CN1646481A - N-(反式-4-异丙基环己基羰基)-d-苯丙氨酸的晶形 - Google Patents
N-(反式-4-异丙基环己基羰基)-d-苯丙氨酸的晶形 Download PDFInfo
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Abstract
N-(反式-4-异丙基环己基羰基)-D-苯丙氨酸,又称为那格列奈,其新晶形可通过以下方法制备:将包括溶剂合物在内的任何形式的那格列奈溶解在有机溶剂中以形成溶液,然后由溶液中沉淀那格列奈,分离并干燥沉淀出的那格列奈晶形。可通过冷却溶液或通过加入可与第一种溶剂混溶但那格列奈仅微溶于其中的另一种溶剂或通过二者并用来诱导那格列奈沉淀。可获得的具体的那格列奈晶形取决于溶剂,例如,用上述方法制备的那格列奈的R’-型晶形具有与以前公知的那格列奈晶形不同的熔点、红外光谱和X-射线衍射图谱。
Description
本发明涉及制备N-(反式-4-异丙基环己基羰基)-D-苯丙氨酸(又称为那格列奈)的不同晶形的方法。具体而言,本发明涉及形成在此称为那格列奈的R’-型晶体或晶形的那格列奈晶体。
式(I)的那格列奈是一种对降低血糖水平具有治疗效用的已知物质。
那格列奈在美国专利No.4,816,484中公开,在此将其全部内容明确引入作为参考。
已知那格列奈有数种晶形。所述晶形的例子包括称为B-型和H-型晶体的形式。B-型和H-型晶体及其制备方法在美国专利No.5,463,116中有描述,在此将其全部内容引入作为参考。
根据本发明的一个方面,在此提供了制备那格列奈的不同晶形的方法,该方法包括以下步骤:将包括溶剂合物如水合物、甲醇合物、乙醇合物和丙酮合物在内的任何形式的那格列奈溶解在包括混合溶剂在内的溶剂中、形成那格列奈晶体、分离并干燥沉淀出的那格列奈晶形。
在本发明的一项实施方案中,那格列奈的R’-型晶形可通过包括以下步骤的方法制备:将那格列奈溶解在那格列奈在环境温度下易溶于其中的溶剂中以形成溶液、用可与第一种溶剂混溶且那格列奈仅微溶于其中的另一种溶剂处理该溶液以诱导那格列奈的R’-型晶体沉淀、分离并干燥沉淀出的那格列奈晶形,包括溶剂合物如水合物、甲醇合物、乙醇合物和丙酮合物。
对本领域技术人员而言,通过以下的描述、所附的权利要求和附图,本发明的其它目的、特点、优势及各方面将变得显而易见。但应当理解:以下的描述、所附的权利要求、图和具体实施例虽然指出了本发明的优选实施方案,但仅以举例说明的方式给出。对本领域技术人员而言,通过阅读以下内容,在本公开的发明的精神实质及范围内的各种变化和改进将变得非常显而易见。
图1给出了N-(反式-4-异丙基-环己基羰基)-D-苯丙氨酸的B-型晶体的X-射线粉末衍射图谱;
图2给出了N-(反式-4-异丙基-环己基羰基)-D-苯丙氨酸的B-型晶体的红外吸收光谱;
如所述的那样,本发明的一项实施方案提供了R’-型晶形的那格列奈。那格列奈的B-型和R’-型晶形的物理性质的举例如下:
用DSC方法测定了B-型那格列奈晶体的熔点(mp),为128至131℃。
已发现用DSC方法测定的那格列奈的R’-型晶形的熔点的实例为约108℃。
那格列奈的B-型晶形的X-射线粉末衍射图谱的实例如图1所示。那格列奈的B-型晶形的衍射图谱显示在2θ值为3.9、5.0、5.2和14.1时有最大值。
用KBr方法获得的那格列奈的B-型晶形的红外吸收光谱的实例如图2所示。那格列奈的B-型晶形的红外吸收光谱的特征是在3291、2955、1737、1642和1210cm-1左右有吸收。
如以上所简述的那样,本发明的一个方面提供了制备那格列奈的不同晶形的方法,该方法包括以下步骤:将包括溶剂合物如水合物、甲醇合物、乙醇合物和丙酮合物在内的任何形式的那格列奈溶解在包括混合溶剂在内的溶剂中、形成那格列奈晶体、分离并干燥沉淀出的那格列奈晶形。
在一项实施方案中,那格列奈的R’-型晶形可通过包括以下步骤的方法制备:将那格列奈溶解在在此称为第一种溶剂的、那格列奈在环境温度下易溶于其中的溶剂中以形成溶液;用在此称为第二种溶剂的、可与第一种溶剂混溶且那格列奈仅微溶于其中的另一种溶剂处理该溶液,以诱导那格列奈的R’-型晶体沉淀;分离并干燥沉淀出的那格列奈晶形,包括溶剂合物如水合物、甲醇合物、乙醇合物和丙酮合物。
那格列奈在环境温度下易溶于其中、即溶解量为以重量计至少1%的第一种溶剂包括低级醇,如甲醇、乙醇和异丙醇。将极性溶剂如丙酮、四氢呋喃、二噁烷和二氯甲烷用作第一种溶剂也可能是有效的。那格列奈仅微溶于其中、即溶解量为以重量计0.01%或更少的第二种溶剂包括水、己烷、庚烷和乙醚。当使用混合溶剂作为第一种溶剂时,乙醇和甲苯的混合物或甲醇和乙酸乙酯的混合物是有效的,其优选的组合是用水作为第二种溶剂,且更优选的组合是用含有以重量计约0.5至约3%的羟丙基甲基纤维素的水作为第二种溶剂。那格列奈在溶剂中的量优选为所形成混合物重量的1至50%。如果那格列奈的量大于以重量计50%,则初始混悬液的浆液性质差,且难以搅动混合物和溶解固体。另一方面,使用的所需溶剂的体积以重量计小于那格列奈的1%时无效。环境温度、即那格列奈溶于第一种溶剂的温度优选为室温至约溶剂的沸点,且更优选为室温至约70℃。溶解在第一种溶剂中的那格列奈的量优选为所形成溶液重量的5至40%。可将那格列奈在第一种溶剂中的溶液加入第二种溶剂中,或者也可以将第二种溶剂加入那格列奈在第一种溶剂中的溶液中。在所形成的混合物中,第一种溶剂与第二种溶剂的比例优选为以体积计约1∶3至约1∶9。在混合物中加入晶种、优选B-型那格列奈晶种以帮助所需的那格列奈晶形沉淀可能是有利的。可将所形成的含有那格列奈的混合物搅拌或冷却至更低温度达足够长时间以确保所需的那格列奈晶体完全沉淀。
可使用常规方法如加热和搅拌溶解那格列奈。可将包括溶剂合物如水合物、甲醇合物、乙醇合物和丙酮合物在内的任何形式的那格列奈加入溶剂中,或者也可以将溶剂加至那格列奈上、搅拌并加热至环境温度以形成溶液,所述的环境温度为室温至约溶剂的沸点。搅拌、冷却和加入晶种均可用于进一步诱导所需的那格列奈晶形沉淀。沉淀出的晶体可通过常规方法如真空过滤或离心分离。可以洗涤晶体,优选用由结晶时所用的溶剂组成的溶剂或溶剂混合物洗涤。在分离和洗涤过程中,必要时可进行冷却,优选将晶体冷却至约20至约0℃。可将分离出的那格列奈晶体在大气压或减压下、优选在约20至约0.1mmHg的减压条件下、于室温至约80℃的温度下干燥。
另一方面,本发明提供了包含可用以上方法获得的晶体、特别是R’-型晶体及其可药用的赋形剂、稀释剂或载体的药物组合物。
再一方面,本发明提供了制备药物组合物的方法,其包括以下步骤:将有效量的可用本发明第一方面的方法获得的晶体、特别是R’-型晶体及其可药用的赋形剂、稀释剂或载体进行混合。
还有一个方面,本发明提供了用于治疗人或另一种哺乳动物以降低其血糖水平的方法,其包括施用有效量的可用本发明的方法获得的那格列奈晶体,特别是R’-型晶形。
用以下实施例进一步描述了本发明。提供实施例的目的仅仅是根据具体实施方案阐述本发明。虽然该实施例阐述了本发明的某些具体方面,但不应解释为对本公开的发明范围的限制或限定。
实施例
R’-型那格列奈晶体可如下制备:
进行搅拌的同时,在室温下,将H-型那格列奈晶体溶解在乙醇和甲苯的混合物中(以体积计,50%乙醇和50%甲苯;160mg那格列奈/mL)。所有固体均溶解后,加入含1%羟丙基甲基纤维素的水以诱导沉淀(约为所用乙醇-甲苯体积的7倍)。再搅拌2小时后,通过真空过滤收集沉淀出的固体,洗涤并在50℃、减压下干燥过夜,得到R’-型晶体:mp108℃。
尽管已根据其某些优选方案相当详细地描述了本发明,但不超出此处所包括的优选方案的精神实质及范围的其它方案也是可能的。据此将在此提及的所有参考文献和专利(美国专利等)全部引入作为参考,就如同将其在此完整列出一样。
Claims (9)
1.熔点约108℃的那格列奈晶形或其溶剂合物。
2.制备那格列奈的R’-型晶形的方法,该方法包括:
(a)将任何形式的那格列奈溶解在那格列奈在环境温度下易溶于其中的第一种溶剂中以形成溶液;
(b)用可与第一种溶剂混溶且那格列奈仅微溶于其中的第二种溶剂处理该溶液以诱导那格列奈的R’-型晶体沉淀;和
(c)分离并干燥沉淀出的那格列奈晶形。
3.权利要求2的方法,其中通过搅拌、冷却或通过加入那格列奈晶种诱导那格列奈晶形沉淀。
4.权利要求2的方法,其中的环境温度为室温至溶剂的沸点。
5.权利要求2的方法,其中的那格列奈晶形在大气压或减压下、于室温至70℃的温度下干燥。
6.权利要求2的方法,其中第一种溶剂为乙醇和甲苯的混合物。
7.权利要求6的方法,其中第二种溶剂为含有羟丙基甲基纤维素的水。
8.权利要求7的方法,其中第一种溶剂含有以体积计50%的乙醇;第二种溶剂含有1%的羟丙基甲基纤维素;且第一种溶剂与第二种溶剂的比例为以体积计1∶7。
9.权利要求8的方法,其中的环境温度为室温;且那格列奈晶形在减压下、于室温至50℃的温度下干燥。
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US9175008B1 (en) | 2014-11-05 | 2015-11-03 | Cellix Bio Private Limited | Prodrugs of anti-platelet agents |
US9932294B2 (en) | 2014-12-01 | 2018-04-03 | Cellix Bio Private Limited | Compositions and methods for the treatment of multiple sclerosis |
US9206111B1 (en) | 2014-12-17 | 2015-12-08 | Cellix Bio Private Limited | Compositions and methods for the treatment of neurological diseases |
SG11201705524SA (en) | 2015-01-06 | 2017-08-30 | Cellix Bio Private Ltd | Compositions and methods for the treatment of inflammation and pain |
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US5463116A (en) | 1991-07-30 | 1995-10-31 | Ajinomoto Co., Inc. | Crystals of N- (trans-4-isopropylcyclohexlycarbonyl)-D-phenylalanine and methods for preparing them |
ES2100291T3 (es) * | 1991-07-30 | 1997-06-16 | Ajinomoto Kk | Cristales de n-(trans-4-isopropilciclohexilcarbonil)-d-fenilalanina y metodos para prepararlos. |
WO2003022251A1 (en) | 2001-09-12 | 2003-03-20 | Alembic Limited | Novel stable crystal form of n-trans-4-isopropylcyclohexyl carbonyl)-d-phenylalanine and process of preparation |
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- 2003-04-14 EP EP03746296A patent/EP1497258A1/en not_active Withdrawn
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US20080081927A1 (en) | 2008-04-03 |
EP1497258A1 (en) | 2005-01-19 |
US7247746B2 (en) | 2007-07-24 |
WO2003087038A1 (en) | 2003-10-23 |
CA2482669A1 (en) | 2003-10-23 |
JP4615866B2 (ja) | 2011-01-19 |
JP2010265295A (ja) | 2010-11-25 |
BR0309210A (pt) | 2005-02-09 |
US20050256336A1 (en) | 2005-11-17 |
US20080319222A1 (en) | 2008-12-25 |
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