin
EP1724256A3 (en) 2001-01-09 2007-03-21 Warner-Lambert Company LLC Novel process for the synthesis of 5-(4-fluorphenyl)-1-2(2-((2r,4r)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl)-2-isopropyl-4-phenyl-1h-pyrrole-3-carboxylic acid phenylamide
US6476235B2 (en) * 2001-01-09 2002-11-05 Warner-Lambert Company Process for the synthesis of 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide
AUPR255401A0 (en) * 2001-01-16 2001-02-08 Novogen Research Pty Ltd Regulation of lipids and/or bone density and compositions therefor
WO2002057229A1 (en) * 2001-01-19 2002-07-25 Biocon India Limited FORM V CRYSTALLINE [R-(R*,R*)]-2-(4-FLUOROPHENYL)-ß,$G(D)-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1- HEPTANOIC ACID HEMI CALCIUM SALT. (ATORVASTATIN)
SI20814A (sl) 2001-01-23 2002-08-31 LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. Priprava amorfnega atorvastatina
SI20848A (sl) * 2001-03-14 2002-10-31 Lek, Tovarna Farmacevtskih In Kemijskih Izdelkov, D.D. Farmacevtska formulacija, ki vsebuje atorvastatin kalcij
ES2558565T3 (es) * 2001-06-29 2016-02-05 Warner-Lambert Company Llc Formas cristalinas de sal de calcio del ácido [R-(R*,R*)]-2-(4-fluorofenil)-beta,delta-dihidroxi-5-(1-metiletil)-3-fenil-4-fenilamino)carbonil]-1H-pirrol-1-heptanoico (2:1) (atorvastatina)
ATE363917T1 (de) * 2001-07-19 2007-06-15 Pharmacia Corp Kombination von einem aldosterone rezeptor antagonisten und einem hmg coa reduktase hemmer
US7074818B2 (en) 2001-07-30 2006-07-11 Dr. Reddy's Laboratories Limited Crystalline forms VI and VII of Atorvastatin calcium
EE200400048A (et) * 2001-07-30 2004-04-15 Dr. Reddy's Laboratories Ltd. Atorvastatiinkaltsiumi kristalsed vormid VI ja VII
PE20030324A1 (es) * 2001-07-31 2003-04-03 Warner Lambert Co Composiciones farmaceuticas de amlodipina y atorvastatina
AU2002324715B2 (en) * 2001-08-16 2009-03-12 Teva Pharmaceutical Industries Ltd. Processes for preparing calcium salt forms of statins
US6569887B2 (en) * 2001-08-24 2003-05-27 Dov Pharmaceuticals Inc. (−)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as a dopamine-reuptake
US20060173064A1 (en) * 2001-08-24 2006-08-03 Lippa Arnold S (-)-1-(3,4-Dichlorophenyl)-3-azabi cyclo[3.1.0]hexane, compositions thereof, and uses for treating alcohol-related disorders
HU227124B1 (en) * 2001-09-14 2010-07-28 Egis Gyogyszergyar Nyilvanosan Polymorphs of 1-pyrrole derivative, intermediate for the preparation of atorvastatin
US20060020137A1 (en) * 2001-11-29 2006-01-26 Limor Tessler Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
UA77990C2 (en) * 2001-12-12 2007-02-15 Crystalline calcium salt of (2:1) [r-(r*,r*)]-2-(4-fluorophenyl)-?,?-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrroleheptanic acid
CZ296967B6 (cs) 2002-02-01 2006-08-16 Zentiva, A.S. Zpusob výroby amorfní formy hemivápenaté soli (3R,5R) 7-[3-fenyl-4-fenylkarbamoyl-2-(4-fluorfenyl)-5-isopropylpyrrol-1-yl]-3,5-dihydroxyheptanové kyseliny (atorvastatinu)
EP1480950A4 (en) * 2002-02-15 2005-05-18 Teva Pharma NOVEL HEMI-CALCIUM CRYSTALLINE FORMS OF ATORVASTATIN AND METHODS FOR THEIR PREPARATION, AS WELL AS NEW METHODS FOR THE PREPARATION OF FORORVASTATIN HEMI-CALCIUM FORMS I, VIII AND IX
MXPA04007995A (es) * 2002-02-19 2004-11-26 Teva Pharma Desolvatacion de solvatos de hemicalcio de atorvastatina.
IL163666A0 (en) 2002-02-22 2005-12-18 New River Pharmaceuticals Inc Active agent delivery systems and methods for protecting and administering active agents
HUP0201083A2 (hu) * 2002-03-28 2004-06-28 Richter Gedeon Vegyészeti Gyár Rt. Új atorvastatinsók és az azokat tartalmazó gyógyszerkészítmények
ITMI20020907A1 (it) * 2002-04-29 2003-10-29 Chemi Spa Processo di preparazione della forma amorfa del sale di calcio della atorvastatina
US20080081834A1 (en) 2002-07-31 2008-04-03 Lippa Arnold S Methods and compositions employing bicifadine for treating disability or functional impairment associated with acute pain, chronic pain, or neuropathic disorders
ES2287549T3 (es) * 2002-08-06 2007-12-16 Warner-Lambert Company Llc Procedimiento para preparar la fenilamida del acido 5-(4-fluorofenil)-1-(2-((2r,4r)-4-hidroxi-6-oxo-tetrahidropiran-2-il)etil)-2-isopropil-4-fenil-1h-pirrol-3-carboxilico.
GB0218781D0 (en) * 2002-08-13 2002-09-18 Astrazeneca Ab Chemical process
JP2006503024A (ja) * 2002-09-03 2006-01-26 モレペン、ラボラトリーズ、リミテッド Ｖｉ型アトルバスタチンカルシウムまたはその水和物
US20060019269A1 (en) * 2002-10-17 2006-01-26 Decode Genetics, Inc. Susceptibility gene for myocardial infarction, stroke, and PAOD, methods of treatment
US20080293750A1 (en) * 2002-10-17 2008-11-27 Anna Helgadottir Susceptibility Gene for Myocardial Infarction, Stroke, Paod and Methods of Treatment
HRP20020885B1 (en) * 2002-11-11 2007-05-31 GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. SUBSTITUTED 9a-N-{N'-[4-(SULFONYL)PHENYLCARBAMOYL]}DERIVATIVES 9-DEOXO-9-DIHYDRO-9a-AZA-9a-HOMOERITHROMYCIN A AND 5-O-DESOZAMINYL-9-DEOXO-9-DIHYDRO-9a-AZA-9a-HOMOERITHRONOLIDE A
EP1572643A2 (en) * 2002-11-28 2005-09-14 Teva Pharmaceutical Industries Ltd. Crystalline form f of atorvastatin hemi-calcium salt
EP1424324A1 (en) * 2002-11-28 2004-06-02 Teva Pharmaceutical Industries Limited Crystalline form F of Atorvastatin hemi-calcium salt
EP1603554A1 (en) * 2003-03-17 2005-12-14 Japan Tobacco Inc. Method for increasing the oral bioavailability of s-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl]-2-methylpropanethioate
RS20050760A (sr) * 2003-04-14 2008-04-04 Warner-Lambert Company Llc., Postupak za izradu fenilamida 5-(4- fluorofenil)-1-(2-((2r, 4r)-4-hidroksi- 6-okso-tetrahidro-piran-2-il)etil)-2- izopropil-4-fenil-1h-pirol-3- karboksilne kiseline
TWI494102B (zh) * 2003-05-02 2015-08-01 Japan Tobacco Inc 包含ｓ-〔２（〔〔１-（２-乙基丁基）環己基〕羰基〕胺基）苯基〕２-甲基丙烷硫酯及ｈｍｇ輔酶ａ還原酶抑制劑之組合
US20040248972A1 (en) * 2003-05-16 2004-12-09 Ambit Biosciences Corporation Compounds and uses thereof
AU2004247627A1 (en) * 2003-05-16 2004-12-23 Ambit Biosciences Corporation Pyrrole compounds and uses thereof
US20050182125A1 (en) * 2003-05-16 2005-08-18 Ambit Biosciences Corporation Pyrrole compounds and uses thereof
US20040242670A1 (en) * 2003-06-02 2004-12-02 Sonny Sebastian Process for preparation of amorphous atorvastatin calcium
GB0312896D0 (en) 2003-06-05 2003-07-09 Astrazeneca Ab Chemical process
US7790197B2 (en) * 2003-06-09 2010-09-07 Warner-Lambert Company Llc Pharmaceutical compositions of atorvastatin
US20040253305A1 (en) * 2003-06-12 2004-12-16 Luner Paul E. Pharmaceutical compositions of atorvastatin
US20050271717A1 (en) * 2003-06-12 2005-12-08 Alfred Berchielli Pharmaceutical compositions of atorvastatin
US7655692B2 (en) 2003-06-12 2010-02-02 Pfizer Inc. Process for forming amorphous atorvastatin
UY28501A1 (es) 2003-09-10 2005-04-29 Astrazeneca Uk Ltd Compuestos químicos
AU2004272365A1 (en) * 2003-09-17 2005-03-24 Warner-Lambert Company Llc Crystalline forms of `R-(R*,R*))-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-`(phenylamino)carbonyl!-1H-pyrrole-1-heptanoic acid
GB0324791D0 (en) 2003-10-24 2003-11-26 Astrazeneca Ab Chemical process
BRPI0417138A (pt) * 2003-12-05 2007-02-21 Warner Lambert Co n-alquil-pirroles como inibidores de hmg-coa-redutase
EP1709008A1 (en) * 2004-01-19 2006-10-11 Ranbaxy Laboratories Limited Salts of hmg-coa reductase inhibitors and use thereof
CA2456430A1 (en) * 2004-01-28 2005-07-28 Brantford Chemicals Inc. Improved process for the preparation of amorphous atorvastatin calcium
US8158362B2 (en) * 2005-03-30 2012-04-17 Decode Genetics Ehf. Methods of diagnosing susceptibility to myocardial infarction and screening for an LTA4H haplotype
US20100216863A1 (en) * 2004-01-30 2010-08-26 Decode Genetics Ehf. Susceptibility Gene for Myocardial Infarction, Stroke, and PAOD; Methods of Treatment
AU2005223491A1 (en) * 2004-03-17 2005-09-29 Ranbaxy Laboratories Limited Crystalline form of atorvastatin hemi calcium
CA2627940A1 (en) 2004-03-17 2005-10-06 Ranbaxy Laboratories Limited Process for the production of atorvastatin calcium in amorphous form
WO2005100313A1 (en) * 2004-04-16 2005-10-27 Pfizer Products Inc. Process for forming amorphous atorvastatin calcium
NZ550061A (en) * 2004-04-16 2009-05-31 Warner Lambert Co 7-[imidazol-1-yl]-3,5-dihydroxyheptanoic acids and lactone forms
ES2739493T3 (es) * 2004-05-05 2020-01-31 Pfizer Prod Inc Formas de sal de de atorvastatina con benetamina
CA2573969C (en) * 2004-07-16 2014-02-04 Lek Pharmaceuticals D.D. Oxidative degradation products of atorvastatin calcium
CA2701710C (en) 2004-07-20 2013-08-27 Warner-Lambert Company Llc Novel forms of [r-(r*,r*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid calcium salt (2:1)
CN101027282A (zh) * 2004-07-22 2007-08-29 特瓦制药工业有限公司 阿托伐他汀半钙的新晶形及其制备方法
US20070043100A1 (en) * 2005-08-16 2007-02-22 Hagen Eric J Novel polymorphs of azabicyclohexane
EP1784389A4 (en) 2004-08-27 2009-03-25 Biocon Ltd PROCESS FOR THE PREPARATION OF AMORPHIC ATORVASTATIN CALCIUM
KR100923939B1 (ko) * 2004-09-28 2009-10-29 테바 파마슈티컬 인더스트리즈 리미티드 실질적으로 불순물을 함유하지 않는 아토르바스타틴 칼슘의형태를 제조하는 방법
TW200630335A (en) 2004-10-18 2006-09-01 Teva Pharma Processes for preparing amorphous atorvastatin hemi-calcium
JP2008517992A (ja) 2004-10-28 2008-05-29 ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー アモルファスのアトルバスタチンを形成する方法
WO2006048888A1 (en) * 2004-11-01 2006-05-11 Jubilant Organosys Limited Novel process for the preparation of amorphous atorvastatin calcium salt
WO2006048894A1 (en) * 2004-11-05 2006-05-11 Morepen Laboratories Limited Novel crystalline forms of atorvastatin calcium and processes for preparing them.
US20060100263A1 (en) * 2004-11-05 2006-05-11 Anthony Basile Antipyretic compositions and methods
WO2006054308A2 (en) 2004-11-22 2006-05-26 Dexcel Pharma Technologies Ltd. Stable atorvastatin formulations
CA2590533C (en) * 2004-11-23 2010-09-07 Warner-Lambert Company Llc 7-(2h-pyrazol-3-yl)-3,5-dihydroxy-heptanoic acid derivatives as hmg co-a reductase inhibitors for the treatment of lipidemia
CA2589537A1 (en) * 2004-12-02 2006-06-08 Stephen Craig Dyar Pharmaceutical compositions of amorphous atorvastatin and process for preparing same
WO2006059210A2 (en) * 2004-12-03 2006-06-08 Warner-Lambert Company Llc Fused bicyclic pyrrols as hmg-coa reductase inhibitors
EP1671947A1 (en) * 2004-12-20 2006-06-21 Ratiopharm GmbH Process for preparing pyrrole derivatives and intermediates
RO123642B1 (ro) * 2005-04-08 2015-07-30 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Procedeu pentru prepararea unei noi forme cristaline polimorfe a sării de hemicalciu a atorvastatinului
EP1919466B9 (en) 2005-07-11 2012-05-16 Cortria Corporation Formulations for treatment of lipoprotein abnormalities comprising a statin and a methylnicotinamide derivative
RU2008107336A (ru) 2005-07-27 2009-09-10 Дов Фармасьютикал, Инк. (Us) Новые 1-арил-з-азабицикло{3.1.0.} гексаны: получение и применение для лечения психоневрологических расстройств
US20070032665A1 (en) * 2005-08-04 2007-02-08 Srinivasulu Gudipati Preparation of atorvastatin calcium form i
WO2007020421A1 (en) 2005-08-15 2007-02-22 Arrow International Limited Crystalline and amorphous sodium atorvastatin
BRPI0614279A2 (pt) 2005-08-15 2012-11-06 Arrow Int Ltd atorvastatina sódica cristalina e amorfa
WO2007030302A2 (en) * 2005-09-01 2007-03-15 Prescient Medical, Inc. Drugs coated on a device to treat vulnerable plaque
CA2547216A1 (en) 2005-09-21 2007-03-21 Renuka D. Reddy Process for annealing amorphous atorvastatin
ES2304335T3 (es) 2005-11-21 2010-05-19 Warner-Lambert Company Llc Formas nuevas del acido (r-(r*,r*))-2-(4-fluorofenil)-b,b-dihidroxi-5-(1-metiletil)-3-fenil-4-((fenilamino)carbonil)1h-pirrol-1-heptanoico, de magnesio.
WO2007070667A2 (en) * 2005-12-13 2007-06-21 Teva Pharmaceutical Industries Ltd. Crystal form of atorvastatin hemi-calcium and processes for preparation thereof
EP1810667A1 (en) 2006-01-20 2007-07-25 KRKA, tovarna zdravil, d.d., Novo mesto Pharmaceutical composition comprising amorphous atorvastatin
AU2007219107B2 (en) * 2006-02-22 2012-12-06 Mylan Laboratories Ltd. New crystalline form of Atorvastatin hemi-calcium
US20080045725A1 (en) * 2006-04-28 2008-02-21 Murry Jerry A Process For The Synthesis of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane
US20070265456A1 (en) * 2006-05-09 2007-11-15 Judith Aronhime Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
CA2654661C (en) 2006-06-26 2012-10-23 Amgen Inc. Compositions comprising modified lcat and use thereof for treating atherosclerosis
JP2008007507A (ja) * 2006-06-28 2008-01-17 Teva Pharmaceutical Industries Ltd 結晶形アトルバスタチン
KR20090083900A (ko) 2006-10-02 2009-08-04 코덱시스, 인코포레이티드 입체이성질체적으로 순수한 스타틴 및 이의 합성 중간체 제조용 조성물 및 제조 방법
US20080269348A1 (en) * 2006-11-07 2008-10-30 Phil Skolnick Novel Arylbicyclo[3.1.0]Hexylamines And Methods And Compositions For Their Preparation And Use
US8138377B2 (en) * 2006-11-07 2012-03-20 Dov Pharmaceutical, Inc. Arylbicyclo[3.1.0]hexylamines and methods and compositions for their preparation and use
US7834195B2 (en) 2007-01-24 2010-11-16 Apotex Pharmachem Inc. Atorvastatin calcium propylene glycol solvates
KR100878140B1 (ko) * 2007-01-29 2009-01-12 한미약품 주식회사 아토바스타틴의 스트론튬염 또는 이의 수화물, 및 이를포함하는 약학 조성물
PT103661B (pt) * 2007-02-23 2010-09-07 Hovione Farmaciencia S A Processo de preparação de minociclina base cristalina
JP2010520273A (ja) * 2007-03-02 2010-06-10 ドン・ア・ファーム・カンパニー・リミテッド ピロリルヘプタン酸誘導体の新規な結晶形態
US20080249141A1 (en) * 2007-04-06 2008-10-09 Palepu Nageswara R Co-therapy with and combinations of statins and 1,4-dihydropyridine-3,5-dicarboxydiesters
WO2008124122A1 (en) * 2007-04-09 2008-10-16 Scidose, Llc Combinations of statins and anti-obesity agent and glitazones
JP2010523659A (ja) * 2007-04-09 2010-07-15 サイドース・エルエルシー スタチン類と抗肥満症薬との組み合わせ
US9133159B2 (en) 2007-06-06 2015-09-15 Neurovance, Inc. 1-heteroaryl-3-azabicyclo[3.1.0]hexanes, methods for their preparation and their use as medicaments
US20090069374A1 (en) * 2007-06-06 2009-03-12 Phil Skolnick Novel 1-Heteroaryl-3-Azabicyclo[3.1.0]Hexanes, Methods For Their Preparation And Their Use As Medicaments
US20110142883A1 (en) * 2007-07-20 2011-06-16 Actavis Group Ptc Ehf Amorphous Coprecipitates of Atorvastatin Pharmaceutically Acceptable Salts
EP2489730B1 (en) 2007-07-26 2015-12-30 Amgen, Inc Modified lecithin-cholesterol acyltransferase enzymes
NZ583607A (en) 2007-09-21 2012-06-29 Epiphany Biosciences Inc Valomaciclovir polymorphs
KR100813666B1 (ko) * 2007-10-23 2008-03-14 (주)에이에스텍 콜레스테롤 합성 저해제로서 아토르바스타틴의 프로드럭
DE102007052071A1 (de) 2007-10-30 2009-05-07 Stada Arzneimittel Ag Stabilisiertes Atorvastatin
US20090124817A1 (en) * 2007-11-09 2009-05-14 The Industry & Academic Cooperation In Chungnam National University Process for Preparing Amorphous Atorvastatin Calcium Nanoparticles
US20110064816A1 (en) * 2008-05-13 2011-03-17 Dr. Reddy's Laboratories Ltd. Atorvastatin compositions
US8115015B2 (en) * 2009-01-26 2012-02-14 Cadila Healthcare Limited Process for the preparation of amorphous atorvastatin calcium
US9388440B2 (en) 2009-04-01 2016-07-12 Mylan Laboratories Limited Enzymatic process for the preparation of (S)-5-(4-fluoro-phenyl)-5-hydroxy-1morpholin-4-yl-pentan-1-one, an intermediate of Ezetimibe and further conversion to Ezetimibe
CZ201039A3 (cs) 2010-01-19 2011-07-27 Zentiva, K. S Zpusob prumyslové výroby amorfní formy hemivápenaté soli (3R,5R) 7-[3-fenyl-4-fenylkarbamoyl-2-(4-fluorfenyl)-5-isopropylpyrrol-1-yl]-3,5-dihydroxyheptanové kyseliny (atorvastatinu) s vysokým specifickým povrchem a jeho použití v lékové forme
HUP1000299A2 (hu) 2010-06-08 2012-02-28 Nanoform Cardiovascular Therapeutics Ltd Nanostrukturált Atorvastatint, gyógyszerészetileg elfogadott sóit és kokristályait tartalmazó készítmény és eljárás elõállításukra
KR20120011249A (ko) 2010-07-28 2012-02-07 주식회사 경보제약 아토바스타틴 헤미칼슘염의 신규한 결정형, 이의 수화물, 및 그의 제조방법
WO2012027331A1 (en) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders
AU2011308911B2 (en) * 2010-09-30 2014-10-02 Wisconsin Alumni Research Foundation (20R,25S)-2-methylene-19,26-dinor-1alpha, 25-dihydroxyvitamin D3 in crystalline form
HU230737B1 (hu) 2010-11-16 2018-01-29 EGIS Gyógyszergyár Nyrt Eljárás rosuvastatin só előállítására
US20120165386A1 (en) * 2010-12-27 2012-06-28 Ranbaxy Laboratories Limited Stable oral pharmaceutial composition of atorvastatin
US9050342B2 (en) 2011-03-29 2015-06-09 Pfizer Inc. Beneficial effects of combination therapy on cholesterol
WO2013004591A1 (en) 2011-07-01 2013-01-10 Dsm Sinochem Pharmaceuticals Netherlands B.V. Micronized crystals of atorvastatin hemicalcium
IN2014CN04119A (zh) 2011-11-15 2015-07-10 Reddys Lab Ltd Dr
JP6635655B2 (ja) 2011-12-08 2020-01-29 アムジエン・インコーポレーテツド ヒトｌｃａｔ抗原結合タンパク質および治療法におけるそれらの使用
EP2844245A1 (en) * 2012-04-30 2015-03-11 F. Hoffmann-La Roche AG New formulation
CN103483238B (zh) * 2013-08-20 2014-12-31 蚌埠丰原医药科技发展有限公司 阿托伐他汀钙三水合物的制备方法
CA2958898A1 (en) 2014-09-15 2016-03-24 The Board Of Trustees Of The Leland Stanford Junior University Targeting aneurysm disease by modulating phagocytosis pathways
EP3811972B1 (en) 2015-02-27 2023-01-11 The Board of Trustees of the Leland Stanford Junior University Combination therapy for treatment of atherosclerosis
CN104945300B (zh) * 2015-06-17 2017-05-10 北京嘉林药业股份有限公司 一种ⅰ型阿托伐他汀钙的纯化方法
EP3184103A1 (en) 2015-12-21 2017-06-28 Hexal AG Pharmaceutical composition comprising atorvastatin or a salt thereof
US10600502B2 (en) 2016-12-20 2020-03-24 Astrazeneca Uk Ltd. Systems and methods for dispensing a statin medication over the counter
KR101723783B1 (ko) 2017-02-24 2017-04-07 주식회사 경보제약 아토바스타틴 헤미칼슘염의 신규한 결정형, 이의 수화물, 및 그의 제조방법
EP3501502A1 (en) 2017-12-20 2019-06-26 Midas Pharma GmbH Fixed dosed pharmaceutical compositions comprising amlodipine, ramipril and atorvastatin
KR20210001641U (ko) 2020-01-08 2021-07-16 주식회사 다마가산업 최소구성의 초저가 콘크리트 타설 레벨표시구
EP4052695A1 (en) 2021-03-05 2022-09-07 Midas Pharma GmbH Stable oral fixed-dose immediate release pharmaceutical compositions comprising amlodipine, atorvastatin and candesartan cilexetil

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0409281A1 (en) * 1989-07-21 1991-01-23 Warner-Lambert Company (R-(R*R*))-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl-3-phenyl-4((phenylamino)-carbonyl)-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof
US5316765A (en) * 1989-09-07 1994-05-31 Karl Folkers Foundation For Biomedical And Clinical Research Use of coenzyme Q10 in combination with HMG-CoA reductase inhibitor therapies
WO1994016693A1 (en) * 1993-01-19 1994-08-04 Warner-Lambert Company Stable oral ci-981 formulation and process of preparing same

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4456753A (en) 1983-02-07 1984-06-26 Pfizer Inc. Process for the manufacture of highly crystalline sodium cefoperazone
JP3528186B2 (ja) 1991-06-24 2004-05-17 日産化学工業株式会社 光学活性キノリンメバロン酸のジアステレオマー塩
DE4235133A1 (de) 1992-10-19 1994-04-21 Bayer Ag Kristallines (R)-(-)-2-Cycloheptyl-N-methylsulfonyl-[4-(2-chinolinyl-methoxy)-phenyl]-acetamid
JP3623531B2 (ja) 1993-06-07 2005-02-23 ビーエーエスエフ アクチェンゲゼルシャフト 結晶質ｌ−アスコルビン酸−２−燐酸エステルマグネシウム塩の製造法
KR100431038B1 (ko) * 1995-07-17 2004-05-12 워너-램버트 캄파니 엘엘씨 결정질[ｒ-(ｒ*,ｒ*)]-2-(4-플루오로페닐)-베타,델타-디히드록시-5-(1-메틸에틸)-3-페닐-4-[(페닐아미노)카르보닐]-1ｈ-피롤-1-헵탄산 헤미 칼슘염 (아토르바스타틴)
HRP960313B1 (en) 1995-07-17 2002-08-31 Warner Lambert Co Form iii crystalline (r- (r*, r*)-2- (4-fluorophenyl) -beta-delta-hydroxy-5-(1-methylethyl) -3-phenyl-4- ((phenylamino) carbonyl -1h-pyrrole-1-heptanoic acid calcium salt (2:1)
JP2003517038A (ja) 1999-12-17 2003-05-20 ワーナー・ランバート・リサーチ・アンド・ディベロップメント・アイルランド・リミテッド 結晶質アトルバスタチン三水和物半カルシウム塩の工場規模での製造方法
IL149088A0 (en) 1999-12-17 2002-11-10 Warner Lambert Res & Dev Ie A process for producing crystalline atorvastatin calcium
ES2558565T3 (es) 2001-06-29 2016-02-05 Warner-Lambert Company Llc Formas cristalinas de sal de calcio del ácido [R-(R*,R*)]-2-(4-fluorofenil)-beta,delta-dihidroxi-5-(1-metiletil)-3-fenil-4-fenilamino)carbonil]-1H-pirrol-1-heptanoico (2:1) (atorvastatina)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0409281A1 (en) * 1989-07-21 1991-01-23 Warner-Lambert Company (R-(R*R*))-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl-3-phenyl-4((phenylamino)-carbonyl)-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof
US5316765A (en) * 1989-09-07 1994-05-31 Karl Folkers Foundation For Biomedical And Clinical Research Use of coenzyme Q10 in combination with HMG-CoA reductase inhibitor therapies
WO1994016693A1 (en) * 1993-01-19 1994-08-04 Warner-Lambert Company Stable oral ci-981 formulation and process of preparing same

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108558726A (zh) * 2018-03-14 2018-09-21 湖北广济药业股份有限公司 一种高纯度阿托伐他汀钙的制备方法
CN110776451A (zh) * 2020-01-02 2020-02-11 湖南迪诺制药股份有限公司 一种i晶型阿托伐他汀钙的制备方法

Also Published As

Publication number Publication date
SK6298A3 (en) 1998-10-07
IL128862A0 (en) 2000-01-31
AR003458A1 (es) 1998-08-05
DK1148049T3 (da) 2005-03-29
EE9800015A (et) 1998-08-17
NO980207L (no) 1998-01-16
PT848705E (pt) 2002-02-28
HK1018052A1 (en) 1999-12-10
CY2358B1 (en) 2004-06-04
MX9709099A (es) 1998-02-28
TW486467B (en) 2002-05-11
WO1997003959A1 (en) 1997-02-06
IL128862A (en) 2007-12-03
ATE208375T1 (de) 2001-11-15
EE03606B1 (et) 2002-02-15
PL193479B1 (pl) 2007-02-28
ES2167587T3 (es) 2002-05-16
RO120070B1 (ro) 2005-08-30
HUP9900678A3 (en) 2000-04-28
DK0848705T3 (da) 2002-02-04
IL203847A0 (en) 2011-08-01
CO4700443A1 (es) 1998-12-29
SI0848705T1 (en) 2002-04-30
NO980207D0 (no) 1998-01-16
CZ294740B6 (cs) 2005-03-16
EP0848705A1 (en) 1998-06-24
CZ12198A3 (cs) 1998-10-14
HU223599B1 (hu) 2004-10-28
HUP9900678A2 (hu) 1999-07-28
CN1190955A (zh) 1998-08-19
DE69616808D1 (en) 2001-12-13
JP2003073353A (ja) 2003-03-12
JP2014051533A (ja) 2014-03-20
ES2233526T3 (es) 2005-06-16
CZ294695B6 (cs) 2005-02-16
CA2220018C (en) 2001-04-17
GEP20002029B (en) 2000-04-10
AT8453U1 (de) 2006-08-15
CZ294108B6 (cs) 2004-10-13
KR19990029043A (ko) 1999-04-15
EP0848705B1 (en) 2001-11-07
PT1148049E (pt) 2005-02-28
DE69616808T2 (de) 2002-05-29
IL122118A0 (en) 1998-04-05
NZ312907A (en) 2000-12-22
CA2220018A1 (en) 1997-02-06
IL122118A (en) 1999-07-14
US5969156A (en) 1999-10-19
SI1148049T1 (en) 2005-02-28
AU725424B2 (en) 2000-10-12
IL177376A0 (en) 2006-12-10
JP3296564B2 (ja) 2002-07-02
UY24285A1 (es) 1997-01-17
EA199800130A1 (ru) 1998-08-27
PE1898A1 (es) 1998-03-04
PL324496A1 (en) 1998-05-25
BG102187A (en) 1998-10-30
AU6484296A (en) 1997-02-18
KR20030097628A (ko) 2003-12-31
IL128864A (en) 2007-10-31
DE69634054D1 (de) 2005-01-20
KR100389518B1 (ko) 2003-11-15
IL177377A0 (en) 2006-12-10
BR9609872A (pt) 1999-03-23
ATE284868T1 (de) 2005-01-15
EA000474B1 (ru) 1999-08-26
JP4790194B2 (ja) 2011-10-12
IL128865A (en) 2006-04-10
IL128865A0 (en) 2000-01-31
SK284202B6 (sk) 2004-10-05
EP1148049B1 (en) 2004-12-15
JPH11509230A (ja) 1999-08-17
UA51661C2 (uk) 2002-12-16
ZA966044B (en) 1997-02-03
KR100431038B1 (ko) 2004-05-12
UY24985A1 (es) 2001-03-16
BG63630B1 (bg) 2002-07-31
DE69634054T2 (de) 2005-12-08
JP2011195592A (ja) 2011-10-06
IL128864A0 (en) 2000-01-31
HRP960339A2 (en) 1998-04-30
NO309898B1 (no) 2001-04-17
EP1148049A1 (en) 2001-10-24
AR003459A1 (es) 1998-08-05
HRP960339B1 (en) 2002-06-30

Similar Documents

Publication Publication Date Title
CN1087288C (zh) 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
AU725368B2 (en) Form III crystalline (R-(R*,R*)-2-(4-fluorophenyl)-beta-delta-dihydroxy-5- (1-methyl-ethyl)-3-phenyl-4-((phenylamino)carbonyl)-1H- pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin)
CN1065536C (zh) 2－甲基－噻吩并苯并二氮杂䓬的结晶形式及制备方法
CN1909897A (zh) 用于治疗阿尔茨海默病的苯基羧化物β－分泌酶抑制剂
JP2003073353A6 (ja) 結晶性の〔Ｒ−（Ｒ＊，Ｒ＊）〕−２−（４−フルオロフェニル）−β，δ−ジヒドロキシ−５−（１−メチルエチル）−３−フェニル−４−〔（フェニルアミノ）カルボニル〕−１Ｈ−ピロール−１−ヘプタン酸ヘミカルシウム塩（アトルバスタチン）
CN1059911A (zh) 孕二烯酮糠酸酯-水合物及其制备方法和药用组合物
CN1216869C (zh) 赛利可喜的多态晶型
CN1061035C (zh) 苯基链烷醇胺衍生物及其制备方法和用途
CN1399633A (zh) 嘧啶衍生物
CN86104740A (zh) 适于直接压片的粒状无水磷酸二钙组合物
CN1095712A (zh) 四氢咔唑衍生物
CN1101259A (zh) 新型七叶亭衍生物及医药组合物
CN1208058C (zh) 噁唑烷酮片剂的配方
CN1852894A (zh) [R－(R*, R*)]－2－(4－氟苯基) －β,δ－二羟基－5－(1－甲基乙基) －3－苯基－4－[(苯基氨基)羰基] －1 H－吡咯－1－庚酸的结晶形式
CN1852862A (zh) 一种新型羟基磷灰石磷酸钙粒子,其制备方法及其用途
EP0848704B1 (en) Form iii crystalline [r-(r*,r*)]-2-(4-fluorophenyl)-beta-delta-dihydroxy-5-(1-methyl-ethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin)
CN1612874A (zh) 罗格列酮乙二磺酸盐和它们作为抗糖尿病药物的用途
CN87105778A (zh) 异喹啉衍生物
CN1093702A (zh) 苯基咪唑啉酮衍生物及其制备方法
CN1324011C (zh) 用于治疗疼痛的氮杂－螺环化合物
CN1024551C (zh) 吲哚衍生物的制备方法
CN1788007A (zh) 苯并咪唑衍生物的晶体及其生产方法
CN1479737A (zh) 钠-质子交换蛋白1型抑制剂的乙醇盐
JP2003073354A6 (ja) 形態ＩＩＩの結晶性の（Ｒ−（Ｒ＊，Ｒ＊））−２−（４−フルオロフェニル）−β，δ−ジヒドロキシ−５−（１−メチル−エチル）−３−フェニル−４−（（フェニルアミノ）カルボニル）−１Ｈ−ピロール−１−ヘプタン酸ヘミカルシウム塩（アトルバスタチン）
CN1158123A (zh) 用于治疗ii型糖尿病的苯并噁唑吡啶衍生物

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
EE01 Entry into force of recordation of patent licensing contract

Assignee: Pfizer Pharmaceuticals Limited

Assignor: Vonil Longbow (Warner & Lambert) Pfizer, Inc.

Contract fulfillment period: Contract performance period from January 10, 2006 to January 10, 2009

Contract record no.: Contract filing No. 061000010077

Denomination of invention: The name of the invention crystallized [R- (R*, R*)]-2- (4- fluoro phenyl) - beta, Delta - two

Granted publication date: 20020710

Record date: 20060818

LIC Patent licence contract for exploitation submitted for record

Free format text: LICENCE; TIME LIMIT OF IMPLEMENTING CONTACT: 2006.1.10 TO 2009.1.10

Name of requester: PFIZER(WARNER-LAMBERT) PHARMACEUTICAL CO., LTD.

Effective date: 20060818

C56 Change in the name or address of the patentee

Owner name: WO NIER LAMBERT, CO., LTD.

Free format text: FORMER NAME: WO NIER LAMBERT COMPANY

CP03 Change of name, title or address

Address after: American New York

Patentee after: Varner-lambert Co., Ltd.

Address before: new jersey

Patentee before: Warner Lambert Co.

ASS Succession or assignment of patent right

Owner name: PFIZER CORP.

Effective date: 20140219

TR01 Transfer of patent right

Effective date of registration: 20140219

Address after: American New York

Patentee after: Varner-lambert Co., Ltd.

Patentee after: Pfizer Corp.

Address before: American New York

Patentee before: Varner-lambert Co., Ltd.

TR01 Transfer of patent right
CX01 Expiry of patent term

Granted publication date: 20020710

EXPY Termination of patent right or utility model