CN115252564A - Preparation method of pemetrexed disodium for injection - Google Patents
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Abstract
The invention provides a preparation method of pemetrexed disodium for injection, which is characterized in that the pemetrexed disodium with target purity is obtained after the obtained pemetrexed disodium is purified, then the pemetrexed disodium with target purity in a prescription amount and mannitol in a prescription amount are weighed and taken out of a box after intermediate links including liquid preparation, stirring, adjustment of the pH value of a liquid medicine, decarburization treatment, filling, half stoppering, freeze drying and full tamponade, so that the pemetrexed disodium for injection meeting the target content is obtained, and the technical problems that the content of the pemetrexed disodium in a final product pemetrexed disodium injection cannot reach the standard due to the fact that the purity of the obtained raw material medicine possibly cannot reach the preset purity, the effect is reduced, and effective treatment cannot be carried out in related technologies are solved.
Description
Technical Field
The application relates to the technical field of medicine preparation, in particular to a preparation method of pemetrexed disodium for injection.
Background
Pemetrexed disodium (Pemetrexed disodium), chemical name: n- [4- [2 (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid disodium salt.
Pemetrexed disodium is a multi-target folic acid antagonist and is used for treating tumors, and the pemetrexed disodium can be used for treating malignant pleural mesothelioma which cannot be operated in combination with cisplatin. The action mechanism of the pemetrexed disodium is presumed to be a spectrum antitumor drug, and preclinical and clinical research results also show that the pemetrexed has certain curative effects on other various solid tumors besides 2 approved indications. Moreover, pemetrexed has synergistic effect in combination with various other anticancer drugs, and can reduce toxicity, which is expected for some patients who suffer from the problem of drug resistance and do not have suitable drugs available.
In the related technology, the preparation of the pemetrexed disodium injection for injection usually directly prepares the obtained raw material medicine, but the purity of the obtained raw material medicine can not reach the preset purity, so that the content of the pemetrexed disodium in the pemetrexed disodium injection which is the final product is not up to the standard, the effect is reduced, and effective treatment can not be carried out.
Therefore, how to ensure the reliability of the product in the process of preparing the pemetrexed disodium injection for injection becomes a problem which needs to be solved by the technical personnel in the field urgently.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of pemetrexed disodium for injection.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
s1: purifying, namely purifying the crude pemetrexed disodium product to obtain pemetrexed disodium with target purity;
s2: mixing, weighing injection water, the purified pemetrexed disodium and mannitol according to the prescription amount, sequentially adding the injection water accounting for 85% of the total amount of a preparation solution and the purified pemetrexed disodium into a preparation solution tank, mixing and stirring until the injection water and the purified pemetrexed disodium are completely dissolved, adding the mannitol, mixing and stirring uniformly, adjusting the pH value of a liquid medicine to 7.0-8.0, and adding the rest injection water until the rest amount of the injection water is mixed uniformly; the mass ratio of pemetrexed disodium to mannitol obtained after purification is 3;
s3: performing activated carbon adsorption, adding medicinal activated carbon, stirring, adsorbing, performing decarburization treatment, and performing intermediate detection;
s4: sterilizing and filling, namely filtering and sterilizing the liquid medicine twice by 0.22 mu m respectively, adjusting the central filling amount according to the content detected by the intermediate, filling the liquid medicine into an injection bottle, and performing half-stoppering to obtain a filled sample;
s5: and (4) freeze-drying, carrying out freeze-drying on the sample obtained after filling, and finally taking out of the box after full-pressure plugging.
Further, the purification step in S1 includes:
s11: dissolving, namely adding the crude pemetrexed disodium into water for injection, and stirring until the crude pemetrexed disodium is completely dissolved;
s12: standing for crystallization, adding an organic solvent, stirring, standing for crystallization;
s13: washing, adding an organic solvent into a filter cake obtained by crystallization for washing;
s14: and (3) drying: drying to obtain pemetrexed disodium;
and in the S1 purification step, drying is carried out after twice according to S12-S13.
Further, the purification step in S1 includes:
s11: dissolving, namely adding the crude pemetrexed disodium into water for injection, and stirring until the crude pemetrexed disodium is completely dissolved;
s12: standing and crystallizing, adding 80-90% ethanol or 75-85% acetonitrile solution, stirring, and standing and crystallizing at 5-15 ℃;
s13: washing and crystallizing to obtain a filter cake, and washing the filter cake by using 80-90% ethanol or 75-85% acetonitrile solution;
s14: and (3) drying: drying to obtain pemetrexed disodium;
and in the S1 purification step, drying is carried out after twice according to S12-S13.
Furthermore, in the step S2, the pH value of the liquid medicine is adjusted to 7.0-8.0 by using 0.08-0.12 mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution.
Further, the volume ratio of the active carbon for the traditional Chinese medicine in the step S3 is 0.20 percent (g/ml) of the total amount of the prepared solution, the stirring and adsorption time is 25-35 min, and the temperature is 10-20 ℃.
Further, after the semi-tamponade in the step S4, the inspection is performed, and the inspection includes a loading inspection, a visible foreign matter inspection and a quality inspection.
Further, the freeze-drying in the step S5 includes pre-freezing, primary drying, and secondary drying.
Furthermore, the prepared pemetrexed disodium for injection has the specification of 0.1g or 0.5g.
Further, the freeze-drying of the pemetrexed disodium for injection when the specification is 0.1g specifically comprises:
s51: pre-freezing, placing the sample on a shelf of a freeze-drying cabinet at-45 ℃, preserving heat for 3 hours when the temperature of the sample reaches-35 ℃, and setting the temperature of the shelf to-2 ℃ after heat preservation is finished;
s52: performing primary drying, vacuumizing the freeze-drying machine case to a pressure below 10pa, heating a shelf to-2 +/-1 ℃, preserving heat until ice crystals disappear, and preserving heat for 3 hours;
s53: secondary drying, adjusting the temperature of the shelf to 20 +/-1 ℃, and preserving heat for 1 hour; and continuously heating the shelf to 40 ℃, starting timing when the temperature of the sample is increased to 35 ℃, keeping the temperature for 5 hours, checking the change condition of the vacuum degree, ending the whole freeze-drying process, fully plugging, and taking out of the box.
Further, the freeze-drying of the pemetrexed disodium for injection when the specification is 0.5g specifically comprises:
s51: pre-freezing, placing the sample on a shelf of a freeze-drying cabinet at-20 +/-1 ℃ for heat preservation for 1 hour, continuously reducing the temperature of the shelf to-45 ℃, and preserving the heat for 8 hours when the temperature of the sample reaches-40 ℃; after the heat preservation is finished, setting the temperature of the shelf at-2 ℃;
s52: performing primary drying, vacuumizing the freeze-drying machine case to a pressure below 10pa, heating the shelf to-2 +/-1 ℃, preserving heat for 15 hours, then heating the shelf to 0 +/-1 ℃, preserving heat until ice crystals disappear, and continuing preserving heat for 4 hours;
s53: secondary drying, adjusting the temperature of the shelf to 20 +/-1 ℃, and preserving heat for 3 hours; and continuously heating the shelf to about 45 ℃, timing when the temperature of the sample is increased to 35 ℃, preserving the heat for 10 hours, checking the change condition of the vacuum degree, ending the whole freeze-drying process, fully pressing the plug, and taking out the product from the box.
The preparation method of pemetrexed disodium for injection has the beneficial effects that:
in the purification step of the pemetrexed disodium, the organic solvent with the same concentration is adopted for repeated crystallization and washing, so that organic impurities in a crude pemetrexed disodium product can be further removed, and the purity of the pemetrexed disodium is improved.
The application discloses injection is adsorbed with active carbon with pemetrexed disodium and is handled, can detach the inorganic impurity in pemetrexed disodium, reduces the influence of impurity to the medicine.
The pemetrexed disodium for injection is unstable at high temperature, so that the steps in the preparation method are performed at normal temperature, and the product deterioration caused by easy oxidation at high temperature is avoided.
Mannitol is used as a medicine auxiliary material, can be used as a dehydrating agent and a hypotensor, can effectively reduce adverse reactions among compound medicines, and can improve the stability of the medicine composition compared with the single use of the pemetrexed disodium serving as an active ingredient, so that the safety of clinical medication is improved, and the industrial production is easy to realize.
The invention provides disodium pemetrexed for injection, which is characterized in that the obtained disodium pemetrexed is purified to obtain disodium pemetrexed with target purity, then the disodium pemetrexed with the target purity in a prescription amount and mannitol in the prescription amount are weighed and discharged from a box after intermediate links including liquid preparation, stirring, pH value adjustment of liquid medicine, decarburization treatment, filling, half stopper adding, freeze drying and full stopper pressing are carried out, so that the disodium pemetrexed for injection meeting the target content is obtained, the technical problems that the content of the pemetrexed in a final product disodium pemetrexed injection does not reach the standard due to the fact that the purity of obtained raw material medicines possibly cannot reach the preset purity, the disodium is reduced in effectiveness and effective treatment cannot be carried out in the related technology are solved, and the disodium pemetrexed for injection with stable content and reliable performance is provided.
Drawings
Fig. 1 is a schematic flow chart of a preparation method of pemetrexed disodium for injection provided in the embodiments of the present application.
Detailed Description
In order to make those skilled in the art better understand the technical solutions of the present application, the technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application, and it is obvious that the described embodiments are only a part of the embodiments of the present application, and not all 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 application.
Example 1
To facilitate understanding, referring to fig. 1, the present application provides an embodiment of a method for preparing pemetrexed disodium for injection, comprising the steps of:
s1: purifying, namely purifying the crude pemetrexed disodium product to obtain pemetrexed disodium with target purity;
s2: mixing, namely weighing injection water, the purified pemetrexed disodium and mannitol according to the prescription amount, sequentially adding the injection water accounting for 85 percent of the total amount of the preparation solution and the purified pemetrexed disodium into a preparation tank, mixing and stirring until the injection water and the purified pemetrexed disodium are completely dissolved, adding the mannitol, mixing and stirring uniformly, adjusting the pH value of the liquid medicine to 7.0-8.0, and adding the rest injection water until the whole amount of the injection water is mixed uniformly; the mass ratio of pemetrexed disodium to mannitol obtained by purification after injection of water in the prescription is 3;
s3: performing activated carbon adsorption, adding medicinal activated carbon, stirring, adsorbing, performing decarburization treatment, and performing intermediate detection;
s4: sterilizing and filling, namely filtering and sterilizing the liquid medicine through two 0.22-micron filter membranes respectively, adjusting the central filling amount according to the content detected by the intermediate, filling the liquid medicine into an injection bottle, and half-plugging to obtain a filled sample;
s5: and (4) freeze drying, namely freeze drying the sample obtained after filling, and finally taking out of the box after full-pressure plugging.
The mannitol is used as a medicine auxiliary material, can be used as a dehydrating agent and a hypotensor, can effectively reduce adverse reactions among compound medicines, and can improve the stability of the medicine composition compared with the single use of the pemetrexed disodium serving as an active ingredient, so that the safety of clinical medication is improved, and the industrial production is easy to realize.
According to the preparation method of the pemetrexed disodium for injection, the pemetrexed disodium with the target purity is obtained after the obtained pemetrexed disodium is purified, the pemetrexed disodium with the target purity in the prescription amount and mannitol in the prescription amount are weighed and taken out of a box after intermediate links including liquid preparation, stirring, pH value adjustment, decarburization treatment, filling, half stoppering, freeze drying and full-pressure stoppering are carried out, so that the pemetrexed disodium with the target content is obtained, the technical problems that the content of pemetrexed disodium in a final product pemetrexed disodium injection cannot reach the standard due to the fact that the purity of obtained raw material medicines possibly cannot reach the preset purity, the effectiveness of the pemetrexed disodium is reduced, effective treatment cannot be carried out in the related technology are solved, and the pemetrexed disodium for injection with the stable content and the reliable performance is provided.
Example 2
As a further improvement to example 1, the purification step in S1 specifically includes:
s11: dissolving, namely adding the crude pemetrexed disodium into water for injection, and stirring until the pemetrexed disodium is completely dissolved, wherein the adding amount of the water for injection is 7 times that of the crude pemetrexed disodium;
s12: standing for crystallization, adding 85% ethanol solution, stirring, standing at 10 deg.C for 1 hr for crystallization;
s13: washing, and washing a filter cake obtained by crystallization by using an ethanol solution with the concentration of 85%;
s14: and (3) drying: vacuumizing and vacuum drying to obtain pemetrexed disodium;
wherein, the purification is carried out twice according to the sequence of S12 to S13 and then is carried out drying.
It should be noted that, the crude pemetrexed disodium contains organic impurities, ethanol used in this embodiment may be miscible with water in any proportion, and pemetrexed disodium is insoluble in ethanol, so that ethanol can dissolve various impurities in the crude pemetrexed disodium to separate out impurities, and meanwhile, pemetrexed disodium is unstable and easily oxidized at high temperature, so that during purification, it is kept standing at 5-15 ℃ to crystallize, wherein the effect of standing at 10 ℃ is optimal, and it is washed with a solvent with the same concentration to remove organic impurities therein.
Example 3
The same purification procedure as in example 2, except that the reaction mixture of S12: standing for crystallization, adding 90% ethanol solution, stirring, and standing for crystallization at 5 deg.C;
s13: washing, and washing a filter cake obtained by crystallization by using an ethanol solution with the concentration of 80%;
example 4
The same purification procedure as in example 2, except that the reaction mixture of S12: standing for crystallization, adding 80% ethanol solution, stirring, and standing for crystallization at 10 deg.C;
s13: washing, and washing a filter cake obtained by crystallization by using an ethanol solution with the concentration of 90%;
example 5
The same purification procedure as in example 2, except that S12: standing for crystallization, adding an acetonitrile solution with the concentration of 80%, stirring, and standing for crystallization at 15 ℃;
s13: washing, and washing a filter cake obtained by crystallization by using an acetonitrile solution with the concentration of 80%;
example 6
The same purification procedure as in example 2, except that the reaction mixture of S12: standing for crystallization, adding an acetonitrile solution with the concentration of 85%, stirring, and standing for crystallization at the temperature of 10 ℃;
s13: washing, and washing a filter cake obtained by crystallization by using an acetonitrile solution with the concentration of 75%;
comparative example 1
The same purification procedure as in example 2, but only one standing crystallization and washing.
Comparative example 2
The same purification procedure as in example 2, wherein S12 is: standing for crystallization, adding 60% ethanol solution, stirring, standing at 10 deg.C for 2 hr for crystallization;
s13: washing, and washing a filter cake obtained by crystallization by using an ethanol solution with the concentration of 60%;
comparative example 3
The same purification procedure as in example 2, wherein S12 is: standing for crystallization, adding 65% acetonitrile solution, stirring, standing at 10 deg.C for 2 hr for crystallization;
s13: washing, and washing a filter cake obtained by crystallization by using an acetonitrile solution with the concentration of 65%;
comparative example 4
The same purification procedure as in example 2 was carried out, wherein the temperature at the time of standing for crystallization in S12 was 30 ℃ and the standing time was 2 hours.
Taking a proper amount of pemetrexed disodium obtained by purification in examples 2-6 and comparative examples 1-4, and carrying out purity and impurity inspection, wherein the specific detection method refers to appendix VD (high performance liquid chromatography) in the second part of Chinese pharmacopoeia 2005 edition and related substances in pemetrexed disodium drug substance measured by high performance liquid chromatography (congratulatory essay, liujun, liujie, 9/22/34/9 th of 2015 of analytical laboratory 2015), and the measurement results are as shown in the following table 1:
TABLE 1 summary of the measurement results
The results in table 1 show that the crude pemetrexed disodium product is subjected to standing crystallization at low temperature by 85% ethanol or 80% acetonitrile solution, and is washed by 85% ethanol or 80% acetonitrile solution, and the dried pemetrexed disodium product has high purity, and can effectively remove organic impurities therein and improve the medicinal performance.
Example 7
The embodiment provides a preparation method of pemetrexed disodium for injection with a prescription specification of 0.1g, which comprises the following steps:
s1: taking pemetrexed disodium obtained by purification in example 2;
s2: mixing, weighing 3000ml of injection water, 100g of purified pemetrexed disodium and 100g of mannitol according to the amount of a prescription, sequentially adding 85% of the injection water and the purified pemetrexed disodium into a preparation tank, mixing and stirring until the injection water and the purified pemetrexed disodium are completely dissolved, adding the mannitol, uniformly mixing and stirring until the solution is clear, adjusting the pH value of the liquid medicine to 7.5 by using 0.1mol/L hydrochloric acid solution, adding the rest injection water until the whole amount is uniformly mixed;
s3: performing activated carbon adsorption, adding 0.20% (g/ml) of medicinal activated carbon in the total amount of the solution, stirring for adsorption, performing decarburization treatment, stirring for adsorption for 30min at 15 deg.C, and performing intermediate detection;
s4: sterilizing and filling, namely sterilizing and filtering the liquid medicine by 0.22 mu m, then transferring the liquid medicine to a filling machine under a hundred-level laminar flow hood, sterilizing and filtering the liquid medicine to a liquid medicine barrel by a 0.22 mu m secondary terminal, adjusting the central filling amount according to the content detected by the intermediate, filling the liquid medicine into an injection bottle, half plugging, and checking the filling amount once every 30 minutes, the visible foreign matters and the quality of the half-pressed plug;
the loading control range is as follows: and +/-3%, and if the canning time is less than 30 minutes, respectively checking the semi-tamponade quality condition once before, during and after the canning.
S5: freeze drying, wherein the samples obtained after filling are sequentially pre-frozen, primarily dried and secondarily dried, and finally taken out of the box after full-pressure plugging;
s51: pre-freezing, cooling the shelf to-45 deg.C 1.5 hr after the product is put into the freeze-drying cabinet, maintaining the temperature for 3 hr when the sample temperature reaches-35 deg.C, and setting the shelf temperature to-2 deg.C after the temperature is maintained.
S52: drying for the first time, cooling the condenser to below-50 deg.C, opening the trap valve, vacuumizing to below 10pa, heating the shelf to-2 + -1 deg.C, maintaining the temperature until the ice crystals disappear, and maintaining the temperature for 3 hr.
S53: secondary drying, namely rapidly increasing the temperature of the shelf to 20 +/-1 ℃ for 1 hour, and preserving the temperature for 1 hour; the shelf is continuously heated to about 40 ℃, and when the temperature of the sample is raised to 35 ℃, the temperature is kept for about 5 hours. Checking the vacuum degree change condition, ending the whole freeze-drying process, fully pressing the plug, and discharging from the box.
Example 8
The procedure of this example is substantially the same as that of example 7, except that:
step S1 is to take the pemetrexed disodium obtained after the purification of the embodiment 3;
in the step S2, 0.1mol/L sodium hydroxide solution is used for adjusting the pH value of the liquid medicine to 7.5;
in the step S3, the adsorption time of the activated carbon is 25min, and the temperature is 20 ℃.
Example 9
The procedure of this example is substantially the same as that of example 7, except that:
step S1 is to take the pemetrexed disodium obtained after the purification of the embodiment 3;
in the step S2, the pH value is adjusted to 8.0 by using 0.08mol/L dilute hydrochloric acid solution;
in the step S3, the adsorption time of the activated carbon is 35min, and the temperature is 10 ℃.
Example 10
The procedure of this example is substantially the same as that of example 7, except that:
step S1 is to take the pemetrexed disodium obtained after the purification of the embodiment 4;
in the step S2, 0.12mol/L sodium hydroxide solution is used for adjusting the pH value to 7.0;
in the step S3, the adsorption time of the activated carbon is 30min, and the temperature is 18 ℃.
Example 11
The embodiment provides a preparation method of pemetrexed disodium for injection with a prescription specification of 0.5g, which comprises the following steps:
s1: taking pemetrexed disodium obtained by purification in example 2;
s2: mixing, weighing 15000ml of injection water, 500g of purified pemetrexed disodium and 500g of mannitol according to the amount of a prescription, sequentially adding 85% of the injection water and the purified pemetrexed disodium into a preparation tank, mixing and stirring until the injection water and the purified pemetrexed disodium are completely dissolved, adding the mannitol, uniformly mixing and stirring until the solution is clear, adjusting the pH value of the liquid medicine to 7.5 by using 0.1mol/L hydrochloric acid solution, adding the rest injection water until the whole amount is uniformly mixed;
s3: performing activated carbon adsorption, adding 0.20% (g/ml) of medicinal activated carbon in the total amount of the prepared solution, stirring and adsorbing, performing decarburization treatment, wherein the stirring and adsorbing time is 30min, the temperature is 15 ℃, and performing intermediate detection;
s4: sterilizing and filling, namely sterilizing and filtering the liquid medicine by 0.22 mu m, then transferring the liquid medicine to a filling machine under a hundred-level laminar flow hood, sterilizing and filtering the liquid medicine to a liquid medicine barrel by a 0.22 mu m secondary terminal, adjusting the central filling amount according to the content detected by the intermediate, filling the liquid medicine into an injection bottle, half plugging, and checking the filling amount once every 30 minutes, the visible foreign matters and the quality of the half-pressed plug;
the loading control range is as follows: +/-3%, and if the canning time is less than 30 minutes, respectively checking the quality condition of the half-tamponade once before, during and after the canning;
s5: freeze drying, wherein the sample obtained after filling is sequentially subjected to pre-freezing, primary drying and secondary drying, and finally is taken out of the box after full-pressure plugging;
s51: reducing the temperature of the shelf to minus 20 +/-1 ℃ 1 hour after the product is put into the box, and preserving the heat for 1 hour; continuously reducing the temperature of the shelf to about minus 45 ℃, and preserving the heat for 8 hours when the temperature of the sample reaches minus 40 ℃; after the heat preservation is finished, setting the temperature of the shelf at-2 ℃;
s52: reducing the temperature of the condenser to below 50 ℃ below zero, opening a trap valve of the tank, vacuumizing to below 10pa, heating a shelf to 2 ℃ below zero plus or minus 1 ℃, preserving heat for 15 hours, then increasing the temperature of the shelf to 0 ℃ below zero plus or minus 1 ℃, preserving heat until ice crystals disappear, and then continuing preserving heat for 4 hours;
s53: quickly raising the temperature of the shelf to 20 +/-1 ℃ for 1.5 hours, and preserving the heat for 3 hours; the shelf is continuously heated to about 45 ℃, and when the temperature of the sample is raised to 35 ℃, the temperature is kept for about 10 hours. Checking the vacuum degree change condition, ending the whole freeze-drying process, fully pressing the plug, and discharging from the box.
Comparative example 5
The procedure of this example is substantially the same as that of example 7, except that:
step S1, the pemetrexed disodium obtained by purification in comparative example 1 is taken;
in the step S2, the pH value is adjusted to 6.0 by using 0.15mol/L dilute hydrochloric acid solution;
in the step S3, the adsorption time of the activated carbon is 45min, and the temperature is 25 ℃.
Comparative example 6
The procedure of this example is substantially the same as example 7, except that:
step S1, the pemetrexed disodium obtained by purification in the comparative example 2 is taken;
in the step S2, 0.15mol/L sodium hydroxide solution is used for adjusting the pH value to 9.0;
in the step S3, the adsorption time of the activated carbon is 20min, and the temperature is 5 ℃.
And (3) stability test:
according to the requirements of the existing edition of Chinese pharmacopoeia and appendix on drug stability investigation, the samples obtained in examples 7-10 and comparative examples 5-6 are respectively placed under the accelerated condition for 6 months to carry out stable investigation and evaluate the change of the content of pemetrexed disodium and the change of the content of impurities, and the investigation results are as follows 2:
table 2 survey results list
The test results show that the pemetrexed disodium for injection prepared by the preparation method provided by the invention has good stability, and the content of the pemetrexed disodium and the total impurity content of the pemetrexed disodium are slightly changed compared with the initial content after the pemetrexed disodium is placed for 6 months. After the pemetrexed disodium for injection in the comparative example is placed for 6 months, the total impurity content is obviously increased, and the stability is poor.
The above embodiments are only used for illustrating the technical solutions of the present application, and not for limiting the same; although the present application has been described in detail with reference to the foregoing embodiments, it should be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present application.
Claims (10)
1. A preparation method of pemetrexed disodium for injection is characterized by comprising the following steps:
s1: purifying, namely purifying the crude pemetrexed disodium product to obtain pemetrexed disodium with target purity;
s2: mixing, namely weighing injection water, the purified pemetrexed disodium and mannitol according to the prescription amount, sequentially adding the injection water accounting for 85 percent of the total amount of the preparation solution and the purified pemetrexed disodium into a preparation tank, mixing and stirring until the injection water and the purified pemetrexed disodium are completely dissolved, adding the mannitol, mixing and stirring uniformly, adjusting the pH value of the liquid medicine to 7.0-8.0, and adding the rest injection water until the whole amount of the injection water is mixed uniformly; the mass ratio of pemetrexed disodium to mannitol obtained after purification is 3;
s3: performing activated carbon adsorption, adding medicinal activated carbon, stirring, adsorbing, performing decarburization treatment, and performing intermediate detection;
s4: sterilizing and filling, namely filtering and sterilizing the liquid medicine twice by 0.22 mu m respectively, adjusting the central filling amount according to the content detected by the intermediate, filling the liquid medicine into an injection bottle, and performing half-stoppering to obtain a filled sample;
s5: and (4) freeze drying, namely freeze drying the sample obtained after filling, and finally taking out of the box after full-pressure plugging.
2. The method for preparing pemetrexed disodium for injection according to claim 1, wherein the purification step in S1 comprises:
s11: dissolving, namely adding the crude pemetrexed disodium into water for injection, and stirring until the crude pemetrexed disodium is completely dissolved;
s12: standing for crystallization, adding an organic solvent, stirring, standing for crystallization;
s13: washing, adding an organic solvent into a filter cake obtained by crystallization for washing;
s14: and (3) drying: drying to obtain pemetrexed disodium;
and in the S1 purification step, drying is carried out after twice according to S12-S13.
3. The method of claim 1, wherein the purification step in S1 comprises:
s11: dissolving, namely adding the crude pemetrexed disodium into water for injection, and stirring until the crude pemetrexed disodium is completely dissolved;
s12: standing and crystallizing, adding 80-90% ethanol or 75-85% acetonitrile solution, stirring, and standing and crystallizing at 5-15 ℃;
s13: washing and crystallizing to obtain a filter cake, and washing the filter cake by using 80-90% ethanol or 75-85% acetonitrile solution;
s14: and (3) drying: drying to obtain pemetrexed disodium;
and in the S1 purification step, drying is carried out after twice according to S12-S13.
4. The method for preparing pemetrexed disodium for injection according to claim 1, wherein the pH of the liquid medicine is adjusted to 7.0-8.0 in step S2 by using 0.08-0.12 mol/L diluted hydrochloric acid solution or 0.08-0.12 mol/L sodium hydroxide solution.
5. The method for preparing pemetrexed disodium for injection according to claim 1, wherein the volume ratio of the activated carbon for traditional Chinese medicine in step S3 is 0.20% (g/ml) of the total amount of the preparation, the stirring and adsorption time is 25-35 min, and the temperature is 10-20 ℃.
6. The method for preparing pemetrexed disodium for injection according to claim 1, wherein the checking is performed after the half-tamponade in step S4, and the checking includes a charge amount check, a visible foreign matter check and a quality check.
7. The method for preparing pemetrexed disodium for injection according to claim 1, wherein the lyophilization in step S5 includes pre-freezing, primary drying, and secondary drying.
8. The method for preparing pemetrexed disodium for injection according to any one of claims 1 to 7, wherein the prepared pemetrexed disodium for injection has a specification of 0.1g or 0.5g.
9. The method for preparing pemetrexed disodium for injection according to claim 8, wherein the freeze-drying when the pemetrexed disodium for injection is 0.1g specifically comprises:
s51: pre-freezing, placing the sample on a shelf of a freeze-drying cabinet at-45 ℃, preserving heat for 3 hours when the temperature of the sample reaches-35 ℃, and setting the temperature of the shelf to-2 ℃ after heat preservation is finished;
s52: performing primary drying, vacuumizing the freeze-drying machine case to a pressure below 10pa, heating a shelf to-2 +/-1 ℃, preserving heat until ice crystals disappear, and preserving heat for 3 hours;
s53: secondary drying, adjusting the temperature of the shelf to 20 +/-1 ℃, and preserving heat for 1 hour; and continuously heating the shelf to 40 ℃, timing when the temperature of the sample is increased to 35 ℃, keeping the temperature for 5 hours, checking the change condition of the vacuum degree, ending the whole freeze-drying process, fully plugging, and taking out of the box.
10. The method for preparing pemetrexed disodium for injection according to claim 8, wherein the freeze-drying when the pemetrexed disodium for injection is 0.5g specifically comprises:
s51: pre-freezing, placing the sample on a shelf of a freeze-drying cabinet at-20 +/-1 ℃ for heat preservation for 1 hour, continuously reducing the temperature of the shelf to-45 ℃, and preserving the heat for 8 hours when the temperature of the sample reaches-40 ℃; after the heat preservation is finished, setting the temperature of the shelf at-2 ℃;
s52: performing primary drying, vacuumizing the freeze-drying machine case to a pressure below 10pa, heating the shelf to-2 +/-1 ℃, preserving heat for 15 hours, then heating the shelf to 0 +/-1 ℃, preserving heat until ice crystals disappear, and continuing preserving heat for 4 hours;
s53: secondary drying, adjusting the temperature of the shelf to 20 +/-1 ℃, and preserving heat for 3 hours; and continuously heating the shelf to about 45 ℃, starting to time when the temperature of the sample rises to 35 ℃, preserving the heat for 10 hours, checking the change condition of the vacuum degree, ending the whole freeze-drying process, fully pressing the plug, and taking out the box.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1778802A (en) * | 2004-11-25 | 2006-05-31 | 重庆医药工业研究院有限责任公司 | Crystal form of Peimeiqusai disodium and its preparation |
| CN102086204A (en) * | 2010-12-27 | 2011-06-08 | 江苏奥赛康药业有限公司 | Industrialized production method of high-purity pemetrexed disodium |
| CN102106833A (en) * | 2011-02-12 | 2011-06-29 | 海南锦瑞制药股份有限公司 | Pemetrexed disodium freeze-dried powder injection and preparation method thereof |
| CN102206218A (en) * | 2011-03-24 | 2011-10-05 | 石药集团中奇制药技术（石家庄）有限公司 | Method for purifying high-purity pemetrexed disodium |
| CN111333658A (en) * | 2020-05-06 | 2020-06-26 | 贵州联科中贝制药科技有限公司 | Preparation method of pemetrexed disodium hydrate |
-
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- 2022-08-30 CN CN202211044343.9A patent/CN115252564A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1778802A (en) * | 2004-11-25 | 2006-05-31 | 重庆医药工业研究院有限责任公司 | Crystal form of Peimeiqusai disodium and its preparation |
| CN102086204A (en) * | 2010-12-27 | 2011-06-08 | 江苏奥赛康药业有限公司 | Industrialized production method of high-purity pemetrexed disodium |
| CN102106833A (en) * | 2011-02-12 | 2011-06-29 | 海南锦瑞制药股份有限公司 | Pemetrexed disodium freeze-dried powder injection and preparation method thereof |
| CN102206218A (en) * | 2011-03-24 | 2011-10-05 | 石药集团中奇制药技术（石家庄）有限公司 | Method for purifying high-purity pemetrexed disodium |
| CN111333658A (en) * | 2020-05-06 | 2020-06-26 | 贵州联科中贝制药科技有限公司 | Preparation method of pemetrexed disodium hydrate |
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