CN1015106B - 一种口服头孢菌素的结晶性水合物的制备方法 - Google Patents
一种口服头孢菌素的结晶性水合物的制备方法Info
- Publication number
- CN1015106B CN1015106B CN87105009A CN87105009A CN1015106B CN 1015106 B CN1015106 B CN 1015106B CN 87105009 A CN87105009 A CN 87105009A CN 87105009 A CN87105009 A CN 87105009A CN 1015106 B CN1015106 B CN 1015106B
- Authority
- CN
- China
- Prior art keywords
- method described
- water
- hydrate
- capsule
- acid
- 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
Links
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- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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Abstract
一种抗生素,7β-[(Z)-2-(2-氨基噻唑-4-基)-4-羟基-丁-2-烯酰氨基]3-头孢烯-4-羧酸,在(二或三)水合物结晶形态下是稳定的。药理上有效量的此水合物装入明胶硬胶囊,用一条明胶带密封,制成临床使用的可长期贮存的稳定组合物。
Description
本发明涉及含有7β-〔(Z)-2-(2-氨基噻唑-4-基)-4-羧基丁-2-烯酰氨基〕-3-头孢烯-4-羧酸(以下称作7432-S)的稳定的抗生素。更具体地说,涉及该化合物的水合物及该抗生素的稳定的胶囊组合物。
本发明提供了7432-S的稳定的结晶性(二或三)水合物,为一种可用于防治细菌感染的口服头孢菌素。
本发明还提供了含有药理有效量的7432-S水合物的稳定组合物,此组合物是装在明胶硬胶囊内,在胶囊的盖和体连接处的周边用一条明胶带密封。
有广谱高效抗革兰氏阳性和阴性细菌的母体化合物7432-S公开在日本专利申请(Kokai)60-78 987中。
以明胶密封保护的胶囊组合物,写在《日本实用新型公布45-20800中,公开了将液体灌封进胶囊的方法。
已经发现,母体化合物7432-S即使在结晶状态下也不稳定,在长期放置中失去活性或改变颜色。经反复研究发现,其原因是:在所述的先前技术中此化合物的制备是用常规方法在减压下以五氧化二磷干燥,得无水物。另外研究用一些常用的稳定化方法(如加稳定剂水不稳定抗生素的干颗粒化法、颗粒薄膜包衣法),均不能满意地使此抗生素稳定。临床应用要求该化合物有更稳定的形式。
本发明发现:
(1)结晶性的7432-S水合物显示恒定的X-射线衍射花样和高度的化学稳定性;
(2)将水合物装入明胶硬胶囊,在胶囊盖和体连接处的周边用一明胶条密封口,可以防止变色和失活。这项技术在用于装液体的胶囊是已知的,但象在本发明中用于固体粉末则是未知的。
〔Ⅰ〕水合物类
结晶性水合物
本发明者寻找一种方法以改进7432-S的稳定性,发现在一特定条件下制备的结晶性水合物显示几乎相同的X-射线衍射花样和高度的化学稳定性,使能长期储存。这一发现导致了本发明。
结晶性水合物的特征
结晶性水合物是微黄白色至淡黄白色微晶性粉末。
该结晶的元素分析显示水合物含2个分子结晶水,再加上可达1个分子的外加结晶水,这取决于如结晶和干燥的条件。
用费歇尔法测定水的含量是在7-14%的范围内(尤其是在8.7-12.5%),相应于(二或三)水合物或其混合物。
大气压下的差示热分析图显示,在高至约140℃,第1和第2个分子的水仍保留,但第3个分子的水在30-60℃失去。
上述事实说明第3个分子的水是松散地结合在结晶结构上,并易于(如加热,低湿度或减压)失去。
在上述水含量范围内的每种结晶性水合物(即从二水合物到三水合物的范围),如表Ⅰ所示,均显示相同的X-射线衍射花样:
表Ⅰ
d I/I0d I/I0d I/I0d I/I0
5.90 12 20.95 100 28.70 17 35.93 8
7.35 8 21.15 70 29.40 27 36.38 24
9.45 92 21.75 25 29.60 11 37.00 7
10.15 21 22.25 49 29.90 16 38.30 26
12.08 46 23.85 62 30.40 19 38.65 10
14.87 30 24.50 39 31.10 53 39.20 15
15.65 14 24.80 16 31.60 23 39.60 21
16.25 13 25.50 34 31.78 34 40.27 15
18.35 24 25.85 66 33.02 28 41.22 22
18.90 71 26.60 16 33.55 23 42.55 8
19.14 77 27.02 59 33.86 17 44.20 9
19.40 60 27.30 35 35.20 16
20.58 88 28.35 54 35.65 10
不管原料的比例是多少,本发明的结晶性水合物含96-100%(特别是99.0-99.8%)的在7-侧链双键的顺式几何异构体(即(Z)-几何异构体)。
本发明的结晶性水合物在红外吸收光谱(溴化钾圆片)中,在1700CM-处呈现强吸收带。此带在无水结晶中观察不到。
制备结晶性水合物的方法
(1)通法
可用下法制备结晶性水合物:原料7432-S溶解在酸水溶液中,使溶液的pH在约室温(具体在0-70℃)上升(具体是升至pH1.5-5.0)以分出结晶。必要时,搅拌混合物使结晶完全。分离出湿的结晶,在室温和约大气压下,在相对湿度不低于15%的惰性气体中干燥。
(2)原料
原料可以是湿的或无水的,也可以是游离化合物或在氨基成盐(如酸加成盐)或在羧基成盐(如碱金属盐)。本发明的方法结合予处理(如纯化、异构化成顺式异构体、分离),是用水溶性盐(如碱金属盐、盐酸盐)作为原料以得到酸水溶液,这是本发明较好的实施方法。
(3)酸
7432-S的酸水溶液可将游离酸或铵盐悬浮在水中或将羧酸盐作为原料溶解在水中,然后加酸制备。所述的酸可以是无机酸(如盐酸、硫酸、磷酸)、羧酸(如乙酸、苹果酸、富马酸、柠檬酸)、磺酸(如甲磺酸、乙磺酸、甲苯磺酸)、酸式盐(如二甲胺盐酸盐、7432-S硫酸盐)或能酸化原料水溶液的其他亲水酸等。最好使用0-20(特别是1-10)摩尔当量的酸。
(4)共溶剂
水溶液可以含有0-70%与水相混溶的有机溶剂,如醇(如甲醇、乙醇、异丙醇、叔丁醇、甲氧乙醇)、酰胺(如二甲基甲酰胺)、腈(如乙腈)、亚砜(如二甲基亚砜)、醚(如二噁烷、四氢呋喃、
二甲氧乙烷)、酮(如丙酮、甲乙酮)等,作为共溶剂。
(5)浓度
在酸水溶液中原料的浓度最好是在2.0-15.0%(尤其是3.0-5.0%)的范围内。
(6)中和
可以中和酸水溶液至予定的pH值的一种碱(固体或液体)均可用于在室温(约0-70℃,特别是10-50℃)调节酸水溶液至等电点(pH约1.5-5.0,特别是2.0-3.5)。或者,酸溶液可用水稀释将pH升高至足以分出水合物。具有代表性的碱包括有机碱(如三乙胺)和无机碱(如氢氧化铵、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾)。其中水溶性碱操作起来方便。虽然不局限于这些。不溶于水的碱(如阴离子交换树脂)也可用于此目的。
(7)结晶
可使结晶分离和成熟,分离出结晶的悬浮液最好在0-70℃(特别是在5-35℃)下搅拌10分钟至50小时。
(8)干燥
干燥最好在温和条件下,在约室温(如约0-60℃)和大气压下,相对湿度不低于15%的惰性气体(如空气、氮气、二氧化碳)中干燥(如静止式、通流式、循环式或流化床干燥)这取决于搅动和粉末流动的状态。
在实验室规模观察到下述情况:例如,当干燥是在大气压下的密闭容器中进行时,空气的相对湿度是15-50%(特别是20-30%),温度25-60℃,在1-8小时内水含量达到第一个平
顶,相应于二水合物。在空气相对湿度是45%或更高(特别是50-80%),在25-60℃(特别是10-25℃),在1-8小时内达到第二个平顶,相应于三水合物。
在通流或循环干燥器中,取决于搅动和粉末流动条件。例如,在相对湿度50-60%和25-40℃的空气中通流干燥,直至时间对排出空气温度曲线,或时间对排出空气湿度曲线的转折点(当原料含30-60%水时约2-10小时),此时得到的产物其主要成分相当于二水合物。
在流化床干燥器的情况下,取决于空气流动的条件,例如在相对湿度50-60%和10-35℃(特别是20-30℃)的空气中干燥,直至时间对排出空气温度,或时间对排出空气湿度曲线的第一转折点(当原料含30-60%水时约1小时),得到的产物相当于三水合物;当达到上述曲线的第二个转折点时(当原料含30-60%水时约1.5小时)得到的产物相当于主要成分为二水合物。
对大规模生产,循环干燥、通流干燥、流化床干燥均宜采用。
在典型的流化床干燥器的情况下,取决于对每份湿结晶重量的空气流动速率或其他条件,在相对湿度20-80%(特别是50-60%)和10-60℃(特别是20-30℃)的空气中干燥,直至时间对排出空气温度,或时间对排出空气湿度曲线的第一个转折点(当原料含30-60%水时约1至5小时)时,得到结晶三水合物;达到第二个转折点时(当原料含30-60%水时约3-7小时),得到以结晶性二水合物为主要成分的产物。
在高于60℃,有干燥剂存在,在减压或其他相似的剧烈条件下干燥,可使结晶水低于两个(水分子)生成不稳定的产物(如,在
25-28℃,0.01毫米汞柱和有氯化钙存在时干燥,在3小时内可使水含量下降至1.5-4.8%;在25℃干燥氮气流循环干燥,在30分钟内可使水含量降至1.08%)。
结晶性水合物的稳定性
本发明结晶性水合物的稳定性由加速试验证实,在一个月后,仍保持97.8%的效能。与此相比无水物的保留值为73.6%。
结晶性水合物的应用
药理有效量的本发明结晶性水合物可以口服组合物的形式使用(特别是胶囊、颗粒、片剂),用于防治细菌感染。另外,结晶性水合物也可以贮存一定时间后用于进一步的加工。
〔Ⅱ〕密封的胶囊
密封的胶囊
本发明者寻找一种便宜的能长期保持7432-S水合物稳定的组合物,发现将水合物装入明胶硬胶囊并用明胶带封住可使它极不易变色和失活。
胶囊生产的方法
本发明胶囊的制备:将药理有效量的水合物与添加剂(如充填剂、润滑剂)相混合,然后装入胶囊,在胶囊盖和体整个连接处的周边涂上明胶水溶液,干燥形成明胶带。
明胶硬胶囊可是通常的商品胶囊,没有特殊的大小及颜色的限制,可以含染料和/或色素。
虽然任何添加剂(如充填剂、润滑剂)并不是保护水合物使之不变色或不失活所必需的,但最好应用它们,这是为了便于将药理有效量的水合物装入胶囊。充填剂可以是常用于粉剂或颗粒剂的那些,如
糖(如葡萄糖、果糖、乳糖)、淀粉(如玉米淀粉、马铃薯淀粉)、或纤维素(如结晶纤维素、甲基纤维素、甲基乙基纤维素)。润滑剂可以是粉剂、颗粒剂或片剂常用的那些,如精制滑石粉、硬脂酸或其盐(如钠盐、镁盐、或钙盐)、硼砂、液体石蜡、苯甲酸钠、聚乙二醇(平均分子量:6000)、巴西棕榈蜡、或氢化油。
明胶水溶液可如下制备,按常规方法将10到30%(最好是15到25%)明胶溶于水,水中可含有1-40%低级烷基醇(如20%-30%甲醇、乙醇、丙醇,或甘油)、醚(如0.5-10%聚氧乙烯脱水山梨醇单油酸酯,即多乙氧基醚)、酮或酯,此溶液可涂在胶囊的连接处,在0-80℃干燥(如空气流或加热)。通常,在2-4号胶囊上涂5-50毫克含可药用色素的明胶溶液。
下面的例子和实验用以说明本发明。但不能将他们理解成对本发明范围的限制。水含量是用费歇尔法测定的。
〔Ⅰ〕水合物类
例1
7432-S粗品(25克)在6N盐酸(75毫升)中的溶液在15-20℃放置1小时,以分离出盐酸盐。过滤收集结晶,用含1滴浓盐酸的乙腈(75毫升)洗涤,干燥得到7532-S盐酸盐单水合物(18克)。
此单水合物(1.0克)在3N盐酸(4毫升)中的溶液,加水(30毫升)和碱调至pH1.5,在25-45℃搅拌2.5小时。过滤收集分出的结晶,并以水洗涤。结晶用循环干燥器在10℃干燥5小时,得到含水量10.2%的结晶性7432-S水合物(0.7克),几何异构体比例(顺/反)=98.8∶0.2。
例 2
7432-S的粗结晶(1.17克)悬浮在叔丁醇(3毫升)和乙腈(3毫升)的混合液中,向此悬浮液中加入35%盐酸(1毫升,5摩尔当量)使成溶液。此溶液用叔丁醇(3毫升)、乙腈(9毫升)和水(5毫升)的混合液稀释。用三乙胺调至pH2.3,并在30-35℃搅拌3小时。收集分出的结晶,用乙腈、叔丁醇和水(2∶1∶1,5毫升)的混合液和水(10毫升)洗涤,在25-30℃用通流干燥器干燥2小时,得到水含量8.75%的结晶性水合物(1.06克)。几何异构体比例(顺/反)=99.2∶0.8。
例 3
向7432-S结晶性粗品(1.0克)在水(8毫升)和乙腈(1毫升)混合液的悬浮液中加入碳酸氢钠(0.41克,2摩尔当量)生成一清彻的溶液。此溶液用甲醇(6毫升)稀释,以活性炭(0.1克)处理,在室温搅拌10分钟,过滤除去活性炭。滤液用6N盐酸(1.62毫升,4.5摩尔当量)酸化,然后倒入水(3.4毫升)和乙腈(5毫升)的混合液中。此混合物以30%碳酸钾调至pH2.3,在40℃搅拌1小时,在20-25℃搅拌1.5小时。收集分出的结晶,相继用甲醇、乙腈和水(1∶1∶2,5毫升)的混合液、水(20毫升)、和甲醇(5毫升)洗涤,在20-25℃通流干燥1.5小时,得到水含量9.35%的结晶性水合物(0.876克)。几何异构体比例(顺/反)=99.6∶0.4。
例 4
向碳酸氢钠(1.848克,3摩尔当量)在水(42毫升)的溶液中,加入7432-S粗品结晶(4.66克)。溶液以乙腈(19毫
升)、活性氧化铝(2.34克)和活性炭(0.466克)处理,在15-20℃搅拌30分钟,过滤除去活性炭和氧化铝。滤液倒入到乙腈(37毫升)、62%硫酸(3.95克)和水(28毫升)的混合液中。混合物在20-25℃用30%碳酸钾水溶液稀释使调节至pH3.0,并在同样温度搅拌30分钟。过滤收集分出的结晶。在20-25℃循环干燥2-3小时,得到水含量12.2%的结晶性水合物(4.384克)。几何异构体比例(顺/反)=99.6∶0.4。
在相似条件下,7432-S(1.0克)在碳酸氢钠水溶液(12毫升)的溶液中,以活性氧化铝和活性碳处理。溶液相继用溶剂(水、异丙醇或乙腈;6毫升)稀释和用85%磷酸(8摩尔当量)酸化,然后在20-25℃用30%碳酸钾水溶液调至pH3.0,并在同样温度搅拌30分钟。过滤收集分出的结晶,在20-25℃通流干燥2-3小时,得到水含量11.0%的结晶性水合物(约0.90克)。几何异构体比例(顺/反)=99.2-99.7/0.8-0.3。
在同样条件下,但以甲磺酸(4摩尔当量)代替磷酸,得到结晶性水合物(0.879克)。水含量11.4%。几何异构体比例(顺/反)=99.6/0.4。
例 5
在2-5℃,向7432-S粗品结晶(2.0克)在二甲氧基乙烷(18毫升)和乙醇(2毫升)混合液的悬浮液中加入6N盐酸(0.89毫升;1.3摩尔当量),混合物在同样温度搅拌2小时。过滤收集分出的盐酸盐结晶,用二甲氧基乙烷和乙醇(9∶1)的混合液(10毫升)和乙腈(10毫升)洗涤,在25-30℃干燥2小时,得到盐酸盐(1.878克)。
此盐酸盐(1.0克)在甲醇(6毫升)和水(5毫升)混合液的悬浮液,经加入碳酸氢钠(0.61克,3摩尔当量)使溶解成一溶液。向此溶液中加入活性碳(0.1克),在25-30℃搅拌10分钟,过滤除去活性碳。滤液倒入35%盐酸(1.01毫升,4摩尔当量)、水(3毫升)和乙腈(6毫升)的混合液中,用30%碳酸钾水溶液调节至pH3.0,在25-30℃搅拌30分钟,并在5-7℃1小时。过滤收集分出的结晶,相继用乙醇(5毫升)和水(10毫升)洗涤,在20-25℃通流干燥2小时,得到水含量10.6%的结晶性水合物(0.82克)。几何异构体比例(顺/反)=99.5∶0.5。
例 6
向碳酸氢钠(1.3克,2.2摩尔当量)在水(18毫升)的溶液中,加入7432-S的粗品结晶(3.0克)。此溶液用活性氧化铝(1.5克)和活性炭(0.3克)处理,在20-25℃搅拌30分钟,过滤除去活性碳和氧化铝。滤液倒入苹果酸(10摩尔当量)(17毫升)和乙腈(36毫升)的混合液中。混合物在20-25℃以30%碳酸钾水溶液中和,使调节至pH3.0,并在同样温度搅拌30分钟。过滤收集分出的结晶,在20-30℃循环干燥2小时,得到水含量11.7%的结晶性水合物(2.665克)。几何异构体(顺/反)比例=99.1∶0.9。
在同样条件下,但用富马酸(10摩尔当量)代替苹果酸,得到水含量10.1%的结晶性水合物。
相似地,7432-S(1.0克)在碳酸氢钠水溶液中的溶液,用活性氧化铝和活性碳处理。此溶液与甲酸(4摩尔当量)在乙腈水溶液的溶液相结合。此混合物如上述处理,得到水含量12.7%的结晶
性水合物(0.925克)。几何异构体的比例(顺/反)=99.8∶0.2。
所述的甲酸量可增至75摩尔当量,得到相同的结晶性水合物。
例 7
以例3中方法制备的7432-S水合物(1克)的样品,分别置于一紧闭的容器中,并通过选择适宜的潮湿干燥剂使其相对湿度固定在0%、12%、20%、44%、57%或75%,并在室温放置6小时。然后每个样品的水含量以费歇尔法测定,分别给出的数值为1.05%、5.83%、8.54%、11.21%、12.19%、和12.21%。
这些数值显示,在相对湿度20%时,主要成分是二水合物(计算的水含量=8.07%);在相对湿度高于44%时,主要成分是三水合物(计算的水含量=11.64%)。
在相对湿度高于20%的情况下,再继续干燥30小时,从6小时到30小时水含量的损失少于0.2%。
例 8
以例3方法制备的7343-S样品(1克),分别置于紧闭的容器中,并通过选择适宜的湿潮干燥剂以固定其相对湿度为20%、44%、57%或75%,在40℃放置1个月。然后每个样品的水含量以费歇尔法测定,得到的数值分别为7.92%、10.69%、11.73%和12.4%。从第30小时到1个月,水含量的损失低于0.5%,表示水含量稳定。
〔Ⅱ〕密封的胶囊
在下述例9-14和参考例1-6中7432-S水合物是结晶状的,用费歇尔法测定,含约10%结晶水。
例 9
在10升V-型混合器中将水合物(1千克)、结晶纤维素(1.18千克)和硬脂酸镁(0.02千克)(均为60目细粉)混合20分钟。将此混合的粉(各253毫克)装入2号含二氧化钛(3.5%)的白色硬明胶囊然后(用日本Elanco公司的硬胶囊密封机S-100)在胶囊盖和体连接处的周边涂上明胶密封液〔17-26毫克,60℃;明胶(21.13%)和多乙氧基醚80(2%)的水溶液〕。并且在空气流下室温干燥5分钟。产物的每个胶囊具有100毫克7432-S的效力。
例 10
在10升V-型混合器中,将水合物(1千克)、乳糖(1.9千克)和氢化蓖麻油(0.1千克)(均为60目细粉)混合20分钟。混合的粉(各172毫克)装入2号含二氧化钛(6%)的白色明胶硬胶囊,然后(用日本Elanco公司的硬胶囊密封机S-100)在胶囊盖和体连接处的周边涂上明胶密封液〔20-25毫克,55℃,明胶(22%)、甘油(5%)和乙醇(30%)的水溶液〕。在室温和空气流下干燥5分钟。产物的每个胶囊具有50毫克7432-S的效力。
例 11
在10升V-型混合器中,将水合物(1千克)、结晶纤维素(0.5千克)和巴西棕榈蜡细粉(0.02千克)(均为60目细粉)混合20分钟。混合的粉(各171毫克)装入4号含二氧化钛(2.1%)的白色明胶硬胶囊内。然后(用日本Elanco公司的硬胶囊密封机S-100)在胶囊盖和体连接处的周边涂上明胶密封液
〔10-20毫克,60℃;明胶(22%)和多乙氧基醚80(2%)的水溶液〕。在室温和空气流下干燥4分钟。产物的每只胶囊具有100毫克7432-S的效力。
例 12
按例9的方法制造的胶囊,只是应用4号透明明胶硬胶囊。
例 13
按例9的方法制造的胶囊,只是用含微量1号兰色染料、3号红色染料和二氧化钛的4号不透明兰色明胶硬胶囊。
例 14
按例9的方法制造的胶囊,只是用含微量1号兰色染料、3号红色染料、5号黄色染料和二氧化钛的不透明的4号红色明胶硬胶囊。参考例1(对例9)
在10升V-型混合器中,将水合物(1千克)、结晶纤维素(1.08千克)、抗氧剂苄基羟基茴香醚(10毫克60目粉)和硬脂酸镁(0.02千克)混合20分钟。此混合的粉(各253毫克)装入2号含3.5%二氧化钛的白色明胶硬胶囊。产物的每个胶囊具有100毫克7432-S的效力。
参考例2(对例10)
在10升V-型混合器中,将水合物(1千克)、结晶纤维素(1.18千克)和硬脂酸镁(0.02千克)(均为60目细粉)混合20分钟。此混合的粉(各253毫克)装入2号含二氧化钛(3.5%)的白色明胶硬胶囊。产物的每只胶囊具有100毫克7432-S的效力。
参考例3-6(对例11-14)
将例11-14的各胶囊,在涂密封明胶溶液之前标明为参考例3-6的胶囊,用于下述试验。
对胶囊的试验
下述试验表示了用高压液相色谱观察到的组合物的稳定性:柱=Polygosil 6010C18直径4毫米×250毫米(M.Nagel & Co.);流动相=0.05M醋酸铵/甲醇(96/4);流速=1.5毫升/分;内标=烟酰胺;紫外检测=在254nm。
试验1
胶囊(各10只胶囊)置于500毫升玻璃容器,塞严,放入45±1℃的箱内。7432-S的含量每月用高压液相色谱测定,测定4个月。
表2指明与新制成胶囊含量相比较的保留的百分含量。
未密封的胶囊,即使存在有抗氧化剂作为稳定剂,与本发明的胶囊相比,明显的不稳定。
表2
试验2
胶囊(各10只胶囊)放在白且厚的纸上、放入25±1℃箱内,在10000勒克司荧光灯下照射。7432-S的含量每月用高压液相色谱测定,共两个月,并用色差仪(Color-studioofNihon Densyoku Kogyo)按NBS色差单位测定颜色改变。
表3表明了与新制造的胶囊相比较的保留含量和按NBS单位的颜色改变。
表3
NBS单位是美国国家标准局的色差单位。下表显示其数值对外观的一般概念。
从这些试验可以得出结论,本发明的组合物,即是在加速的条件下(如加热、照射),可保持7432-S稳定,并能防止颜色改变。胶囊与密封液用对比的颜色(因其可自由选择),可使破损的密封带易于检测出。
表
NBS单位 差异 NBS单位 差异
0~0.5 无明显变色 3.0~6.0 明显变色
0.5~1.5 微变 6.0~12.0 显著变色
1.5~3.0 变色 >12.0 严重变色
Claims (9)
1、制备具有如下X-射线衍射花样的7β-[(Z)-2-(2-氨基噻唑-4-基)-4-羧基丁-2-烯酰氨基]-3-头孢烯-4-羧酸的结晶性二或三水合物的方法,
d I/I0d I/I0d I/I0d I/I0
5.90 1 2 20.95 100 28.70 1 7 35.93 0 8
7.35 0 8 21.15 7 0 29.40 2 7 36.38 2 4
9.45 9 2 21.75 2 5 29.60 1 1 37.00 0 7
10.15 2 1 22.25 4 9 29.90 1 6 38.30 2 6
12.08 4 6 23.85 6 2 30.40 1 9 38.65 1 0
14.87 3 0 24.50 3 9 31.10 5 3 39.20 1 5
15.65 1 4 24.80 1 6 31.60 2 3 39.60 2 1
16.25 1 3 25.50 3 4 31.78 3 4 40.27 1 5
18.35 2 4 25.85 6 6 33.02 2 8 41.22 2 2
18.90 7 1 26.60 1 6 33.55 2 3 42.55 0 8
19.14 7 7 27.02 5 9 33.86 1 7 44.20 0 9
19.40 6 0 27.30 3 5 35.20 1 6
20.58 8 8 28.35 5 4 35.65 1 0
该方法包括在0-60℃和相对湿度不低于15%的惰性气体中用静止式、通流式、循环式或流化床干燥法,干燥7β-[(Z)-2-(2-氨基噻唑-4-基)-4-羧基丁-2-烯酰氨基]-3-头孢烯-4-羧酸的湿结晶。
2、如权利要求1中所述的方法,其中干燥是用25-40℃和相对湿度约为50-60%的空气,在通流式干燥器内进行的。
3、如权利要求1中所述的方法,其中干燥是用10-35℃,相对湿度50-60%的空气,在流化床干燥器内进行的。
4、如权利要求1中所述的方法,其中干燥持续到时间对排出空气温度或者时间对排出空气湿度曲线的第一个转折点,得到三水合物;或持续到同曲线的第二个转折点,得到二水合物。
5、如权利要求1中所述的方法,其中湿结晶是由提高此化合物的酸水溶液的pH以使之结晶和由结晶的成熟化来制备的。
6、如权利要求5中所述的方法,其中结晶时的pH是1.5-5.0。
7、如权利要求5中所述的方法,其中原料在酸水溶液中的浓度是在2.0-15.0%之间。
8、如权利要求5中所述的方法,其中提高酸水溶液的pH是用三乙胺、氢氧化铵、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、或阴离子交换树脂,或水稀释法来实现的。
9、如权利要求5中所述的方法,其中结晶的成熟化是在0-70℃继续10分钟至50小时。
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1987
- 1987-06-19 NZ NZ220764A patent/NZ220764A/xx unknown
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- 1987-07-02 CN CN87105009A patent/CN1015106B/zh not_active Expired
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Cited By (1)
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CN1307211C (zh) * | 1998-10-27 | 2007-03-28 | 伊斯曼化学公司 | 烯烃聚合方法,新型聚乙烯以及由其制造的薄膜和制品 |
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