阅读说明：本技术 一种注射用头孢哌酮钠舒巴坦钠有关物质测定方法 (Method for determining related substances of cefoperazone sodium and sulbactam sodium for injection ) 是由 马莉 李珠珠 史权杰 于 2020-11-17 设计创作，主要内容包括：本发明公开了一种注射用头孢哌酮钠舒巴坦钠有关物质测定方法,利用溶液配制设备进行溶液的配制,将头孢哌酮钠舒巴坦钠粉末通过进料斗投入混合罐中,接着向混合罐中通水,关闭进料斗,启动驱动机构和升温机构。该注射用头孢哌酮钠舒巴坦钠有关物质测定方法,通过搅拌架一和搅拌架二在混合罐中进行正反向转动,可以使头孢哌酮钠舒巴坦钠粉末快速的进行溶解,升温机构提高溶液的温度,进一步的加速药品粉末的溶解效率,有效地提高头孢哌酮钠舒巴坦钠粉末的溶解效果,采用新建立的RP-HPLC法能有效的分离和定量测定注射用头孢哌酮钠舒巴坦钠中的14个杂质,色谱的系统适用性良好,能更有效地控制该产品质量,有利于安全推广与应用。(The invention discloses a method for determining related substances of cefoperazone sodium and sulbactam sodium for injection, which comprises the steps of preparing a solution by using solution preparation equipment, putting cefoperazone sodium and sulbactam sodium powder into a mixing tank through a feed hopper, then introducing water into the mixing tank, closing the feed hopper, and starting a driving mechanism and a heating mechanism. According to the method for determining the related substances of the cefoperazone sodium and sulbactam sodium for injection, the first stirring frame and the second stirring frame rotate in the mixing tank in the forward and reverse directions, so that cefoperazone sodium and sulbactam sodium powder can be dissolved quickly, the temperature of the solution is increased by the temperature increasing mechanism, the dissolving efficiency of the medicine powder is further accelerated, the dissolving effect of the cefoperazone sodium and sulbactam sodium powder is effectively improved, 14 impurities in the cefoperazone sodium and sulbactam sodium for injection can be effectively separated and quantitatively determined by adopting a newly established RP-HPLC method, the system applicability of a chromatograph is good, the product quality can be controlled more effectively, and the method is favorable for safe popularization and application.)

1. A method for measuring related substances of cefoperazone sodium and sulbactam sodium for injection is characterized by comprising the following steps: the method specifically comprises the following steps:

firstly, preparing a solution by using solution preparation equipment, putting cefoperazone sodium and sulbactam sodium powder into a mixing tank (12) through a feed hopper (13), then introducing water into the mixing tank (12), closing the feed hopper (13), and starting a driving mechanism (2) and a heating mechanism (3);

step two, an output shaft of the driving motor (23) rotates, the driving shaft (22) is driven to rotate through the output shaft of the driving motor (23), the driving shaft (22) drives the driving gear (242) to rotate, the driven gear (243) which is in meshing transmission with the surface of the driving gear (242) rotates synchronously, the driven gear (243) is utilized to realize the rotation of the rotating frame (245) in the mounting block (241), the second stirring frame (162) is driven to rotate in the mixing tank (12) through the rotating frame (245) and the connecting rod (246), meanwhile, the driving gear (242) drives the stirring shaft (163) to rotate in the mixing tank (12), so that the first stirring frame (161) and the second stirring frame (162) rotate in opposite directions in the mixing tank (12), and the first stirring frame (161) and the second stirring frame (162) fully stir the solution in the mixing tank (12);

step three, hot water is introduced into the heat conducting coil pipe (35) through the water inlet pipe (31), after the hot water enters the heat conducting coil pipe (35), the heat of the hot water is dissipated by utilizing the heat conducting fins (33), the solution in the mixing tank (12) is heated through the heat conducting sleeve (32), and the cefoperazone sodium and sulbactam sodium powder is completely dissolved in the solution by matching with the continuous stirring of the stirring component (16);

fourthly, connecting one end of a connecting pipe (42) with a liquid injection port of the chromatograph by using a hose, opening a control valve of a discharge pipe (41), sending the solution in the mixing tank (12) out through the discharge pipe (41), filtering undissolved particles in the solution by using a filter membrane (43) in the connecting pipe (42), and sending the filtered solution into a chromatographic column in the chromatograph;

step five, using octadecylsilane chemically bonded silica as a filler in a chromatographic column, wherein a mobile phase A is a mixed solution of phosphate buffer solution and methanol with a volume ratio of 99:1, a mobile phase B is methanol, a detection wavelength is 220nm, a flow rate is 1.0ml/min, a column temperature is 30 ℃, and a gradient elution program of the chromatographic column is as follows: 0-12min, 100% mobile phase A; 12-20min, 100-86% mobile phase A; 20-40min, 86% mobile phase A; 40-45min, 86-81% mobile phase A; 45-70min, 81% mobile phase A; 70-75min, 81-65% mobile phase A; 75-100min, 65% mobile phase A; 100-100.1min, 65-100% mobile phase A; 100.1-110min, 100% mobile phase A, then taking sulbactam impurity A, 6-aminopenicillanic acid, cefoperazone impurity A, cefoperazone impurity B, cefoperazone impurity C, cefoperazone impurity D, cefoperazone impurity E, cefoperazone impurity F, cefoperazone impurity G, cefoperazone PZ, cefoperazone 7-TMCA, cefoperazone ring-opening compound, cefoperazone oxidation compound, cefoperazone ring-opening lactone, cefoperazone and sulbactam contrast, adding water to dissolve and dilute into mixed solution containing 10 mu G of each impurity, sulbactam and 2mg of cefoperazone in each 1ml, using as system applicability solution, precisely measuring 20 mu l of system applicability solution, injecting into liquid chromatograph, recording chromatogram, and finishing the measurement of related substances of cefoperazone sodium sulbactam.

2. The method for determining cefoperazone sodium/sulbactam sodium related substance for injection according to claim 1, wherein the method comprises the following steps: the solution preparation equipment comprises a mixing mechanism (1), a driving mechanism (2), a heating mechanism (3) and a discharging mechanism (4), wherein the driving mechanism (2) is arranged above the mixing mechanism (1), the heating mechanism (3) is arranged inside the mixing mechanism (1), and the discharging mechanism (4) is arranged at the bottom of the mixing mechanism (1).

3. The method for determining cefoperazone sodium and sulbactam sodium related substance for injection according to claim 2, wherein the method comprises the following steps: the mixing mechanism (1) comprises a fixing seat (11), a mixing tank (12), a feeding hopper (13), two lugs (14), a temperature detector (15) and a stirring assembly (16), wherein the fixing seat (11) is provided with two parts at the bottom of the mixing tank (12), the tops of the two fixing seats (11) are respectively fixedly connected with the two sides of the bottom of the mixing tank (12), the left side of the top of the mixing tank (12) is fixedly connected with the bottom end of the feeding hopper (13), the inside of the feeding hopper (13) is communicated with the inside of the mixing tank (12), the right side of the top of the mixing tank (12) is fixedly connected with the surface of the temperature detector (15), the bottom end of the temperature detector (15) penetrates through the mixing tank (12) and extends to the inside of the mixing tank (12), the lugs (14) are symmetrically arranged on the circumferential surface of the mixing tank (12), and one side, opposite to the two lugs (14), is fixedly connected with the surface of the mixing tank (12), the stirring assembly (16) is positioned inside the mixing tank (12) and is in rotating connection.

4. The method for determining cefoperazone sodium and sulbactam sodium related substance for injection according to claim 2, wherein the method comprises the following steps: stirring subassembly (16) are including stirring frame one (161), stirring frame two (162) and (mixing) shaft (163), and stirring frame one (161) and stirring frame two (162) all are located the inside rotation of blending tank (12) and are connected, the top of stirring frame one (161) and the bottom fixed connection of (mixing) shaft (163), and the inside of stirring frame two (162) and the surface rotation of (mixing) shaft (163) are connected.

5. The method for determining cefoperazone sodium and sulbactam sodium related substance for injection according to claim 2, wherein the method comprises the following steps: the driving mechanism (2) comprises a fixed frame (21), a driving shaft (22), a driving motor (23) and a transmission assembly (24), the bottom of the fixed frame (21) is fixedly connected with the top of the mixing tank (12), the bottom of the driving motor (23) is fixedly connected with the top of the fixed frame (21), the driving shaft (22) is positioned in the fixed frame (21) and is rotationally connected, the bottom end of the output shaft of the driving motor (23) is fixedly connected with the top end of the driving shaft (22) through a coupler, and the bottom end of the driving shaft (22) penetrates through the mixing tank (12) and extends to the interior of the mixing tank (12), the top of the transmission component (24) is fixedly connected with the top of the inner wall of the mixing tank (12), and the interior of the transmission component (24) is rotationally connected with one end of the driving shaft (22) extending to the interior of the mixing tank (12), the bottom of the transmission component (24) is rotatably connected with the top end of the stirring shaft (163).

6. The method for determining cefoperazone sodium/sulbactam sodium related substance for injection according to claim 5, wherein the method comprises the following steps: the transmission assembly (24) comprises an installation block (241), a driving gear (242), a driven gear (243), a rotating shaft (244), a rotating frame (245) and a connecting rod (246), the top of the installation block (241) is fixedly connected with the top of the inner wall of the mixing tank (12), a rotating groove (247) is formed in the bottom of the installation block (241), the inner part of the rotating groove (247) is rotatably connected with the peripheral surface of the rotating frame (245), the top end of the rotating shaft (244) is rotatably connected with the top of the inner wall of the rotating groove (247), the surface of the rotating shaft (244) is fixedly connected with the inner part of the driven gear (243), the surface of the driving gear (242) is in meshing transmission with the surface of the driven gear (243), the surface of the driven gear (243) is in meshing transmission with the inner wall of the rotating frame (245), the bottom of the driving gear (242) is fixedly connected with the top end of a stirring shaft, and the top of the driving gear (242) is fixedly connected with the bottom end of the driving shaft (22), one end of the connecting rod (246) is fixedly connected with the bottom of the rotating frame (245), and the bottom end of the connecting rod (246) is fixedly connected with the top of the second stirring frame (162).

7. The method for determining cefoperazone sodium and sulbactam sodium related substance for injection according to claim 2, wherein the method comprises the following steps: heating mechanism (3) are including inlet tube (31), heat conduction cover (32), heat conduction coil pipe (35), heat conduction fin (33), outlet pipe (34), and the inner wall fixed connection of heat conduction cover (32) and blending tank (12), heat conduction coil pipe (35) are located the inside of heat conduction cover (32), and the fixed surface of one side and heat conduction coil pipe (35) of heat conduction fin (33) is connected, inlet tube (31) and outlet pipe (34) communicate with the both ends of heat conduction coil pipe (35) respectively.

8. The method for determining cefoperazone sodium and sulbactam sodium related substance for injection according to claim 2, wherein the method comprises the following steps: discharge mechanism (4) include discharging pipe (41), connecting pipe (42), filter membrane (43), rubber circle (44), and the top of discharging pipe (41) and the top intercommunication of blending tank (12), the bottom of discharging pipe (41) and the one end threaded connection of connecting pipe (42), rubber circle (44) are provided with two, and filter membrane (43) are located between two rubber circles (44), rubber circle (44) are located the inside of connecting pipe (42).

Technical Field

The invention relates to the technical field of medicine determination, in particular to a method for determining substances related to cefoperazone sodium and sulbactam sodium for injection.

Background

Cefoperazone sodium and sulbactam sodium for injection are a compound preparation of cephalosporin and lactamase inhibitor, wherein the cefoperazone sodium has a beta-lactam structure, and sulbactam is a semi-synthetic beta-lactamase inhibitor and can enhance the antibacterial effect and antibacterial spectrum when being used together with cefoperazone sodium. Can be used for treating respiratory infection, urinary tract infection, peritonitis, cholecystitis, cholangitis and other intra-abdominal infection caused by sensitive bacteria, septicemia, meningitis, skin and soft tissue infection, bone and joint infection, pelvic inflammatory disease and other reproductive system infection.

When the cefoperazone sodium and sulbactam sodium for injection is measured, liquid chromatography is usually adopted, before the cefoperazone sodium and sulbactam sodium enter a chromatographic column, a system applicability solution needs to be prepared from the cefoperazone sodium and sulbactam sodium, at present, the cefoperazone sodium and sulbactam sodium are manually added into a beaker for dissolution, a stirring rod is used for stirring the solution, so that the cefoperazone sodium and sulbactam sodium are fully dissolved, then filtering the particles in the solution by using a filter membrane, finally injecting the system applicability solution into a chromatographic column for measuring related substances, wherein the operation process is complicated, and the cefoperazone sodium and sulbactam sodium has low dissolving efficiency and poor dissolving effect, brings adverse effect to the determination of cefoperazone sodium and sulbactam sodium related substances, and the technical personnel in the field provide a method for determining cefoperazone sodium and sulbactam sodium related substances for injection in order to solve the problems.

Disclosure of Invention

Technical problem to be solved

Aiming at the defects of the prior art, the invention provides a method for determining related substances of cefoperazone sodium and sulbactam sodium for injection, the stirring component is driven by the driving mechanism to rotate in the mixing tank, the first stirring frame and the second stirring frame rotate in the mixing tank in forward and reverse directions, so that the cefoperazone sodium and sulbactam sodium powder can be rapidly dissolved, then the temperature of the solution is increased by the temperature-increasing mechanism, the dissolving efficiency of the cefoperazone sodium and sulbactam sodium powder is further accelerated, and can effectively improve the dissolving effect of the cefoperazone sodium and sulbactam sodium powder, solves the problems that when related substances of the cefoperazone sodium and sulbactam sodium are measured, the cefoperazone sodium and sulbactam sodium are added into the beaker to be dissolved by adopting an artificial mode, the operation process is more complicated, and the dissolution efficiency of the cefoperazone sodium and sulbactam sodium is low, the dissolution effect is poor, and the adverse effect is brought to the determination of related substances of the cefoperazone sodium and sulbactam sodium.

(II) technical scheme

In order to achieve the purpose, the invention is realized by the following technical scheme: a method for determining related substances of cefoperazone sodium and sulbactam sodium for injection specifically comprises the following steps:

firstly, preparing a solution by using solution preparation equipment, putting cefoperazone sodium and sulbactam sodium powder into a mixing tank through a feed hopper, then introducing water into the mixing tank, closing the feed hopper, and starting a driving mechanism and a heating mechanism;

step two, driving an output shaft of a motor to rotate, driving a driving shaft to rotate through the output shaft of the driving motor, driving a driving gear to rotate through the driving shaft, synchronously rotating a driven gear in meshing transmission with the surface of the driving gear, realizing the rotation of a rotating frame in an installation block by utilizing the driven gear, driving a stirring frame II to rotate in a mixing tank through a rotating frame and a connecting rod, simultaneously driving a stirring shaft to rotate in the mixing tank through the driving gear, enabling the stirring frame I and the stirring frame II to rotate in opposite directions in the mixing tank, and fully stirring the solution in the mixing tank by the stirring frame I and the stirring frame II;

step three, introducing hot water into the heat conducting coil pipe through the water inlet pipe, utilizing the heat conducting fins to radiate the heat of the hot water after the hot water enters the heat conducting coil pipe, heating the solution in the mixing tank through the heat conducting sleeve, and matching with the continuous stirring of the stirring assembly, completely dissolving the cefoperazone sodium and sulbactam sodium powder in the solution;

step four, connecting one end of the connecting pipe with a liquid injection port of the chromatograph by using a hose, opening a control valve of the discharge pipe, sending out the solution in the mixing tank through the discharge pipe, filtering undissolved particles in the solution by using a filter membrane in the connecting pipe, and sending the filtered solution into a chromatographic column in the chromatograph;

step five, using octadecylsilane chemically bonded silica as a filler in a chromatographic column, wherein a mobile phase A is a mixed solution of phosphate buffer solution and methanol with a volume ratio of 99:1, a mobile phase B is methanol, a detection wavelength is 220nm, a flow rate is 1.0ml/min, a column temperature is 30 ℃, and a gradient elution program of the chromatographic column is as follows: 0-12min, 100% mobile phase A; 12-20min, 100-86% mobile phase A; 20-40min, 86% mobile phase A; 40-45min, 86-81% mobile phase A; 45-70min, 81% mobile phase A; 70-75min, 81-65% mobile phase A; 75-100min, 65% mobile phase A; 100-100.1min, 65-100% mobile phase A; 100.1-110min, 100% mobile phase A, then taking sulbactam impurity A, 6-aminopenicillanic acid, cefoperazone impurity A, cefoperazone impurity B, cefoperazone impurity C, cefoperazone impurity D, cefoperazone impurity E, cefoperazone impurity F, cefoperazone impurity G, cefoperazone PZ, cefoperazone 7-TMCA, cefoperazone ring-opening compound, cefoperazone oxidation compound, cefoperazone ring-opening lactone, cefoperazone and sulbactam contrast, adding water to dissolve and dilute into mixed solution containing 10 mu G of each impurity, sulbactam and 2mg of cefoperazone in each 1ml, using as system applicability solution, precisely measuring 20 mu l of system applicability solution, injecting into liquid chromatograph, recording chromatogram, and finishing the measurement of related substances of cefoperazone sodium sulbactam.

Preferably, the solution preparation equipment comprises a mixing mechanism, a driving mechanism, a heating mechanism and a discharging mechanism, wherein the driving mechanism is arranged above the mixing mechanism, the heating mechanism is arranged in the mixing mechanism, and the discharging mechanism is arranged at the bottom of the mixing mechanism.

Preferably, the mixing mechanism includes fixing base, blending tank, feeder hopper, hangers, thermoscope and stirring subassembly, and the bottom that the fixing base is located the blending tank is provided with two, two the top of fixing base respectively with the both sides fixed connection of blending tank bottom, the left side at blending tank top and the bottom fixed connection of feeder hopper, and the inside of feeder hopper and the inside intercommunication of blending tank, the right side at blending tank top is connected with the fixed surface of thermoscope, and the bottom of thermoscope runs through the blending tank and extends to the inside of blending tank, the hangers is located the global symmetry of blending tank and is provided with two, and two relative one sides of hangers all are connected with the fixed surface of blending tank, the stirring subassembly is located the inside rotation of blending tank and is connected.

Preferably, the stirring assembly comprises a first stirring frame, a second stirring frame and a stirring shaft, the first stirring frame and the second stirring frame are both located in the mixing tank and are rotatably connected, the top of the first stirring frame is fixedly connected with the bottom end of the stirring shaft, and the inner part of the second stirring frame is rotatably connected with the surface of the stirring shaft.

Preferably, actuating mechanism includes mount, drive shaft, driving motor, transmission assembly, and the bottom of mount and the top fixed connection of blending tank, driving motor's bottom and the top fixed connection of mount, and the drive shaft is located the inside rotation of mount and is connected, the top fixed connection of shaft coupling and drive shaft is passed through to the bottom of driving motor output shaft, and the bottom of drive shaft runs through the blending tank and extends to the inside of blending tank, the top of transmission assembly and the top fixed connection of blending tank inner wall, and the inside of transmission assembly and the one end rotation that the drive shaft extends to the blending tank inside are connected, the bottom of transmission assembly is connected with the top rotation of (mixing) shaft.

Preferably, the transmission assembly comprises an installation block, a driving gear, a driven gear, a rotating shaft, a rotating frame and a connecting rod, the top of the installation block is fixedly connected with the top of the inner wall of the mixing tank, a rotating groove is formed in the bottom of the installation block, the inside of the rotating groove is rotatably connected with the circumferential surface of the rotating frame, the top of the rotating shaft is rotatably connected with the top of the inner wall of the rotating groove, the surface of the rotating shaft is fixedly connected with the inside of the driven gear, the surface of the driving gear is in meshed transmission with the surface of the driven gear, the surface of the driven gear is in meshed transmission with the inner wall of the rotating frame, the bottom of the driving gear is fixedly connected with the top of the stirring shaft, the top of the driving gear is fixedly connected with the bottom of the driving shaft, one end of the connecting rod is fixedly connected with the bottom of the rotating.

Preferably, the heating mechanism includes inlet tube, heat conduction cover, heat conduction coil pipe, heat conduction fin, outlet pipe, and the inner wall fixed connection of heat conduction cover and blending tank, the heat conduction coil pipe is located the inside of heat conduction cover, and one side of heat conduction fin is connected with the fixed surface of heat conduction coil pipe, inlet tube and outlet pipe communicate with the both ends of heat conduction coil pipe respectively.

Preferably, discharge mechanism includes discharging pipe, connecting pipe, filter membrane, rubber circle, and the top of discharging pipe and the top intercommunication of blending tank, the bottom of discharging pipe and the one end threaded connection of connecting pipe, the rubber circle is provided with two, and the filter membrane is located between two rubber circles, the rubber circle is located the inside of connecting pipe.

(III) advantageous effects

The invention provides a method for determining substances related to cefoperazone sodium and sulbactam sodium for injection. Compared with the prior art, the method has the following beneficial effects:

(1) the method comprises the steps of preparing a solution by using solution preparation equipment, driving a stirring frame II to rotate inside a mixing tank through a rotating frame and a connecting rod, driving a stirring shaft to rotate inside the mixing tank through a driving gear, enabling the stirring frame I and the stirring frame II to rotate in opposite directions in the mixing tank, fully stirring the solution inside the mixing tank by the stirring frame I and the stirring frame II, introducing hot water into a heat conducting coil pipe through a water inlet pipe, utilizing heat conducting fins to radiate the heat of the hot water after the hot water enters the heat conducting coil pipe, heating the solution inside the mixing tank through a heat conducting sleeve, and matching with the continuous stirring of a stirring assembly to enable the cefoperazone sodium and sulbactam powder to be completely dissolved in the solution, driving the stirring assembly to rotate in the mixing tank through a driving mechanism, the first stirring frame and the second stirring frame rotate in the mixing tank in the forward and reverse directions, so that the cefoperazone sodium and sulbactam sodium powder can be rapidly dissolved, the temperature of the solution is increased through the heating mechanism, the dissolving efficiency of the cefoperazone sodium and sulbactam sodium powder is further accelerated, and the dissolving effect of the cefoperazone sodium and sulbactam sodium powder can be effectively improved.

(2) According to the method for determining related substances of cefoperazone sodium and sulbactam sodium for injection, octadecylsilane chemically bonded silica is used as a filler in a chromatographic column, a mobile phase A is a phosphate buffer solution-methanol mixed solution with a volume ratio of 99:1, a mobile phase B is methanol, a detection wavelength is 220nm, a flow rate is 1.0ml/min, a column temperature is 30 ℃, and a gradient elution program of the chromatographic column is as follows: 0-12min, 100% mobile phase A; 12-20min, 100-86% mobile phase A; 20-40min, 86% mobile phase A; 40-45min, 86-81% mobile phase A; 45-70min, 81% mobile phase A; 70-75min, 81-65% mobile phase A; 75-100min, 65% mobile phase A; 100-100.1min, 65-100% mobile phase A; 100.1-110min, 100% mobile phase A, then taking sulbactam impurity A, 6-aminopenicillanic acid, cefoperazone impurity A, cefoperazone impurity B, cefoperazone impurity C, cefoperazone impurity D, cefoperazone impurity E, cefoperazone impurity F, cefoperazone impurity G, cefoperazone PZ, cefoperazone 7-TMCA, cefoperazone ring-opening compound, cefoperazone oxidation compound, cefoperazone ring-opening lactone, cefoperazone and sulbactam contrast, adding water to dissolve and dilute to prepare a mixed solution containing 10 mu G of each impurity, sulbactam and 2mg of cefoperazone in each 1ml, using as a system applicability solution, precisely measuring 20 mu l of the system applicability solution, injecting into a liquid chromatograph, recording chromatogram, completing the measurement of related substances of the cefoperazone sodium sulbactam, adopting the method to effectively separate and quantitatively measure 14 impurities in the cefoperazone sodium sulbactam for injection, the system applicability of the chromatogram is good, the product quality can be more effectively controlled, and the safe popularization and application are facilitated.

Drawings

FIG. 1 is a schematic view of the construction of a solution preparing apparatus according to the present invention;

FIG. 2 is a schematic view of the construction of the transmission assembly of the present invention;

FIG. 3 is a bottom view of the mounting block and turret structure of the present invention;

FIG. 4 is a schematic view of the structure of the warming mechanism of the present invention;

fig. 5 is a schematic diagram of the structure of the discharging mechanism of the invention.

In the figure, 1, a mixing mechanism; 11. a fixed seat; 12. a mixing tank; 13. a feed hopper; 14. hanging a lug; 15. a temperature detector; 16. a stirring assembly; 161. a first stirring frame; 162. a second stirring frame; 163. a stirring shaft; 2. a drive mechanism; 21. a fixed mount; 22. a drive shaft; 23. a drive motor; 24. a transmission assembly; 241. mounting blocks; 242. a drive gear; 243. a driven gear; 244. a rotating shaft; 245. a rotating frame; 246. a connecting rod; 247. a rotating groove; 3. a temperature raising mechanism; 31. a water inlet pipe; 32. a heat conducting sleeve; 33. a heat conductive fin; 34. a water outlet pipe; 35. a heat conducting coil; 4. a discharging mechanism; 41. a discharge pipe; 42. a connecting pipe; 43. filtering the membrane; 44. a rubber ring.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Referring to fig. 1-5, the present invention provides a technical solution: a method for determining related substances of cefoperazone sodium and sulbactam sodium for injection specifically comprises the following steps:

firstly, preparing a solution by using solution preparation equipment, putting cefoperazone sodium and sulbactam sodium powder into a mixing tank 12 through a feed hopper 13, then introducing water into the mixing tank 12, closing the feed hopper 13, and starting a driving mechanism 2 and a heating mechanism 3;

step two, the output shaft of the driving motor 23 rotates, the driving shaft 22 is driven to rotate through the output shaft of the driving motor 23, the driving shaft 22 drives the driving gear 242 to rotate, the driven gear 243 in surface meshing transmission with the driving gear 242 rotates synchronously, the driven gear 243 is utilized to realize the rotation of the rotating frame 245 in the mounting block 241, the rotating frame 245 and the connecting rod 246 drive the second stirring frame 162 to rotate in the mixing tank 12, meanwhile, the driving gear 242 drives the stirring shaft 163 to rotate in the mixing tank 12, so that the first stirring frame 161 and the second stirring frame 162 rotate in opposite directions in the mixing tank 12, and the first stirring frame 161 and the second stirring frame 162 fully stir the solution in the mixing tank 12;

step three, hot water is introduced into the heat conducting coil 35 through the water inlet pipe 31, after the hot water enters the heat conducting coil 35, the heat of the hot water is dissipated by utilizing the heat conducting fins 33, the solution in the mixing tank 12 is heated through the heat conducting sleeve 32, and the cefoperazone sodium and sulbactam sodium powder is completely dissolved in the solution by matching with the continuous stirring of the stirring component 16;

step four, connecting one end of a connecting pipe 42 with a liquid injection port of the chromatograph by using a hose, opening a control valve of a discharge pipe 41, sending the solution in the mixing tank 12 out through the discharge pipe 41, filtering undissolved particles in the solution by using a filter membrane 43 in the connecting pipe 42, and sending the filtered solution into a chromatographic column in the chromatograph;

step five, using octadecylsilane chemically bonded silica as a filler in a chromatographic column, wherein a mobile phase A is a mixed solution of phosphate buffer solution and methanol with a volume ratio of 99:1, a mobile phase B is methanol, a detection wavelength is 220nm, a flow rate is 1.0ml/min, a column temperature is 30 ℃, and a gradient elution program of the chromatographic column is as follows: 0-12min, 100% mobile phase A; 12-20min, 100-86% mobile phase A; 20-40min, 86% mobile phase A; 40-45min, 86-81% mobile phase A; 45-70min, 81% mobile phase A; 70-75min, 81-65% mobile phase A; 75-100min, 65% mobile phase A; 100-100.1min, 65-100% mobile phase A; 100.1-110min, 100% mobile phase A, then taking sulbactam impurity A, 6-aminopenicillanic acid, cefoperazone impurity A, cefoperazone impurity B, cefoperazone impurity C, cefoperazone impurity D, cefoperazone impurity E, cefoperazone impurity F, cefoperazone impurity G, cefoperazone PZ, cefoperazone 7-TMCA, cefoperazone ring-opening compound, cefoperazone oxidation compound, cefoperazone ring-opening lactone, cefoperazone and sulbactam contrast, adding water to dissolve and dilute into mixed solution containing 10 mu G of each impurity, sulbactam and 2mg of cefoperazone in each 1ml, using as system applicability solution, precisely measuring 20 mu l of system applicability solution, injecting into liquid chromatograph, recording chromatogram, and finishing the measurement of related substances of cefoperazone sodium sulbactam.

The solution preparation equipment comprises a mixing mechanism 1, a driving mechanism 2, a warming mechanism 3 and a discharging mechanism 4, wherein the driving mechanism 2 is arranged above the mixing mechanism 1, the warming mechanism 3 is arranged in the mixing mechanism 1, and the discharging mechanism 4 is arranged at the bottom of the mixing mechanism 1.

Mixing mechanism 1 includes fixing base 11, blending tank 12, feeder hopper 13, hangers 14, thermoscope 15 and stirring subassembly 16, and fixing base 11 is located the bottom of blending tank 12 and is provided with two, two the top of fixing base 11 respectively with the both sides fixed connection of blending tank 12 bottom, the left side at blending tank 12 top and the bottom fixed connection of feeder hopper 13, and the inside of feeder hopper 13 and the inside intercommunication of blending tank 12, the right side at blending tank 12 top and the fixed surface of thermoscope 15 are connected, and the bottom of thermoscope 15 runs through blending tank 12 and extend to the inside of blending tank 12, the global symmetry that hangers 14 are located blending tank 12 is provided with two, and the relative one side of two hangers 14 all is connected with the fixed surface of blending tank 12, stirring subassembly 16 is located the inside rotation of blending tank 12 and is connected.

The stirring assembly 16 comprises a first stirring frame 161, a second stirring frame 162 and a stirring shaft 163, wherein the first stirring frame 161 and the second stirring frame 162 are both located inside the mixing tank 12 and are connected in a rotating mode, the top of the first stirring frame 161 is fixedly connected with the bottom end of the stirring shaft 163, and the inside of the second stirring frame 162 is connected with the surface of the stirring shaft 163 in a rotating mode.

Actuating mechanism 2 includes mount 21, drive shaft 22, driving motor 23, transmission assembly 24, and the bottom of mount 21 and the top fixed connection of blending tank 12, the bottom of driving motor 23 and the top fixed connection of mount 21, and driving shaft 22 is located the inside rotation of mount 21 and is connected, the top fixed connection of shaft coupling and drive shaft 22 is passed through to the bottom of driving motor 23 output shaft, and the bottom of drive shaft 22 runs through blending tank 12 and extends to the inside of blending tank 12, the top of transmission assembly 24 and the top fixed connection of blending tank 12 inner wall, and the inside of transmission assembly 24 and the one end rotation that driving shaft 22 extended to blending tank 12 inside are connected, the bottom of transmission assembly 24 and the top rotation of (mixing) shaft 163 are connected.

The transmission assembly 24 comprises three mounting blocks 241, three driving gears 242, three driven gears 243, a rotating shaft 244, a rotating frame 245 and a connecting rod 246, the three driven gears 243 are arranged inside the rotating groove 247, the top of the mounting block 241 is fixedly connected with the top of the inner wall of the mixing tank 12, the bottom of the mounting block 241 is provided with the rotating groove 247, the inside of the rotating groove 247 is rotatably connected with the peripheral surface of the rotating frame 245, the top end of the rotating shaft 244 is rotatably connected with the top of the inner wall of the rotating groove 247, the surface of the rotating shaft 244 is fixedly connected with the inside of the driven gear 243, the surface of the driving gear 242 is in meshing transmission with the surface of the driven gear 243, the surface of the driven gear 243 is in meshing transmission with the inner wall of the rotating frame 245, the bottom of the driving gear 242 is fixedly connected with the top end of the stirring shaft 163, the top of the driving gear 242 is fixedly connected with the bottom end of the driving shaft, and the bottom end of the connecting rod 246 is fixedly connected with the top of the second stirring frame 162.

The heating mechanism 3 comprises a water inlet pipe 31, a heat conducting sleeve 32, a heat conducting coil 35, heat conducting fins 33 and a water outlet pipe 34, wherein the water inlet pipe 31 is positioned at the bottom of the mixing tank 12, the water outlet pipe 34 is positioned above the right side of the mixing tank 12, the heat conducting sleeve 32 is fixedly connected with the inner wall of the mixing tank 12, the heat conducting coil 35 is positioned inside the heat conducting sleeve 32, one side of the heat conducting fins 33 is fixedly connected with the surface of the heat conducting coil 35, and the water inlet pipe 31 is communicated with the two ends of the heat conducting coil 35 through the water outlet pipe 34.

The discharging mechanism 4 comprises a discharging pipe 41, a connecting pipe 42, a filter membrane 43 and a rubber ring 44, the top end of the discharging pipe 41 is communicated with the top end of the mixing tank 12, the bottom end of the discharging pipe 41 is in threaded connection with one end of the connecting pipe 42, the rubber ring 44 is provided with two filter membranes 43, the filter membrane 43 is located between the two rubber rings 44, and the rubber ring 44 is located inside the connecting pipe 42.

And those not described in detail in this specification are well within the skill of those in the art.

The working principle of the solution preparation equipment is as follows: when the device is used, cefoperazone sodium and sulbactam sodium powder is put into the mixing tank 12 through the feed hopper 13, then water is introduced into the mixing tank 12, the feed hopper 13 is closed, the driving mechanism 2 and the warming mechanism 3 are started, the output shaft of the driving motor 23 rotates, the driving shaft 22 is driven to rotate through the output shaft of the driving motor 23, the driving shaft 22 drives the driving gear 242 to rotate, the driven gear 243 which is in meshing transmission with the surface of the driving gear 242 synchronously rotates, the driven gear 243 realizes the rotation of the rotating frame 245 in the mounting block 241, the rotating frame 245 and the connecting rod 246 drive the stirring frame II 162 to rotate in the mixing tank 12, meanwhile, the driving gear 242 drives the stirring shaft 163 to rotate in the mixing tank 12, so that the stirring frame I161 and the stirring frame II 162 rotate in opposite directions in the mixing tank 12, and the stirring frame I161 and the stirring frame II 162 fully stir the solution in the mixing tank 12, let in hot water through inlet tube 31 in to heat conduction coil 35, hot water is back in getting into heat conduction coil 35, utilize heat conduction fin 33 to disperse out with hydrothermal heat, heat the inside solution of blending tank 12 through heat conduction cover 32, the continuous stirring of cooperation stirring subassembly 16, make cefoperazone sodium sulbactam sodium powder dissolve completely in solution, use the hose to be connected with the notes liquid mouth of chromatograph the one end of connecting pipe 42, open the control valve of discharging pipe 41, the solution in the blending tank 12 passes through discharging pipe 41 and sends out, utilize filter membrane 43 inside connecting pipe 42 to filter the granule that can not dissolve in the solution, the solution after the filtration is sent into in the inside chromatographic column of chromatograph.

It is noted that, herein, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.