CN108469151B - Freeze-drying process for commercial production of disodium levoornidazole phosphate for injection - Google Patents
Freeze-drying process for commercial production of disodium levoornidazole phosphate for injection Download PDFInfo
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- CN108469151B CN108469151B CN201810138711.3A CN201810138711A CN108469151B CN 108469151 B CN108469151 B CN 108469151B CN 201810138711 A CN201810138711 A CN 201810138711A CN 108469151 B CN108469151 B CN 108469151B
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B5/00—Drying solid materials or objects by processes not involving the application of heat
- F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
- F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
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- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
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Abstract
The invention belongs to the technical field of chemical preparations, and particularly relates to a freeze-drying process for commercial production of disodium levoornidazole phosphate for injection. According to the technical scheme, the annealing process is added in the liquid medicine pre-freezing process, solute migration of a product in the freeze-drying process can be obviously improved, and the primary drying rate is obviously improved. The sample prepared by the freeze-drying process has complete appearance, is loose and does not shrink, and has small water difference; and after the annealing process is added, the production time is not prolonged compared with the prior art, and the production energy consumption is not increased.
Description
Technical Field
The invention belongs to the technical field of chemical preparations, and particularly relates to a freeze-drying process for commercial production of disodium levoornidazole phosphate for injection.
Technical Field
Ornidazole is a common anti-anaerobic bacteria medicament at present, is used as a third-generation anti-anaerobic bacteria infection medicament after metronidazole and tinidazole, has a better effect clinically due to definite curative effect and small side effect, and is widely accepted. Recent studies have shown that l-ornidazole is superior to ornidazole in terms of its medicinal effect and adverse reaction as its l-isomer.
However, both ornidazole and l-ornidazole have low solubility and the solution is stable only in acidic environment. Therefore, when the ornidazole/levoornidazole is required to be prepared into an injection preparation, the pH value is selected to be adjusted to be below 4 so as to meet the preparation requirement.
Chinese patent (CN 200510068419) describes an intravenous preparation of l-ornidazole and its preparation method, and the described intravenous injection preparation has a pH value of 4.0. In general, injection solutions with lower pH values are more irritating to blood vessels, easily cause discomfort to patients during use, and may cause phlebitis more seriously.
Therefore, clinically, an ornidazole preparation for intravenous administration is needed, the solvent of the ornidazole preparation is water, and the pH value of the ornidazole preparation is close to the environment of a human body so as to improve the compliance of a patient.
The disodium levoornidazole phosphate is the sodium salt of a levorotatory isomer phosphate derivative of ornidazole, and pharmacokinetic research shows that the disodium levoornidazole phosphate can be rapidly decomposed into the levoornidazole in vivo, and the levoornidazole is used as an effective component to play a role in resisting anaerobes and microorganisms. Compared with ornidazole/L-ornidazole, the disodium levoornidazole phosphate has good water solubility, the pH value of the injection preparation can be closer to the physiological condition of a human body, the vascular irritation is less, and the compliance of a patient is better in the using process. Meanwhile, the disodium levoornidazole phosphate is relatively sensitive to temperature and moisture and is not suitable for long-term storage and transportation, so that a disodium levoornidazole phosphate preparation which has a pH value close to the physiological environment of a human body and is easy to store and transport needs to be developed for clinical use.
Chinese patent (CN 200810020928) describes a method for preparing a levoornidazole disodium phosphate intravenous preparation, wherein the described intravenous preparation is a freeze-dried preparation, and discloses a freeze-drying process
Chinese patent (CN 201510741404) describes a freeze-dried preparation of disodium levoornidazole phosphate and a preparation method thereof, and discloses a freeze-drying process.
In the process of further research, we have found that when the pH of the solution is adjusted to be closer to the environment in the human body (e.g. about pH5.0 to pH 5.5), the glass transition temperature and the disintegration temperature of the product are both lower, and if commercial batches (20L to 200L) are produced using the prior art, we have found that the following problems are easily caused during the lyophilization process:
(1) In commercial batch production, the product needs about 2 hours to be cooled to-40 ℃ (the glass transition temperature of the disodium levoornidazole phosphate), while when the product is frozen, a certain temperature difference exists between the internal temperature (the temperature of the upper part is higher than that of the lower part, and the temperature of the center is higher than that of the edge), and solute migration is easily generated in the 2-hour product cooling process;
(2) The crystallization process of the product during cooling is random, and the initial freezing temperature and time of the product at different positions on the same layer plate are greatly different, so that the internal structure of the frozen product is greatly different, and the final moisture and uniformity of the product are influenced;
(3) After the pre-freezing is carried out by using the prior art, the collapse temperature of the product is about-29 ℃ (as shown in the attached figure 1 of the specification), the product is easy to collapse in the drying process, and a moisture sublimation channel is blocked, so that the product is locally fused, and the final moisture and the shape of the product are influenced.
Due to the phenomena of solute migration, great increase of primary drying time, high residual moisture of products, great moisture difference and the like, the energy consumption and the controllability in the production process are high, and the appearance and the stability of the products are affected to different degrees. Therefore, a stable and efficient freeze-drying process of the disodium levoornidazole phosphate for injection is needed in production.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a freeze-drying process for commercial production of disodium levoornidazole phosphate for injection, aiming at improving the solute migration of a product in the freeze-drying process and increasing the primary drying rate by introducing annealing operation into the existing freeze-drying process so as to obtain the qualified disodium levoornidazole phosphate for freeze-drying injection.
The freeze-drying process for commercial production of the injection levoornidazole disodium phosphate is implemented according to the following steps:
a. setting the temperature of a plate layer of a freeze dryer to be-10-5 ℃;
b. b, subpackaging the liquid medicine into penicillin bottles, placing the penicillin bottles into a freeze dryer, and keeping the temperature for 0.5 to 2 hours at the temperature set in the step a;
c. reducing the temperature of the plate layer to-35 to-50 ℃, and preserving the heat for 1 to 3 hours;
d. raising the temperature of the plate layer to-30 to-20 ℃, and preserving the heat for 2 to 4 hours;
e. reducing the temperature of the plate layer to-40 to-50 ℃, and preserving the heat for 2 to 4 hours;
f. starting vacuum control, and keeping the vacuum degree at 0.1-0.2 mbar;
g. raising the temperature of the plate layer to-25 to-10 ℃, and keeping the temperature for 10 to 16 hours;
h. raising the temperature of the plate layer to 0-5 ℃, and keeping for 2-6 hours;
i. raising the temperature of the plate layer to 20-25 ℃, and keeping the temperature for 8-12 hours;
j. and (3) filling nitrogen into the box body, controlling the pressure in the box to be 800-900 mbar, breaking the vacuum by a plug, and discharging the box body after the vacuum is reduced to normal pressure.
Another preferred technical scheme of the invention is as follows:
a. the temperature of the plate layer of the freeze dryer is set to be-10 to 0 ℃,
b. subpackaging the liquid medicine into penicillin bottles, placing the penicillin bottles into a freeze dryer, and preserving the heat for 0.5 to 1 hour at the temperature set in the step a;
c. reducing the temperature of the plate layer to-45 to-50 ℃, and preserving the heat for 1 to 2 hours;
d. raising the temperature of the plate layer to-30 to-20 ℃, and preserving the heat for 2 to 4 hours;
e. reducing the temperature of the plate layer to-45 to-50 ℃, and preserving the heat for 2 to 4 hours;
f. starting vacuum control, and keeping the vacuum degree at 0.1-0.2 mbar;
g. raising the temperature of the plate layer to-25 to-15 ℃, and keeping the temperature for 10 to 14 hours;
h. raising the temperature of the plate layer to 0 ℃, and keeping the temperature for 2-4 hours;
i. raising the temperature of the plate layer to 25 ℃, and keeping the temperature for 8-12 hours;
j. and (3) filling nitrogen into the box body, controlling the pressure in the box to be 800-900 mbar, breaking the vacuum by a pressure plug until the pressure is normal, and discharging the box.
Wherein the volume of the liquid medicine in the step b is 20-200L.
The pH value of the liquid medicine in the step b is within the range of 5.0-5.5, and preferably within the range of 5.2-5.5.
And c, cooling operation in the steps e, wherein the cooling rate is 40-50 ℃/h.
And g, performing the temperature rise operation for 1 to 2 hours.
And (h) performing the temperature rise operation, wherein the temperature rise time is 4-6 hours.
The holding time in step i is specifically:
(1) Keeping the vacuum degree at 0.1-0.2 mbar, raising the temperature of the plate layer to 25 ℃, and keeping for 2-4 hours; (2) Keeping the temperature of the plate layer at 25 ℃, adjusting the vacuum degree to 0.02-0.03 mbar, and keeping for 6-8 hours.
Compared with the prior art, the invention has the characteristics and beneficial effects that:
aiming at the problems of the existing freeze-drying process, the research is carried out on the pre-freezing process, and the result shows that the collapse temperature of the product can be improved to a certain extent by adopting an annealing process in the pre-freezing process. Annealing at-30 deg.C to obtain a collapse temperature of about-22 deg.C (as shown in figure 2 of the attached figure), which is increased by about 7 deg.C compared with that of non-annealed; annealing at-20 deg.C to raise collapse temperature by-19 deg.C (as shown in figure 3 of the specification) than un-annealing by 10 deg.C. Therefore, the mechanical strength of the product of the disodium levoornidazole phosphate is obviously improved by annealing.
Meanwhile, the annealing process can strengthen crystallization, change the form and size distribution of ice crystals and eliminate solute migration generated in the freezing process. During the production process, we find that the moisture difference of the unannealed product is large, and the RSD value is usually higher than 10; while the moisture difference of the products by annealing is small, the RSD value is generally less than 3. The annealing process significantly improves the uniformity of the product.
In conclusion, the annealing process is added in the pre-freezing process, so that the solute migration of the product in the freeze-drying process can be obviously improved, and the primary drying rate is obviously improved.
The sample prepared by the freeze-drying process has complete appearance, looseness, no atrophy and small water difference; and after the annealing process is added, the production time is not prolonged compared with the prior art, and the production energy consumption is not increased.
Drawings
FIG. 1 is a graph of product collapse at-29 ℃ after prefreezing using prior art techniques;
FIG. 2 is a graph of collapse of a-22 ℃ product annealed at-30 ℃;
FIG. 3 is a graph of collapse of a-19 ℃ product annealed at-20 ℃;
FIG. 4 is an external view of a product of example 1 of the present invention;
FIG. 5 is an external view of the product of comparative example 2.
Detailed Description
Example 1
The freeze-drying process for commercial production of the disodium levoornidazole phosphate for injection in the embodiment is carried out according to the following steps:
(1) Preparing 20L of a left ornidazole disodium phosphate liquid medicine, and adjusting the pH value to be 5.2-5.5;
(2) Adjusting the temperature of a plate layer of a freeze dryer to-10 ℃;
(3) Filtering the liquid medicine through a filter element with the diameter of 0.22 mu m, filling the liquid medicine into a penicillin bottle, filling the liquid medicine into a freeze dryer after half plugging;
(4) Keeping the sample at-10 ℃ for 1h, adjusting the temperature of the plate layer, cooling to-50 ℃, keeping the temperature for 1h, wherein the cooling rate is 40-50 ℃/h;
(5) Adjusting the temperature of the plate layer, heating to-30 ℃ within 0.5h, and keeping for 3h;
(6) Adjusting the temperature of the plate layer, cooling to-50 ℃, keeping the temperature for 3 hours at the cooling rate of 40-50 ℃/hour;
(7) Adjusting the temperature of the plate layer, heating to-20 ℃ for 1 hour, keeping for 12 hours and keeping the vacuum degree of 0.1-0.2 mbar;
(8) Adjusting the temperature of the plate layer, heating to 0 ℃ for 6 hours, keeping for 2 hours and keeping the vacuum degree of 0.1-0.2 mbar;
(9) Adjusting the temperature of the plate layer, raising the temperature to 25 ℃ within 1 hour, keeping the temperature for 2 hours and keeping the vacuum degree to be 0.1-0.2 mbar; adjusting the vacuum degree to 0.02-0.03 mbar and keeping the vacuum degree for 8 hours.
(10) And (3) filling nitrogen into the box body, controlling the pressure in the box to be 800-900 mbar, breaking vacuum by a plug until the pressure is normal pressure, taking the box out, and rolling a cover to obtain a sample.
Example 2
The freeze-drying process for commercial production of the disodium levoornidazole phosphate for injection in the embodiment is carried out according to the following steps:
(1) Preparing 20L of liquid medicine, and adjusting the pH value to be between 5.0 and 5.1;
(2) Adjusting the temperature of a plate layer of a freeze dryer to 0 ℃;
(3) Filtering the liquid medicine through a filter element with the diameter of 0.22 mu m, filling the liquid medicine into a penicillin bottle, filling the liquid medicine into a freeze dryer after half plugging;
(4) After the sample is kept at 0 ℃ for 0.5h, adjusting the temperature of the plate layer, cooling to-45 ℃, wherein the cooling rate is 40-50 ℃/h, and keeping for 2h;
(5) Adjusting the temperature of the plate layer, heating to-25 ℃ within 0.5h, and keeping for 2h;
(6) Adjusting the temperature of the plate layer, cooling to-45 ℃, keeping the cooling rate at 40-50 ℃/h for 3h;
(7) Adjusting the temperature of the plate layer, heating to-20 ℃ for 1h, keeping for 12h and keeping the vacuum degree of 0.1-0.2 mbar;
(8) Adjusting the temperature of the plate layer, heating to 0 ℃ for 4 hours, keeping for 2 hours and keeping the vacuum degree of 0.1-0.2 mbar;
(9) Adjusting the temperature of the plate layer, raising the temperature to 25 ℃ for 1 hour, keeping the temperature for 1 hour and keeping the vacuum degree to be 0.1-0.2 mbar; adjusting the vacuum degree to 0.02-0.03 mbar and keeping for 6 hours.
(10) And (3) filling nitrogen into the box body, controlling the pressure in the box to be 800-900 mbar, breaking vacuum by a plug until the pressure is normal pressure, taking the box out, and rolling a cover to obtain a sample.
Example 3
The freeze-drying process for commercial production of the disodium levoornidazole phosphate for injection in the embodiment is carried out according to the following steps:
(1) Preparing 200L of liquid medicine, and adjusting the pH value to be between 5.2 and 5.5;
(2) Adjusting the temperature of a plate layer of a freeze dryer to 0 ℃;
(3) Filtering the liquid medicine through a filter element with the diameter of 0.22 mu m, filling the liquid medicine into a penicillin bottle, filling the penicillin bottle with a half plug, and filling the penicillin bottle into a freeze dryer;
(4) Keeping the sample at 0 ℃ for 1h, adjusting the temperature of the plate layer, cooling to-45 ℃, keeping the temperature reduction rate at 40-50 ℃/h for 2h;
(5) Adjusting the temperature of the plate layer, heating to-25 ℃ within 0.5h, and keeping for 2h;
(6) Adjusting the temperature of the plate layer, cooling to-45 ℃, keeping the cooling rate at 40-50 ℃/h for 3h;
(7) Adjusting the temperature of the plate layer, heating to-20 ℃ for 1h, keeping for 12h and keeping the vacuum degree of 0.1-0.2 mbar;
(8) Adjusting the temperature of the plate layer, heating to 0 ℃ within 6 hours, keeping for 2 hours and keeping the vacuum degree of 0.1-0.2 mbar;
(9) Adjusting the temperature of the plate layer, raising the temperature to 25 ℃ within 1 hour, keeping the temperature for 2 hours and keeping the vacuum degree to be 0.1-0.2 mbar; adjusting the vacuum degree to 0.02-0.03 mbar and keeping for 8 hours.
(10) And (3) filling nitrogen into the box body, controlling the pressure in the box to be 800-900 mbar, breaking the vacuum by a plug until the pressure is normal, taking out the box, and rolling a cover to obtain a sample.
Comparative example 1
The freeze-drying process for the commercial production of the disodium levoornidazole phosphate for injection of the comparison example is carried out according to the following steps:
(1) Preparing 200L of liquid medicine, and adjusting the pH value to be between 5.2 and 5.5;
(2) Adjusting the temperature of a plate layer of a freeze dryer to 0 ℃;
(3) Filtering the liquid medicine through a filter element with the diameter of 0.22 mu m, filling the liquid medicine into a penicillin bottle, filling the liquid medicine into a freeze dryer after half plugging;
(4) After the sample is kept at 0 ℃ for 0.5h, adjusting the temperature of the plate layer, cooling to-50 ℃, and keeping the temperature for 3h, wherein the cooling rate is 40-50 ℃/h;
(5) Adjusting the temperature of the plate layer, heating to-20 ℃ within 5 hours, keeping the temperature for 22 hours and keeping the vacuum degree of 0.1-0.2 mbar;
(6) Adjusting the temperature of the plate layer, heating to 0 ℃ within 6 hours, keeping for 2 hours and keeping the vacuum degree of 0.1-0.2 mbar;
(7) Adjusting the temperature of the plate layer, raising the temperature to 25 ℃ for 1 hour, and keeping the temperature for 2 hours at a vacuum degree of 0.1-0.2 mbar; adjusting the vacuum degree to 0.02-0.03 mbar and keeping the vacuum degree for 8 hours.
(8) And (3) filling nitrogen into the box body, controlling the pressure in the box to be 800-900 mbar, breaking the vacuum by a plug until the pressure is normal, taking out the box, and rolling a cover to obtain a sample.
Comparative example 2
The freeze-drying process for the commercial production of the disodium levoornidazole phosphate for injection of the comparison example is carried out according to the following steps:
(1) Preparing 200L of liquid medicine, and adjusting the pH value to be between 5.2 and 5.5;
(2) Adjusting the temperature of a plate layer of a freeze dryer to 0 ℃;
(3) Filtering the liquid medicine through a filter element with the diameter of 0.22 mu m, filling the liquid medicine into a penicillin bottle, filling the liquid medicine into a freeze dryer after half plugging;
(4) After the sample is kept at 0 ℃ for 0.5h, adjusting the temperature of the plate layer, cooling to-50 ℃, wherein the cooling rate is 20-25 ℃/h, and keeping for 3h;
(5) Adjusting the temperature of the plate layer, raising the temperature to-20 ℃ for 5 hours, keeping the temperature for 10 hours and keeping the vacuum degree to be 0.1-0.2 mbar;
(6) Adjusting the temperature of the plate layer, heating to 0 ℃ within 6 hours, keeping for 2 hours and keeping the vacuum degree of 0.1-0.2 mbar;
(7) Adjusting the temperature of the plate layer, raising the temperature to 25 ℃ for 1 hour, and keeping the temperature for 2 hours at a vacuum degree of 0.1-0.2 mbar; adjusting the vacuum degree to 0.02-0.03 mbar and keeping for 8 hours.
(8) And (3) filling nitrogen into the box body, controlling the pressure in the box to be 800-900 mbar, breaking the vacuum by a plug until the pressure is normal, taking out the box, and rolling a cover to obtain a sample.
The results of comparing the samples prepared by the processes are as follows:
the comparison result shows that the annealing process is used for commercial production, the appearance of the sample is complete and loose, the moisture residual quantity is low, and the difference is small; and after the annealing process is added, the production time is not prolonged compared with the prior art, and the production energy consumption is not increased.
And (4) conclusion: the production process provided by the invention can continuously and stably produce the injection-used disodium levoornidazole phosphate with controllable quality.
Claims (1)
1. A freeze-drying process for commercial production of disodium levoornidazole phosphate for injection is characterized by comprising the following steps:
(1) Preparing 20L of liquid medicine, and adjusting the pH value to be between 5.0 and 5.1;
(2) Adjusting the temperature of a plate layer of a freeze dryer to 0 ℃;
(3) Filtering the liquid medicine through a filter element with the diameter of 0.22 mu m, filling the liquid medicine into a penicillin bottle, filling the liquid medicine into a freeze dryer after half plugging;
(4) After the sample is kept at 0 ℃ for 0.5h, adjusting the temperature of the plate layer, cooling to-45 ℃, wherein the cooling rate is 40-50 ℃/h, and keeping for 2h;
(5) Adjusting the temperature of the plate layer, heating to-25 ℃ within 0.5h, and keeping for 2h;
(6) Adjusting the temperature of the plate layer, cooling to-45 ℃, keeping the temperature for 3 hours at the cooling rate of 40-50 ℃/hour;
(7) Adjusting the temperature of the plate layer, heating to-20 ℃ for 1h, keeping for 12h and keeping the vacuum degree of 0.1-0.2 mbar;
(8) Adjusting the temperature of the plate layer, heating to 0 ℃ for 4 hours, keeping for 2 hours and keeping the vacuum degree of 0.1-0.2 mbar;
(9) Adjusting the temperature of the plate layer, raising the temperature to 25 ℃ for 1 hour, keeping the temperature for 1 hour and keeping the vacuum degree to be 0.1-0.2 mbar; adjusting the vacuum degree to 0.02-0.03 mbar and keeping for 6 hours;
(10) Filling nitrogen into the box body, controlling the pressure in the box to be 800-900 mbar, breaking vacuum by a plug until the pressure is normal, taking out the box, and obtaining a sample after cover rolling;
or according to the following steps:
(1) Preparing 200L of liquid medicine, and adjusting the pH value to be between 5.2 and 5.5;
(2) Adjusting the temperature of a plate layer of a freeze dryer to 0 ℃;
(3) Filtering the liquid medicine through a filter element with the diameter of 0.22 mu m, filling the liquid medicine into a penicillin bottle, filling the liquid medicine into a freeze dryer after half plugging;
(4) Keeping the sample at 0 ℃ for 1h, adjusting the temperature of the plate layer, cooling to-45 ℃, keeping the temperature reduction rate at 40-50 ℃/h for 2h;
(5) Adjusting the temperature of the plate layer, heating to-25 ℃ within 0.5h, and keeping for 2h;
(6) Adjusting the temperature of the plate layer, cooling to-45 ℃, keeping the temperature for 3 hours at the cooling rate of 40-50 ℃/hour;
(7) Adjusting the temperature of the plate layer, heating to-20 ℃ for 1 hour, keeping for 12 hours and keeping the vacuum degree of 0.1-0.2 mbar;
(8) Adjusting the temperature of the plate layer, heating to 0 ℃ for 6 hours, keeping for 2 hours and keeping the vacuum degree of 0.1-0.2 mbar;
(9) Adjusting the temperature of the plate layer, raising the temperature to 25 ℃ within 1 hour, keeping the temperature for 2 hours and keeping the vacuum degree to be 0.1-0.2 mbar; adjusting the vacuum degree to 0.02-0.03 mbar, and keeping for 8 hours;
(10) And (3) filling nitrogen into the box body, controlling the pressure in the box to be 800-900 mbar, breaking vacuum by a plug until the pressure is normal pressure, taking the box out, and rolling a cover to obtain a sample.
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| CN101897672B (en) * | 2009-05-27 | 2012-02-22 | 华北制药集团制剂有限公司 | Method for preparing lyophilized acyclovir preparation for injection |
| CN102813908B (en) * | 2011-06-09 | 2015-10-21 | 江苏豪森医药集团连云港宏创医药有限公司 | A kind of freeze-dry process preparing injection bivalirudin |
| CN106310217A (en) * | 2015-06-16 | 2017-01-11 | 北京济美堂医药研究有限公司 | Freeze-drying process for preparation of bortezomib for injection |
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