CN111700864B - Preparation method of voriconazole for injection - Google Patents

Preparation method of voriconazole for injection Download PDF

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CN111700864B
CN111700864B CN202010598469.5A CN202010598469A CN111700864B CN 111700864 B CN111700864 B CN 111700864B CN 202010598469 A CN202010598469 A CN 202010598469A CN 111700864 B CN111700864 B CN 111700864B
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CN111700864A (en
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王雅琦
张欣
阳秀平
梁臻
黄浩喜
苏忠海
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Hainan Beite Pharmaceutical Co ltd
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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    • 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
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    • 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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Abstract

The invention discloses a preparation method of voriconazole for injection, which comprises the steps of carrying out cooling, prefreezing and annealing treatment on a sample solution containing voriconazole, then sublimating to a terminal point, resolving and drying to obtain voriconazole for injection, wherein the sublimation is divided into a first stage and a second stage, the temperature of the first stage is higher than that of the second stage, and the pressure of the first stage is lower than that of the second stage; the first stage and the second stage are both carried out under the conditions that the vacuum degree is not higher than 20Pa and the temperature is not higher than 15 ℃. According to the invention, the sublimation mode of high temperature and low pressure at the early stage and low temperature and high pressure at the later stage is adopted, so that the heat and mass transfer process is improved, on one hand, the uniformity of crystallization is promoted, the difference in batches is avoided, the redissolution time is reduced, and the clarity of the redissolution liquid medicine is improved; on the other hand, the sublimation efficiency is improved, the freeze-drying period is shortened, and the production cost is reduced. Meanwhile, by optimizing the prefreezing process, the crystallization form is further improved, and the comprehensive advantages of the product are improved, so that the clinical medication advantages are improved.

Description

Preparation method of voriconazole for injection
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a preparation method of voriconazole for injection.
Background
The chemical name of the voriconazole is (2R,3S) -2- (2, 4-difluorophenyl) -3- (5-fluoro-4-pyrimidine) -1- (1H-1,2, 4-triazole-1-yl) -2-butanol, and the molecular formula is C 16 H 14 F 2 N 5 O, molecular weight of 349.3, structural formula:
Figure BDA0002558261700000011
voriconazole for injection was developed by Pfizer corporation as a broad-spectrum triazole antifungal, suitable for the following fungal infections: invasive aspergillus, candidemia in non-neutropenic patients, severe invasive infection with fluconazole-resistant candida, severe infection with podophyceae and fusarium. Mainly used for treating progressive and possibly life-threatening patients infected by fungi.
The voriconazole for injection has large filling amount and high liquid level height, and the problems of long freeze-drying period and high production cost exist according to the conventional freeze-drying procedure in order to obtain a freeze-dried preparation with low water content; and the liquid medicine volume in the container is higher, and the phenomenon that nucleation temperature difference is great, ice crystal form is different appears easily in the process of prefreezing, leads to vapor sublimation resistance great, and drying rate difference is big, further leads to freeze-drying cycle length, leads to the result that the finished product is inhomogeneous, the cake is coarse simultaneously.
Disclosure of Invention
The invention overcomes the defects of the prior art, and provides a preparation method of voriconazole for injection, which is expected to solve the problems of long freeze-drying period, uneven finished product and rough pressed powder.
In order to solve the technical problem, one embodiment of the present invention adopts the following technical solutions:
a preparation method of voriconazole for injection comprises the steps of carrying out cooling, pre-freezing and annealing treatment on a sample solution containing voriconazole, then sublimating to the end point, and then carrying out resolution drying to obtain voriconazole for injection, wherein the sublimation is divided into a first stage and a second stage, the temperature of the first stage is higher than that of the second stage, and the pressure of the first stage is lower than that of the second stage; the first stage and the second stage are both carried out under the conditions that the vacuum degree is not higher than 20Pa and the temperature is not higher than 15 ℃.
Preferably, the temperature of the first stage is 0-10 ℃, the vacuum degree is 10-15 Pa, and the temperature of the sample is increased to-15 to-5 ℃; the temperature of the second stage is-5-0 ℃, the vacuum degree is 16-20 Pa, and the sublimation is carried out to the end point.
Preferably, the temperature of the first stage is 5-10 ℃, the vacuum degree is 10-12 Pa, and the temperature of the sample is increased to-15 to-5 ℃.
Preferably, the temperature of the second stage is-3 to 0 ℃, the vacuum degree is 18 to 20Pa, and the sublimation is carried out to the end point. The supercooling in the present invention means: before pre-freezing, the sample solution is lowered to below freezing point, but is kept from crystallizing. The inventor has proved through a large number of experiments that the supercooling step has a certain influence on the product quality. Improper supercooling temperature and supercooling time both tend to cause ice crystal inhomogeneity, thereby destroying the appearance of the final product. In order to take account of both the product quality and the freeze-drying time, the supercooling treatment temperature is preferably-5 to 0 ℃, and the time is preferably 2 to 4 hours.
The inventor proves through a large number of experiments that the effect of the invention is less influenced by the pre-freezing step, and the pre-freezing can be carried out according to the conventional means of the technicians in the field under the condition of adopting the two-stage sublimation method of the invention. For example, the technical effect of the invention can be realized within the range of-45 to-40 ℃ and 3 to 7 hours in the pre-freezing step.
The annealing treatment of the invention refers to: after pre-freezing, the sample is first heated and then lowered to about the pre-freezing temperature. In the preparation method, annealing treatment is preferably carried out by firstly heating to-10 to-5 ℃, keeping for 3-5h, and then cooling to-45 to-40 ℃ and keeping for 4-6 h.
The inventor has proved through a large number of experiments that the effect of the analysis drying step on the technical effect of the invention is small, and the technical effect of the invention can be realized by analyzing and drying according to the conventional means of the skilled person under the condition of adopting the two-stage sublimation method of the invention. For example: the solution can be resolved and dried for 3 to 7 hours at the temperature of 30 to 50 ℃; or, firstly setting the temperature to be 30-50 ℃, preserving the heat for 3-5h, then reducing the vacuum degree to the ultimate vacuum, and continuously preserving the heat for 1-2h for desorption drying.
Any freeze drying apparatus that can achieve the above conditions can be used in the present invention. In the invention, after the septum valve of the freeze dryer is closed, the vacuum degree of the front box of the freeze dryer is not changed, and the sublimation is finished. The ultimate vacuum in the present invention is the minimum vacuum level that can be achieved by the freeze drying equipment (e.g., the minimum vacuum level that can be achieved by the front box of a freeze dryer). The sample in the present invention refers to a liquid or non-liquid voriconazole-containing sample, which contains sublimable components such as water or ice, and may also contain other components that can be used in combination with voriconazole. The sample is fluid before being treated by the method, and the state of the sample can be changed into semi-fluid or solid in the treatment process, so that the sample finally becomes fine and uniform crystals.
Compared with the prior art, the invention has at least the following beneficial effects: according to the invention, the sublimation modes of high temperature and low pressure at the early stage and low temperature and high pressure at the later stage are adopted, so that the heat and mass transfer process is improved, on one hand, the uniformity of crystallization is promoted, the difference in batches is avoided, the redissolution time is reduced, and the clarity of the redissolution liquid is improved; on the other hand, the sublimation efficiency is improved, the freeze-drying period is shortened, and the production cost is reduced. Meanwhile, by optimizing the prefreezing process, the crystallization form is further improved, and the comprehensive advantages of the product are improved, so that the clinical medication advantages are improved.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not limit the invention.
Example 1
1) Preparation: weighing voriconazole and sulfobutyl-beta-cyclodextrin (SBECD) according to the weight ratio of 1:18, adding SBECD into a proper amount of water, adding voriconazole after SBECD is completely dissolved, continuously stirring until the voriconazole is completely dissolved and uniformly mixing to obtain a sample containing the voriconazole;
2) sterile filtering, filling and half plugging: filtering the sample with 0.45 μm and 0.22 μm sterilizing filters to sterile filling room, filling into 25ml penicillin bottles, and half plugging;
3) vacuum freeze drying:
a. supercooling: placing the subpackaged samples on a clapboard of a freeze dryer, setting the temperature of the clapboard to be 0 ℃, and keeping the temperature for 4 hours;
b. pre-freezing: setting the temperature of the clapboard to be-45 ℃, and keeping the temperature for 3 hours;
c. and (3) annealing treatment: raising the temperature of the clapboard to-10 ℃, keeping the temperature for 5 hours, and then lowering the temperature to-45 ℃ and keeping the temperature for 4 hours;
d. vacuumizing: starting a vacuum pump, and vacuumizing the front box to 12 Pa;
e. sublimation: setting the temperature of a partition plate to be 10 ℃, heating the sample through the partition plate to enable the temperature of the sample to rise to-5 ℃, then setting the vacuum degree of a front box to be 20Pa, setting the temperature of the partition plate to be 0 ℃, continuously keeping the temperature until the middle partition valve is closed, wherein the vacuum degree of the front box is not obviously changed, and the whole process takes about 57 hours;
f. and (3) resolving and drying: setting the temperature of the partition plate to be 30 ℃, continuously preserving heat until the vacuum degree of the front box is not obviously changed after the partition valve is closed, consuming about 5 hours, then reducing the vacuum degree of the front box to the limit vacuum, and continuously preserving heat for 2 hours.
4) Taking out of the box and rolling the cover: and (5) pressing the plug after freeze-drying is finished, discharging and capping after repressing.
Example 2
1) Preparation: weighing voriconazole and SBECD according to the weight ratio of 1:15, adding SBECD into water, adding voriconazole after SBECD is completely dissolved, continuously stirring until the mixture is completely dissolved and uniformly mixed to obtain a sample containing the voriconazole;
2) sterile filtering, filling and half plugging: filtering the sample with 0.45 μm and 0.22 μm sterilizing filters to sterile filling room, filling into 25ml penicillin bottles, and half plugging;
3) vacuum freeze drying:
a. supercooling: placing the subpackaged samples on a clapboard of a freeze dryer, setting the temperature of the clapboard to be-5 ℃, and keeping the temperature for 2 hours;
b. pre-freezing: setting the temperature of the clapboard to-42 ℃, and keeping the temperature for 4 hours;
c. annealing treatment: raising the temperature of the clapboard to-5 ℃, keeping the temperature for 3h, and then lowering the temperature to-40 ℃ and keeping the temperature for 6 h;
d. vacuumizing: starting a vacuum pump, and vacuumizing the front box to 10 Pa;
e. sublimation: setting the temperature of a partition plate to be 8 ℃, heating the sample through the partition plate to increase the temperature of the sample to-6 ℃, then setting the vacuum degree of a front box to be 18Pa, setting the temperature of the partition plate to be-3 ℃, and continuously keeping the temperature until the vacuum degree of the front box is not obviously changed after a partition valve is closed, wherein the time of the whole process is about 60 hours;
f. and (3) resolving and drying: setting the temperature of the partition plate to be 40 ℃, continuously preserving heat until the vacuum degree of the front box is not obviously changed after the partition valve is closed, consuming about 4 hours, then reducing the vacuum degree of the front box to the limit vacuum, and continuously preserving heat for 2 hours.
4) Taking out of the box and rolling a cover: and (5) after freeze-drying, pressing, discharging and capping.
Example 3
1) Preparation: weighing voriconazole and SBECD according to the weight ratio of 1:16, adding SBECD into a proper amount of water, adding voriconazole after SBECD is completely dissolved, continuously stirring until the mixture is completely dissolved and uniformly mixed to obtain a sample containing voriconazole;
2) sterile filtering, filling and half plugging: filtering the sample with 0.45 μm and 0.22 μm sterilizing filters to sterile filling room, filling into 25ml penicillin bottles, and half plugging;
3) vacuum freeze drying:
a. supercooling: placing the subpackaged samples on a clapboard of a freeze dryer, setting the temperature of the clapboard to be-4 ℃, and keeping the temperature for 3 hours;
b. pre-freezing: setting the temperature of the clapboard to-40 ℃, and keeping the temperature for 6 hours;
c. annealing treatment: raising the temperature of the clapboard to-8 ℃, keeping the temperature for 4h, and then lowering the temperature to-43 ℃ and keeping the temperature for 5 h;
d. vacuumizing: starting a vacuum pump, and vacuumizing the front box to 12 Pa;
e. sublimation: setting the temperature of a clapboard to be 5 ℃, heating the clapboard to raise the temperature of a sample to-8 ℃, then setting the vacuum degree of a front box to be 20Pa, setting the temperature of the clapboard to-2 ℃, and continuously keeping the temperature until the vacuum degree of the front box is not obviously changed after a middle partition valve is closed, wherein the time of the whole process is about 56 hours;
f. and (3) resolving and drying: setting the temperature of the partition plate to be 50 ℃, continuously preserving heat until the vacuum degree of the front box is not obviously changed after the partition valve is closed, consuming about 3 hours, then reducing the vacuum degree of the front box to the ultimate vacuum, and continuously preserving heat for 1 hour.
4) Taking out of the box and rolling the cover: and (5) after freeze-drying, pressing, discharging and capping.
Example 4
1) Preparation: weighing voriconazole and SBECD according to the weight ratio of 1:16, adding SBECD into a proper amount of water, adding voriconazole after SBECD is completely dissolved, continuously stirring until the mixture is completely dissolved and uniformly mixed to obtain a sample containing the voriconazole;
2) sterile filtering, filling and half plugging: filtering the sample with 0.45 μm and 0.22 μm sterilizing filters to sterile filling room, filling into 25ml penicillin bottles, and half plugging;
3) and (3) vacuum freeze drying:
a. supercooling: placing the subpackaged samples on a clapboard of a freeze dryer, setting the temperature of the clapboard to be-2 ℃, and keeping the temperature for 4 hours;
b. pre-freezing: setting the temperature of the clapboard to-42 ℃, and keeping the temperature for 6 hours;
c. annealing treatment: raising the temperature of the clapboard to-7 ℃, keeping the temperature for 4h, and then lowering the temperature to-42 ℃ and keeping the temperature for 5 h;
d. vacuumizing: starting a vacuum pump, and vacuumizing the front box to 15 Pa;
e. sublimation: setting the temperature of a partition plate to be 0 ℃, heating the sample through the partition plate to increase the temperature of the sample to-15 ℃, then setting the vacuum degree of a front box to be 16Pa, setting the temperature of the partition plate to be-5 ℃, and continuously keeping the temperature until the vacuum degree of the front box is not obviously changed after a partition valve is closed, wherein the time of the whole process is about 58 hours;
f. and (3) resolving and drying: setting the temperature of the clapboard at 30 ℃, and continuously preserving heat and drying for 7 hours.
4) Taking out of the box and rolling the cover: and (5) after freeze-drying, pressing, discharging and capping.
Example 5
1) Preparation: weighing voriconazole and SBECD according to the weight ratio of 1:15, adding SBECD into a proper amount of water, adding voriconazole after SBECD is completely dissolved, continuously stirring until the mixture is completely dissolved and uniformly mixed to obtain a sample containing the voriconazole;
2) sterile filtration, filling and half stoppering: filtering the sample with 0.45 μm and 0.22 μm sterilizing filters to sterile filling room, filling into 25ml penicillin bottles, and half plugging;
3) vacuum freeze drying:
a. supercooling: placing the subpackaged samples on a clapboard of a freeze dryer, setting the temperature of the clapboard to be-1 ℃, and keeping the temperature for 4 hours;
b. pre-freezing: setting the temperature of the clapboard to-40 ℃, and keeping the temperature for 7 hours;
c. and (3) annealing treatment: raising the temperature of the clapboard to-6 ℃, keeping the temperature for 5 hours, and then lowering the temperature to-40 ℃ and keeping the temperature for 5 hours;
d. vacuumizing: starting a vacuum pump, and vacuumizing the front box to 14 Pa;
e. sublimation: setting the temperature of a partition plate to be 2 ℃, heating the sample through the partition plate to increase the temperature of the sample to-10 ℃, then setting the vacuum degree of a front box to be 16Pa, setting the temperature of the partition plate to be-4 ℃, and continuously keeping the temperature until the vacuum degree of the front box is not obviously changed after a partition valve is closed, wherein the time of the whole process is about 56 hours;
f. and (3) resolving and drying: setting the temperature of the clapboard at 50 ℃, and continuously preserving heat and drying for 5 hours.
4) Taking out of the box and rolling the cover: and (5) after freeze-drying, pressing, discharging and capping.
Comparative example 1
1) Preparation: weighing voriconazole and SBECD according to the weight ratio of 1:16, adding voriconazole into SBECD water after SBECD is completely dissolved, continuously stirring until the mixture is completely dissolved and uniformly mixed to obtain a sample containing voriconazole;
2) sterile filtering, filling and half plugging: filtering the sample with 0.45 μm and 0.22 μm sterilizing filters to sterile filling room, filling into 25ml penicillin bottles, and half plugging;
3) vacuum freeze drying:
a. pre-freezing: placing the subpackaged samples on a clapboard of a freeze dryer, setting the temperature of the clapboard to be-40 ℃, and keeping the temperature for 4 hours;
b. sublimation: setting the temperature of a partition plate to be-45 ℃, starting a vacuum pump until the vacuum degree in the front box reaches 13.33Pa, closing the freeze dryer, setting the partition plate to be-10 ℃, heating through the partition plate to raise the temperature of the sample to-20 ℃, finishing sublimation, and consuming about 24 hours in the whole sublimation process;
c. and (3) resolving and drying: setting the temperature of the clapboard to be 10 ℃, and continuously preserving heat and drying for 10 hours.
4) Taking out of the box and rolling a cover: and (5) pressing the plug after freeze-drying is finished, discharging and capping after repressing.
Comparative example 2
1) Preparation: weighing voriconazole and SBECD according to the weight ratio of 1:15, adding SBECD into water, adding voriconazole after SBECD is completely dissolved, continuously stirring until the mixture is completely dissolved and uniformly mixed to obtain a sample containing the voriconazole;
2) sterile filtering, filling and half plugging: filtering the sample with 0.45 μm and 0.22 μm sterilizing filters to sterile filling room, filling into 25ml penicillin bottles, and half plugging;
3) vacuum freeze drying:
a. pre-freezing: placing the subpackaged samples on a clapboard of a freeze dryer, setting the temperature of the clapboard to be minus 45 ℃, and keeping the temperature for 6 hours;
b. annealing treatment: raising the temperature of the clapboard to-10 ℃, keeping the temperature for 3h, and then lowering the temperature to-45 ℃ and keeping the temperature for 6 h;
c. sublimation: setting the temperature of a partition plate to be minus 40 ℃, starting a vacuum pump until the vacuum degree in the front box reaches 13.33Pa, closing the freeze dryer, setting the temperature of the partition plate to be minus 10 ℃, heating through the partition plate to raise the temperature of the sample to be minus 12 ℃, finishing sublimation, and consuming about 44 hours in the whole sublimation process;
d. and (3) resolving and drying: setting the temperature of the clapboard to be 10 ℃, and continuously preserving heat and drying for 10 hours;
4) taking out of the box and rolling the cover: and (5) pressing the plug after freeze-drying is finished, discharging and capping after repressing.
Comparative example 3
1) Preparation: weighing voriconazole and SBECD according to the weight ratio of 1:16, adding SBECD into a proper amount of water, adding voriconazole after SBECD is completely dissolved, continuously stirring until the mixture is completely dissolved and uniformly mixing to obtain a sample containing the voriconazole;
2) sterile filtering, filling and half plugging: filtering the sample with 0.45 μm and 0.22 μm sterilizing filters to sterile filling room, filling into 25ml penicillin bottles, and half plugging;
3) vacuum freeze drying:
a. supercooling: placing the subpackaged samples on a clapboard of a freeze dryer, setting the temperature of the clapboard to be-5 ℃, and keeping the temperature for 2 hours;
b. pre-freezing: setting the temperature of the clapboard to-45 ℃, and keeping the temperature for 4 hours;
c. vacuumizing: starting a vacuum pump, and vacuumizing the front box to 12 Pa;
d. sublimation: setting the temperature of a clapboard to be 0 ℃, heating the clapboard to increase the temperature of the sample to about-10 ℃, then setting the temperature of the clapboard to be 5 ℃, continuously keeping the temperature until the vacuum degree of a front box is not obviously changed after an intermediate valve is closed, and the whole process takes about 98 hours;
e. and (3) resolving and drying: setting the temperature of the partition plate to be 35 ℃, continuously preserving heat until the vacuum degree of the front box is not obviously changed after the partition valve is closed, consuming about 5 hours, then reducing the vacuum degree of the front box to the limit vacuum, and continuously preserving heat for 2 hours.
4) Taking out of the box and rolling the cover: and (5) pressing the plug after freeze-drying is finished, discharging and capping after repressing.
Comparative example 4
1) Preparation: weighing voriconazole and SBECD according to the weight ratio of 1:16, adding SBECD into a proper amount of water, adding voriconazole after SBECD is completely dissolved, continuously stirring until the mixture is completely dissolved and uniformly mixing to obtain a sample containing the voriconazole;
2) sterile filtering, filling and half plugging: filtering the sample with 0.45 μm and 0.22 μm sterilizing filters to sterile filling room, filling into 25ml penicillin bottles, and half plugging;
3) vacuum freeze drying:
a. supercooling: placing the subpackaged samples on a clapboard of a freeze dryer, setting the temperature of the clapboard to be-3 ℃, and keeping the temperature for 3 hours;
b. pre-freezing: setting the temperature of the clapboard to-45 ℃, and keeping the temperature for 4 hours;
c. annealing treatment: raising the temperature of the clapboard to-10 ℃, keeping the temperature for 3h, and then lowering the temperature to-45 ℃ and keeping the temperature for 5 h;
d. vacuumizing: starting a vacuum pump, and vacuumizing the front box to 20 Pa;
e. sublimation: setting the temperature of a clapboard to be 5 ℃, heating the clapboard to raise the temperature of a sample to about-5 ℃, then setting the temperature of the clapboard to be 10 ℃, and continuously keeping the temperature until the vacuum degree of a front box is not obviously changed after an intermediate valve is closed, wherein the time of the whole process is about 94 hours;
f. and (3) resolving and drying: setting the temperature of the partition plate to be 50 ℃, continuously preserving heat until the vacuum degree of the front box is not obviously changed after the partition valve is closed, consuming about 4 hours, then reducing the vacuum degree of the front box to the ultimate vacuum, and continuously preserving heat for 1 hour.
4) Taking out of the box and rolling the cover: and (5) pressing the plug after freeze-drying is finished, discharging and capping after repressing.
The relevant attributes of the lyophilized products of the above examples and comparative examples are shown in table 1.
TABLE 1 Freeze-dried product attributes for each example and comparative example
Figure BDA0002558261700000121
Note: the clarity standards "no turbidity to 0.5" and "no turbidity to 1" in the table are consistent with the relevant regulations in the fourth 0902 clarity inspection method of the pharmacopoeia 2015 edition of china.
As can be seen from the results in Table 1, in comparative example 1, although the freeze-drying period is short, the crystal appearance of the product is coarse and uneven, the moisture content is high, the re-dissolving time is long, and the clarity is poor; the appearance defects of the product in the comparative example 2 are not obviously improved compared with the product in the comparative example 1, and the problems of redissolution time and clarity of the product are not solved; the crystal appearance and the redissolution time of the product in the comparative example 3 are obviously improved, but the clarity does not meet the standard, and the freeze-drying period has no advantages; the crystal of the product of the comparative example 4 is fine and uniform in appearance, short in redissolution time and good in clarity, but the freeze-drying period is long, and the freeze-drying time is prolonged by more than 40% compared with that of the embodiment of the invention.
The products obtained in the embodiments 1-5 of the invention have the advantages of fine and uniform appearance, short redissolution time, good clarity and short freeze-drying period, and have very obvious comprehensive advantages compared with the comparative examples 1-4.
Although the invention has been described herein with reference to illustrative embodiments thereof, it should be understood that numerous other modifications and embodiments can be devised by those skilled in the art that will fall within the scope and spirit of the principles of this disclosure.

Claims (3)

1. A preparation method of voriconazole for injection is characterized in that,
dissolving sulbutylbetacyclodextrin and voriconazole in a proper amount of water to obtain a voriconazole-containing sample, and then performing vacuum freeze drying to obtain voriconazole for injection; the vacuum freeze drying sequentially comprises:
supercooling: reducing the temperature of a voriconazole-containing sample to below a freezing point, but keeping the voriconazole-containing sample not to crystallize, wherein the supercooling treatment temperature is-5-0 ℃, and the time is 2-4 hours;
pre-freezing: keeping the temperature of the clapboard at-45 to-40 ℃ for 3 to 7 hours;
and (3) annealing treatment: firstly, heating the partition plate to-10 to-5 ℃, keeping the temperature for 3 to 5 hours, then cooling the partition plate to-45 to-40 ℃, and keeping the temperature for 4 to 6 hours;
sublimation: the sublimation is divided into a first stage and a second stage, the temperature of the first stage is higher than that of the second stage, and the pressure of the first stage is lower than that of the second stage; the first stage and the second stage are both carried out under the conditions that the vacuum degree is not higher than 20Pa and the temperature is not higher than 15 ℃; the temperature of the first stage is 0-10 ℃, the vacuum degree is 10-15 Pa, and the temperature of the sample is increased to-15 to-5 ℃; the temperature of the second stage is-5-0 ℃, the vacuum degree is 16-20 Pa, and the sublimation is carried out until the end point;
and (3) resolving and drying: firstly, setting the temperature to be 30-50 ℃, preserving heat for 3-5h, then reducing the vacuum degree to the ultimate vacuum, and continuously preserving heat for 1-2 h; or setting the temperature to be 30-50 ℃, and preserving the heat for 3-7 hours.
2. The preparation method of voriconazole for injection according to claim 1, wherein the temperature of the first stage is 5-10 ℃, the vacuum degree is 10-12 Pa, and the temperature of the sample is raised to-15 to-5 ℃.
3. The preparation method of voriconazole for injection according to claim 2, wherein the temperature of the second stage is-3 to 0 ℃, the vacuum degree is 18 to 20Pa, and the voriconazole is sublimated to the end point.
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