技术领域technical field
本发明涉及药物共晶技术领域，具体地是提供一种环丙沙星与四氯对苯二甲酸的药物共晶体的结构及其制备方法。所述共晶对提高环丙沙星的溶解性、稳定性等具有较好的效果，在药物共晶法提高难溶药物溶解度领域有着重要的应用前景。The invention relates to the technical field of drug co-crystals, and specifically provides a structure of a drug co-crystal of ciprofloxacin and tetrachloroterephthalic acid and a preparation method thereof. The co-crystal has a good effect on improving the solubility and stability of ciprofloxacin, and has an important application prospect in the field of improving the solubility of insoluble drugs by drug co-crystal method.
技术背景technical background
喹诺酮类抗菌药物作为抗菌感染化疗药物已经有接近30年的历史。因为氟喹诺酮类抗菌谱广、活性强，使得此类药物中某些新的品种治疗系统性感染成为现实。氟喹喏酮的母体药物为氟喹诺酮类抗生素——环丙沙星，C17H18FN3O3，白色结晶性粉末，商品名为“西普乐”，英文名为Ciprofloxacin。环丙沙星难溶于水，文献报道仅有0.09mg/mL。目前工业上普遍采用的增大溶解度的方法是制成盐酸盐，但过量盐酸盐的摄入会对人体造成不良影响，因此通过共晶的方法增大溶解度就显得尤为重要。Quinolones have been used as chemotherapy drugs for antibacterial infections for nearly 30 years. Due to the wide antibacterial spectrum and strong activity of fluoroquinolones, some new varieties of these drugs have become a reality for the treatment of systemic infections. The parent drug of fluoroquinolones is fluoroquinolone antibiotics—ciprofloxacin, C17 H18 FN3 O3 , white crystalline powder. Ciprofloxacin is poorly soluble in water, with only 0.09mg/mL reported in the literature. At present, the method commonly used in the industry to increase solubility is to make hydrochloride, but excessive intake of hydrochloride will cause adverse effects on the human body, so it is particularly important to increase solubility through eutectic methods.
本发明特提出了环丙沙星和四氯对苯二甲酸形成的联合药物共晶体及其制备工艺，通过X-射线单晶衍射确定该药物共晶体的结构，该结构的环丙沙星和四氯对苯二甲酸共晶体可充分改善环丙沙星药物的稳定性、溶解度等物理化学性质，从而提高药效和生物利用度，克服了环丙沙星水中溶解度小的问题。有望在环丙沙星的制剂方面应用，改善盐酸盐所形成的单一用药机制。The present invention specially proposes the joint drug co-crystal formed by ciprofloxacin and tetrachloroterephthalic acid and its preparation process, and determines the structure of the drug co-crystal by X-ray single crystal diffraction, the structure of ciprofloxacin and Tetrachloroterephthalic acid co-crystal can fully improve the stability, solubility and other physical and chemical properties of ciprofloxacin, thereby improving drug efficacy and bioavailability, and overcoming the problem of low solubility of ciprofloxacin in water. It is expected to be applied in the preparation of ciprofloxacin to improve the single drug mechanism formed by hydrochloride.
发明内容Contents of the invention
本发明要解决的技术问题是针对目前环丙沙星在水中的溶解度差、药效不能得到充分释放等问题，特提出一种环丙沙星和四氯对苯二甲酸形成的联合药物共晶体的制备工艺及其结构确定，该结构的药物共晶体可以显著提高环丙沙星在水中的溶解度。The technical problem to be solved in the present invention is to solve the current problems such as the poor solubility of ciprofloxacin in water and the inability to fully release the drug effect. The preparation process and its structure are determined, and the drug co-crystal with this structure can significantly improve the solubility of ciprofloxacin in water.
本发明采用如下技术方案：The present invention adopts following technical scheme:
本发明所述的药物共晶体，其包含1分子环丙沙星1.5分子四氯对苯二甲酸，其结构如下式所示：The drug co-crystal of the present invention comprises 1 molecule of ciprofloxacin and 1.5 molecules of tetrachloroterephthalic acid, and its structure is shown in the following formula:
其中所述[环丙沙星][四氯对苯二甲酸]1.5分子式为C29H21Cl5FN3O9，结晶于三斜晶系P-1空间群，晶胞参数为：a＝0.92235(8)nm,b＝1.13207(1)nm,c＝1.56694(1)nm。α＝89.989(2),β＝75.496(2),γ＝85.944(2)。The molecular formula of [ciprofloxacin][tetrachloroterephthalic acid]1.5 is C29 H21 Cl5 FN3 O9 , crystallized in the triclinic system P-1 space group, and the unit cell parameters are: a= 0.92235(8)nm, b=1.13207(1)nm, c=1.56694(1)nm. α=89.989(2), β=75.496(2), γ=85.944(2).
本发明的药物共晶体采用如下工艺制备，该制备方法包括以下步骤：The drug co-crystal of the present invention is prepared by the following process, and the preparation method comprises the following steps:
称取计量比的环丙沙星和四氯对苯二甲酸分别分散或溶于水和甲醇溶液中，两者混合搅拌一定时间，将混合液倒入一定溶剂的反应釜中，在一定温度下(100-160℃)保温若干天，程序降温后得到无色针状晶体。产率：80～98％.按上述方法制备的环丙沙星和四氯对苯二甲酸的药物共晶体，其晶体结构为：不对称单元包含一个质子化的环丙沙星阳离子、一个四氯对苯二甲酸分子以及半个完全去质子的四氯对苯二甲酸阴离子，分子结构如图3所示。同样，四氯对苯二甲酸分子中羧基上的质子传递到了环丙沙星哌嗪基团的氮原子上。完全去质子的四氯对苯二甲酸分子与相邻的两个环丙沙星阳离子通过氢键N–H···O相连接，键长键角为154°。图4为完全去质子的四氯对苯二甲酸的氢键连接方式。Disperse or dissolve the ciprofloxacin and tetrachloroterephthalic acid in the measured ratio respectively in water and methanol solution, mix and stir for a certain period of time, pour the mixed solution into a reaction kettle with a certain solvent, and dissolve it at a certain temperature (100-160°C) for several days, and colorless needle-like crystals were obtained after programmed cooling. Yield: 80～98%. According to the drug co-crystal of ciprofloxacin and tetrachloroterephthalic acid prepared by the above method, its crystal structure is: the asymmetric unit contains a protonated ciprofloxacin cation, a tetrachloroterephthalic acid The chloroterephthalic acid molecule and half of the fully deprotonated tetrachloroterephthalic acid anion are shown in Figure 3. Likewise, the proton on the carboxyl group in the tetrachloroterephthalic acid molecule is transferred to the nitrogen atom of the piperazine group of ciprofloxacin. The completely deprotonated tetrachloroterephthalic acid molecule is connected to two adjacent ciprofloxacin cations through hydrogen bonds N–H···O, and the bond length The bond angle is 154°. Fig. 4 shows the hydrogen bonding mode of completely deprotonated tetrachloroterephthalic acid.
采用上述技术方案后，本发明的有益效果是：本发明中原料药环丙沙星作为药物的活性组分(API)，以四氯对苯二甲酸作为共晶体(cocrystal former)，得到一种新型结构的有机药物共晶。通过控制溶剂热反应条件以多种比例结晶形成药物共晶体。因为该共晶体合成采用的试剂甲醇和水均无毒无害、所需的反应设备简单、制作的方法简单易行、产品稳定性高、可重现性好，且制备得到的共晶具有热稳定性好、摩尔收率高等优点，有利于工业化生产。After adopting the above technical scheme, the beneficial effect of the present invention is: in the present invention, raw drug ciprofloxacin is used as the active component (API) of medicine, and tetrachloroterephthalic acid is used as cocrystal (cocrystal former), obtains a kind of Novel structure of organic pharmaceutical co-crystals. Drug co-crystals are formed by crystallization in various ratios by controlling the solvothermal reaction conditions. Because the reagent methanol and water used in the synthesis of the co-crystal are non-toxic and harmless, the required reaction equipment is simple, the production method is simple and easy, the product has high stability and good reproducibility, and the prepared co-crystal has thermal The advantages of good stability and high molar yield are beneficial to industrial production.
本发明对环丙沙星与四氯对苯二甲酸形成的共晶提供制备方法与结构确定。应用溶剂热反应法制备相应的药物共晶体，并优选了最佳合成工艺。采用X射线粉末衍射、红外光谱法以及X射线单晶衍射等手段对所得结构进行了表征和确定。The invention provides a preparation method and structure determination for the eutectic formed by ciprofloxacin and tetrachloroterephthalic acid. The corresponding drug co-crystals were prepared by solvothermal reaction method, and the optimal synthesis process was optimized. The obtained structure was characterized and determined by means of X-ray powder diffraction, infrared spectroscopy and X-ray single crystal diffraction.
附图说明Description of drawings
图1是环丙沙星和四氯对苯二甲酸共晶体的X射线粉末衍射图。Figure 1 is an X-ray powder diffraction pattern of ciprofloxacin and tetrachloroterephthalic acid co-crystal.
图2是环丙沙星和四氯对苯二甲酸共晶体的红外光谱分析图。Figure 2 is an infrared spectrum analysis chart of ciprofloxacin and tetrachloroterephthalic acid co-crystal.
图3是环丙沙星和四氯对苯二甲酸共晶体的分子结构图。Figure 3 is a molecular structure diagram of the co-crystal of ciprofloxacin and tetrachloroterephthalic acid.
图4是去质子的四氯对苯二甲酸分子的氢键连接方式图。Fig. 4 is a diagram showing the hydrogen bonding mode of the deprotonated tetrachloroterephthalic acid molecule.
具体实施方法Specific implementation method
本发明将就以下实施例作进一步说明，但应了解的是，这些实施例仅为例示说明之用，而不应被解释为本发明实施的限制。The present invention will be further described with reference to the following examples, but it should be understood that these examples are for illustrative purposes only and should not be construed as limitations on the implementation of the present invention.
1、环丙沙星和四氯对苯二甲酸共晶体的合成：1. Synthesis of co-crystals of ciprofloxacin and tetrachloroterephthalic acid:
实施实例1Implementation example 1
环丙沙星和四氯对苯二甲酸的摩尔比0.5:1。制备方法：称取16.6mg环丙沙星(0.05mmol)于4mL水中，称取四氯对苯二甲酸30.3mg(0.1mmol)溶于1mL甲醇中，两者混合后，搅拌15min后，将混合液倒入10mL反应釜中，放入烘箱，升温速率5℃/h至140℃，保温三天，降温速率为1℃/h，降至室温有无色针状晶体生成。产率：90％(基于四氯对苯二甲酸)。FT-IR(KBr压片，cm-1)：3493m,3443m,3069w,2851w,2503b,1710s,1629s,1476s,1269s,1035m,806m,607m,607m,545w.The molar ratio of ciprofloxacin and tetrachloroterephthalic acid is 0.5:1. Preparation method: Weigh 16.6mg of ciprofloxacin (0.05mmol) in 4mL of water, weigh 30.3mg (0.1mmol) of tetrachloroterephthalic acid and dissolve it in 1mL of methanol, mix the two, stir for 15min, and mix The liquid was poured into a 10mL reaction kettle, put into an oven, the heating rate was 5°C/h to 140°C, and the temperature was kept for three days, and the cooling rate was 1°C/h. Colorless needle-like crystals were formed when the temperature was lowered to room temperature. Yield: 90% (based on tetrachloroterephthalic acid). FT-IR (KBr pellet, cm-1 ): 3493m, 3443m, 3069w, 2851w, 2503b, 1710s, 1629s, 1476s, 1269s, 1035m, 806m, 607m, 607m, 545w.
实施实例2Implementation example 2
环丙沙星和四氯对苯二甲酸的摩尔比1:1.5。制备方法：称取33.1mg环丙沙星(0.1mmol)于4mL水中，称取四氯对苯二甲酸45.6mg(0.15mmol)溶于1mL甲醇中，两者混合后，搅拌15min后，将混合液倒入10mL反应釜中，放入烘箱，升温速率5℃/h至140℃，保温三天，降温速率为1℃/h，降至室温有无色针状晶体生成。产率：98％(基于环丙沙星)。FT-IR(KBr压片，cm-1)：3493m,3443m,3069w,2851w,2503b,1710s,1629s,1476s,1269s,1035m,806m,607m,607m,545w.The molar ratio of ciprofloxacin and tetrachloroterephthalic acid is 1:1.5. Preparation method: Weigh 33.1mg of ciprofloxacin (0.1mmol) in 4mL of water, weigh 45.6mg (0.15mmol) of tetrachloroterephthalic acid and dissolve it in 1mL of methanol, mix the two, stir for 15min, and mix The liquid was poured into a 10mL reaction kettle, put into an oven, the heating rate was 5°C/h to 140°C, and the temperature was kept for three days, and the cooling rate was 1°C/h. Colorless needle-like crystals were formed when the temperature was lowered to room temperature. Yield: 98% (based on ciprofloxacin). FT-IR (KBr pellet, cm-1 ): 3493m, 3443m, 3069w, 2851w, 2503b, 1710s, 1629s, 1476s, 1269s, 1035m, 806m, 607m, 607m, 545w.
实施实例3Implementation example 3
环丙沙星和四氯对苯二甲酸的摩尔比1:4。制备方法：称取33.1mg环丙沙星(0.1mmol)于4mL水中，称取四氯对苯二甲酸121.6mg(0.4mmol)溶于1mL甲醇中，两者混合后，搅拌15min后，将混合液倒入10mL反应釜中，放入烘箱，升温速率5℃/h至140℃，保温三天，降温速率为1℃/h，降至室温有无色针状晶体生成。产率：80％(基于环丙沙星)。FT-IR(KBr压片，cm-1)：3493m,3443m,3069w,2851w,2503b,1710s,1629s,1476s,1269s,1035m,806m,607m,607m,545w.The molar ratio of ciprofloxacin to tetrachloroterephthalic acid is 1:4. Preparation method: Weigh 33.1mg of ciprofloxacin (0.1mmol) in 4mL of water, weigh 121.6mg (0.4mmol) of tetrachloroterephthalic acid and dissolve it in 1mL of methanol, mix the two, stir for 15min, and mix The liquid was poured into a 10mL reaction kettle, put into an oven, the heating rate was 5°C/h to 140°C, and the temperature was kept for three days, and the cooling rate was 1°C/h. Colorless needle-like crystals were formed when the temperature was lowered to room temperature. Yield: 80% (based on ciprofloxacin). FT-IR (KBr pellet, cm-1 ): 3493m, 3443m, 3069w, 2851w, 2503b, 1710s, 1629s, 1476s, 1269s, 1035m, 806m, 607m, 607m, 545w.
实施实例4Implementation example 4
环丙沙星和四氯对苯二甲酸的摩尔比0.5:1。制备方法：称取16.6mg环丙沙星(0.05mmol)于4mL水中，称取四氯对苯二甲酸30.3mg(0.1mmol)溶于1mL甲醇中，两者混合后，搅拌30min后，将混合液倒入10mL反应釜中，放入烘箱，升温速率5℃/h至160℃，保温三天，降温速率为5℃/h，至室温有无色针状晶体生成。产率：83％(基于四氯对苯二甲酸)。FT-IR(KBr压片，cm-1)：3493m,3443m,3069w,2851w,2503b,1710s,1629s,1476s,1269s,1035m,806m,607m,607m,545w.The molar ratio of ciprofloxacin and tetrachloroterephthalic acid is 0.5:1. Preparation method: Weigh 16.6mg of ciprofloxacin (0.05mmol) in 4mL of water, weigh 30.3mg (0.1mmol) of tetrachloroterephthalic acid and dissolve it in 1mL of methanol, mix the two, stir for 30min, and mix The liquid was poured into a 10mL reaction kettle, put into an oven, the heating rate was 5°C/h to 160°C, and the temperature was kept for three days, the cooling rate was 5°C/h, and colorless needle-like crystals were formed at room temperature. Yield: 83% (based on tetrachloroterephthalic acid). FT-IR (KBr pellet, cm-1 ): 3493m, 3443m, 3069w, 2851w, 2503b, 1710s, 1629s, 1476s, 1269s, 1035m, 806m, 607m, 607m, 545w.
实施实例5Implementation Example 5
环丙沙星和四氯对苯二甲酸的摩尔比0.5:1。制备方法：称取16.6mg环丙沙星(0.05mmol)于4mL水中，称取四氯对苯二甲酸30.3mg(0.1mmol)溶于1mL甲醇中，两者混合后，搅拌30min后，将混合液倒入10mL反应釜中，放入烘箱，升温速率5℃/h至120℃，保温三天，降温速率为5℃/h，有无色针状晶体生成。产率：84％(基于四氯对苯二甲酸)。FT-IR(KBr压片，cm-1)：3493m,3443m,3069w,2851w,2503b,1710s,1629s,1476s,1269s,1035m,806m,607m,607m,545w.The molar ratio of ciprofloxacin and tetrachloroterephthalic acid is 0.5:1. Preparation method: Weigh 16.6mg of ciprofloxacin (0.05mmol) in 4mL of water, weigh 30.3mg (0.1mmol) of tetrachloroterephthalic acid and dissolve it in 1mL of methanol, mix the two, stir for 30min, and mix The liquid was poured into a 10mL reaction kettle, put into an oven, the heating rate was 5°C/h to 120°C, and the temperature was kept for three days, and the cooling rate was 5°C/h, and colorless needle-like crystals were formed. Yield: 84% (based on tetrachloroterephthalic acid). FT-IR (KBr pellet, cm-1 ): 3493m, 3443m, 3069w, 2851w, 2503b, 1710s, 1629s, 1476s, 1269s, 1035m, 806m, 607m, 607m, 545w.
实施实例6Implementation Example 6
环丙沙星和四氯对苯二甲酸的摩尔比1:1.5。制备方法：称取33.1mg环丙沙星(0.1mmol)溶于2mL水中，称取四氯对苯二甲酸45.6mg(0.15mmol)溶于2mL甲醇中，两者混合后，搅拌20min后，将混合液倒入10mL反应釜中，放入烘箱，升温速率5℃/h至160℃，保温三天，降温速率为5℃/h，有无色针状晶体生成。产率：85％(基于环丙沙星)。FT-IR(KBr压片，cm-1)：3493m,3443m,3069w,2851w,2503b,1710s,1629s,1476s,1269s,1035m,806m,607m,607m,545w.The molar ratio of ciprofloxacin and tetrachloroterephthalic acid is 1:1.5. Preparation method: Weigh 33.1mg of ciprofloxacin (0.1mmol) and dissolve it in 2mL of water, weigh 45.6mg (0.15mmol) of tetrachloroterephthalic acid and dissolve it in 2mL of methanol, mix the two, stir for 20min, and dissolve The mixed solution was poured into a 10mL reaction kettle, put into an oven, the heating rate was 5°C/h to 160°C, and kept for three days, the cooling rate was 5°C/h, and colorless needle-like crystals were formed. Yield: 85% (based on ciprofloxacin). FT-IR (KBr pellet, cm-1 ): 3493m, 3443m, 3069w, 2851w, 2503b, 1710s, 1629s, 1476s, 1269s, 1035m, 806m, 607m, 607m, 545w.
实施实例7Implementation example 7
环丙沙星和四氯对苯二甲酸的摩尔比1:2。制备方法：称取33.1mg环丙沙星(0.1mmol)溶于2mL水中，称取四氯对苯二甲酸60.8mg(0.2mmol)溶于2mL甲醇中，两者混合后，搅拌15min后，将混合液倒入10mL反应釜中，放入烘箱，升温速率5℃/h至160℃，保温三天，降温速率为5℃/h，有无色针状晶体生成。产率：90％(基于环丙沙星)。FT-IR(KBr压片，cm-1)：3493m,3443m,3069w,2851w,2503b,1710s,1629s,1476s,1269s,1035m,806m,607m,607m,545w.The molar ratio of ciprofloxacin and tetrachloroterephthalic acid is 1:2. Preparation method: Weigh 33.1mg of ciprofloxacin (0.1mmol) and dissolve it in 2mL of water, weigh 60.8mg (0.2mmol) of tetrachloroterephthalic acid and dissolve it in 2mL of methanol, mix the two, stir for 15min, and dissolve The mixed solution was poured into a 10mL reaction kettle, put into an oven, the heating rate was 5°C/h to 160°C, and kept for three days, the cooling rate was 5°C/h, and colorless needle-like crystals were formed. Yield: 90% (based on ciprofloxacin). FT-IR (KBr pellet, cm-1 ): 3493m, 3443m, 3069w, 2851w, 2503b, 1710s, 1629s, 1476s, 1269s, 1035m, 806m, 607m, 607m, 545w.
实施实例8Implementation example 8
环丙沙星和四氯对苯二甲酸的摩尔比1:2。制备方法：称取33.1mg环丙沙星(0.1mmol)于4mL水中，称取四氯对苯二甲酸60.8mg(0.2mmol)溶于2mL甲醇中，两者混合后，搅拌15min后，将混合液倒入10mL反应釜中，放入烘箱，升温速率5℃/h至160℃，保温三天，降温速率为5℃/h，有无色针状晶体生成。产率：88％(基于环丙沙星)。FT-IR(KBr压片，cm-1)：3493m,3443m,3069w,2851w,2503b,1710s,1629s,1476s,1269s,1035m,806m,607m,607m,545w.The molar ratio of ciprofloxacin and tetrachloroterephthalic acid is 1:2. Preparation method: Weigh 33.1mg of ciprofloxacin (0.1mmol) in 4mL of water, weigh 60.8mg (0.2mmol) of tetrachloroterephthalic acid and dissolve it in 2mL of methanol, mix the two, stir for 15min, and mix The liquid was poured into a 10mL reaction kettle, put into an oven, the heating rate was 5°C/h to 160°C, and kept for three days, the cooling rate was 5°C/h, and colorless needle-like crystals were formed. Yield: 88% (based on ciprofloxacin). FT-IR (KBr pellet, cm-1 ): 3493m, 3443m, 3069w, 2851w, 2503b, 1710s, 1629s, 1476s, 1269s, 1035m, 806m, 607m, 607m, 545w.
实施实例9Implementation example 9
环丙沙星和四氯对苯二甲酸的摩尔比1:4。制备方法：称取33.1mg环丙沙星(0.1mmol)溶于2mL水中，称取四氯对苯二甲酸121.6mg(0.4mmol)溶于2mL甲醇中，两者混合后，搅拌30min后，将混合液倒入10mL反应釜中，放入烘箱，升温速率5℃/h至160℃，保温三天，降温速率为5℃/h，有无色针状晶体生成。产率：85％(基于环丙沙星)。FT-IR(KBr压片，cm-1)：3493m,3443m,3069w,2851w,2503b,1710s,1629s,1476s,1269s,1035m,806m,607m,607m,545w.The molar ratio of ciprofloxacin to tetrachloroterephthalic acid is 1:4. Preparation method: Weigh 33.1mg of ciprofloxacin (0.1mmol) and dissolve it in 2mL of water, weigh 121.6mg (0.4mmol) of tetrachloroterephthalic acid and dissolve it in 2mL of methanol, mix the two, stir for 30min, and dissolve The mixed solution was poured into a 10mL reaction kettle, put into an oven, the heating rate was 5°C/h to 160°C, and kept for three days, the cooling rate was 5°C/h, and colorless needle-like crystals were formed. Yield: 85% (based on ciprofloxacin). FT-IR (KBr pellet, cm-1 ): 3493m, 3443m, 3069w, 2851w, 2503b, 1710s, 1629s, 1476s, 1269s, 1035m, 806m, 607m, 607m, 545w.
实施实例10Implementation example 10
环丙沙星和四氯对苯二甲酸的摩尔比1:3。制备方法：称取33.1mg环丙沙星(0.1mmol)溶于5ml水中，称取四氯对苯二甲酸91.2mg(0.3mmol)溶于2ml甲醇中，两者混合后，搅拌15min后，将混合液倒入10ml反应釜中，放入烘箱，升温速率5℃/h至160℃，保温三天，降温速率为5℃/h，有无色针状晶体生成。产率：88％(基于环丙沙星)。FT-IR(KBr压片，cm-1)：3493m,3443m,3069w,2851w,2503b,1710s,1629s,1476s,1269s,1035m,806m,607m,607m,545w.The molar ratio of ciprofloxacin and tetrachloroterephthalic acid is 1:3. Preparation method: Weigh 33.1mg of ciprofloxacin (0.1mmol) and dissolve it in 5ml of water, weigh 91.2mg (0.3mmol) of tetrachloroterephthalic acid and dissolve it in 2ml of methanol, mix the two, stir for 15min, and dissolve The mixed solution was poured into a 10ml reaction kettle, put into an oven, the heating rate was 5°C/h to 160°C, and kept for three days, the cooling rate was 5°C/h, and colorless needle-like crystals were formed. Yield: 88% (based on ciprofloxacin). FT-IR (KBr pellet, cm-1 ): 3493m, 3443m, 3069w, 2851w, 2503b, 1710s, 1629s, 1476s, 1269s, 1035m, 806m, 607m, 607m, 545w.
2、共晶的结构测定：2. Determination of the structure of the eutectic:
晶体结构测定采用德国布鲁克公司APEX-II X射线衍射仪收集，采用Mo-Kα靶，于296(±2)K下进行测定。收集的数据是通过SAINT程序还原并利用SADAB方法进行半经验吸收校正。并分别采用SHELXTL程序的SHELXS和SHELXL进行结构解析和精修，对F2进行修正，通过全矩阵最小二乘方法，获得全部非氢原子的坐标及各向异性参数。所有氢原子在结构精修过程中被理论固定在母原子上，并赋予比母原子位移参数稍大(C–H,1.2或O–H,1.5倍)的各向同性位移参数。详细的晶体测定数据见表1。The crystal structure was determined by using the APEX-II X-ray diffractometer of Bruker, Germany, using Mo-Kα Target, measured at 296(±2)K. The collected data were reduced by the SAINT program and subjected to semi-empirical absorption correction using the SADAB method. The SHELXS and SHELXL of the SHELXTL program were used for structure analysis and refinement, and F2 was corrected.The coordinates and anisotropy parameters of all non-hydrogen atoms were obtained by the full matrix least squares method. All hydrogen atoms are theoretically fixed on the parent atom during the structure refinement process, and endowed with an isotropic displacement parameter slightly larger (C–H, 1.2 or O–H, 1.5 times) than the parent atom displacement parameter. The detailed crystal determination data are shown in Table 1.
以上述依据本发明的理想实施例为启示，通过上述的说明内容，相关工作人员完全可以在不偏离本项发明技术思想的范围内，进行多样的变更以及修改。本项发明的技术性范围并不局限于说明书上的内容，必须要根据权利要求范围来确定其技术性范围。Inspired by the above-mentioned ideal embodiment according to the present invention, through the above-mentioned description content, relevant workers can make various changes and modifications within the scope of not departing from the technical idea of the present invention. The technical scope of the present invention is not limited to the content in the specification, but must be determined according to the scope of the claims.
表1共晶的主要晶体学数据Table 1 The main crystallographic data of the cocrystal
aR＝Σ||Fo|-|Fc||/Σ|Fo|.a R＝Σ||Fo |-|Fc ||/Σ|Fo |.
bRw＝[Σ[w(Fo2-Fc2)2]/Σw(Fo2)2]1/2.b Rw ＝[Σ[w(Fo2 -Fc2 )2 ]/Σw(Fo2 )2 ]1/2 .
cGOF＝{Σ[w(Fo2-Fc2)2]/(n-p)}1/2.c GOF＝{Σ[w(Fo2 -Fc2 )2 ]/(np)}1/2 .
| Application Number | Priority Date | Filing Date | Title |
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| CN201710211329.6ACN107098858A (en) | 2017-03-31 | 2017-03-31 | A kind of Ciprofloxacin and the eutectiferous structure of tetrachloro-p-phenylene's dioctyl phthalate and its solvothermal preparation method |
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| CN201710211329.6ACN107098858A (en) | 2017-03-31 | 2017-03-31 | A kind of Ciprofloxacin and the eutectiferous structure of tetrachloro-p-phenylene's dioctyl phthalate and its solvothermal preparation method |
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| CN112986468A (en)* | 2019-12-13 | 2021-06-18 | 武汉九州钰民医药科技有限公司 | Analysis method for detecting ciprofloxacin chloride in ciprofloxacin hydrochloride tablet |
| CN113402458A (en)* | 2021-08-15 | 2021-09-17 | 广东温氏大华农生物科技有限公司 | Enrofloxacin eutectic crystal and preparation method thereof |
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103864683A (en)* | 2014-02-14 | 2014-06-18 | 博瑞生物医药泰兴市有限公司 | Medicine eutectic of ciprofloxacin and salicylic acid and preparation process thereof |
| CN105777711A (en)* | 2016-04-07 | 2016-07-20 | 常州大学 | Medicine eutectic of lomefloxacin and 5F-isophthalic acid and preparation method thereof |
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103864683A (en)* | 2014-02-14 | 2014-06-18 | 博瑞生物医药泰兴市有限公司 | Medicine eutectic of ciprofloxacin and salicylic acid and preparation process thereof |
| CN105777711A (en)* | 2016-04-07 | 2016-07-20 | 常州大学 | Medicine eutectic of lomefloxacin and 5F-isophthalic acid and preparation method thereof |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112986468A (en)* | 2019-12-13 | 2021-06-18 | 武汉九州钰民医药科技有限公司 | Analysis method for detecting ciprofloxacin chloride in ciprofloxacin hydrochloride tablet |
| CN112986468B (en)* | 2019-12-13 | 2024-05-03 | 武汉九州钰民医药科技有限公司 | Analysis method for detecting ciprofloxacin chloride in ciprofloxacin hydrochloride tablet |
| CN113402458A (en)* | 2021-08-15 | 2021-09-17 | 广东温氏大华农生物科技有限公司 | Enrofloxacin eutectic crystal and preparation method thereof |
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