JPH0641410B2 - Method for freeze-drying highly concentrated aqueous solution of meclofenoxate hydrochloride - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for freeze-drying a highly concentrated aqueous solution of meclofenoxate hydrochloride.

2. Description of the Related Art Meclofenoxate hydrochloride is a compound represented by the following formula and is widely used as an agent for improving brain metabolism function for oral and injection purposes.

As a general method for producing meclofenoxate hydrochloride,
p-Chlorophenoxyacetic acid chloride and 2-dimethylaminoethanol were reacted according to a conventional method to obtain meclofenoxate, which was then converted into the hydrochloride, and the hydrochloride was recrystallized from isopropyl alcohol. Methods for purification are known. The thus-obtained meclofenoxate hydrochloride crystals have a stable hygroscopic and stable crystal form (hereinafter referred to as type I crystal), and are formulated into tablets or capsules and used as an oral brain metabolism function-improving agent. Is being treated as.

On the other hand, meclofenoxate hydrochloride is easily hydrolyzed in the presence of water to produce p-chlorophenoxyacetic acid and 2-dimethylaminoethanol hydrochloride, and therefore, it should be dissolved before use for use as an injection. A powder injection form must be selected. The meclofenoxate hydrochloride type I crystal obtained by recrystallization from isopropyl alcohol has problems such as residual solvent and inclusion of foreign substances when directly applied to an injection, and therefore the crystal is usually dissolved in distilled water for injection. Then, the filtrate obtained by aseptic filtration is aseptically freeze-dried to produce a powder injection.

Problems to be Solved by the Invention An aqueous solution of meclofenoxate hydrochloride is easily supercooled and has a strong property of solidifying as it is to form a solid solution,
Further, the melting temperature of the solid solution decreases as the concentration of meclofenoxate hydrochloride increases, so that freeze-drying of a high-concentration aqueous solution is extremely inefficient or, in some cases, impossible. Therefore, powdered injections are generally produced by freeze-drying an aqueous solution of 20% (w / v).
In order to improve the productivity of meclofenoxate hydrochloride powder injection, it is desired to establish an efficient freeze-drying method for highly concentrated aqueous solution of 30% (w / v) or more.

Means and Actions for Solving Problems The present inventors have conducted various studies to establish an efficient freeze-drying method for highly concentrated aqueous solution of meclofenoxate hydrochloride, and as a result, cooled the aqueous solution in the preliminary freezing process. Then, the temperature is gradually raised, and when the product temperature reaches −26 to −4 ° C., the heating is suspended for several tens of minutes, so that the colorless semitransparent solid solution becomes a white opaque frozen solution. It has been found that the crystals can be changed to crystals and extremely efficient freeze-drying can be performed.

The present invention is a method for freeze-drying a high-concentration aqueous solution of meclofenoxate hydrochloride of 30% (w / v) or higher, in which the high-concentration aqueous solution of meclofenoxate hydrochloride is cooled to form a solid solution in the preliminary freezing process. The meclofenoxate hydrochloride is characterized in that, when the product temperature is gradually raised to -26 to -4 ° C, the heating is interrupted until the colorless semitransparent solid solution is changed to a white opaque frozen eutectic. A method for freeze-drying a high-concentration aqueous solution of the above is provided.

The method of the present invention can be carried out as follows.
First, a high-concentration aqueous solution of meclofenoxate hydrochloride is substantially frozen at a temperature not higher than, for example, -30 ° C or lower, preferably after cooling to -40 to -50 ° C to form a colorless semitransparent solid solution, Gradually raise the temperature. As the heating rate,
Generally, 0.5 to 2 ° C./minute, preferably 1 ° C./minute is selected. The product temperature is -26 to -4 ° C, preferably -18 to -8 ° C,
More preferably, when it reaches −17 to −15 ° C., a colorless semitransparent solid solution changes to a white opaque frozen eutectic, so heating is interrupted for about 30 to 60 minutes until it completely changes to a frozen eutectic. To do. At this time, the shelf temperature is preferably kept at -15 ° C or lower.

The formed frozen eutectic may be cooled again to −40 to −50 ° C. and then subjected to primary drying. However, since the melting temperature of the frozen eutectic is high (−4 to −6 ° C.), it does not need to be recooled. By subjecting the frozen eutectic body to primary drying and then secondary drying according to a conventional freeze-drying method, it is possible to efficiently freeze-dry a highly concentrated aqueous solution of meclofenoxate hydrochloride.
For example, the primary drying is performed by adjusting the degree of vacuum and the shelf temperature so that the product temperature does not exceed -4 ° C, preferably -7 ° C. Secondary drying starts when the slowest product temperature matches the shelf temperature, and
It is completed in a few hours when the temperature is adjusted to 60 ° C and the vacuum degree is 0.1 to 0.05 mmHg.

The upper limit of the concentration of meclofenoxate hydrochloride to which the method of the present invention can be applied is not particularly limited, but is about 70% (w / v) from a practical viewpoint in consideration of the dissolution rate, the filtration rate and the like.

A typical pattern when a 60% (w / v) aqueous solution of meclofenoxate hydrochloride was freeze-dried according to the method of the present invention is shown in the drawing.

The freeze-dried powder of meclofenoxate hydrochloride obtained by the method of the present invention has a highly hygroscopic and unstable crystal form (hereinafter
Type II crystal). However, this type II crystal
For example, by maintaining the temperature at 40 to 70 ° C. under a relative humidity of 30 to 70% for 5 minutes to 24 hours, it is possible to almost completely convert to the I type crystal. In addition, the X-ray diffraction diagram of the I-type crystal shows the diffraction angle (2θ) 1
Strong diffraction peaks at 7.2 °, 19.3 ° and 26.0 °, II
The X-ray diffraction pattern of the type crystal shows diffraction angles (2θ) of 17.6 ° and 20.8 °.
And characteristic peaks at 24.8 °.

Effect of the Invention According to the method of the present invention, since the melting temperature of the frozen eutectic of meclofenoxate hydrochloride is high, the freeze-drying of 30% (w / v) or more high-concentration meclofenoxate hydrochloride aqueous solution is extremely efficient. You can do it well. On the other hand, in the usual freeze-drying method that does not go through a freeze eutectic, since the melting temperature of the solid solution is low, primary drying is performed while maintaining the product temperature at a low temperature, for example, −32 to −25 ° C. even with a 30% solution. The total drying process takes about 1.3 times longer than that of the method of the present invention, resulting in poor efficiency. Further, when the concentration is 50% or more, by the usual freeze-drying method, during primary drying, foaming and melting occur near the product temperature of -30 to -25 ° C, and freeze-drying is impossible.

Hereinafter, the present invention will be described more specifically with reference to Examples and Comparative Examples.

Example 1 600 g of meclofenoxate hydrochloride was dissolved in distilled water for injection to make the total amount 1. This is the Menplan filter (0.
22 μm), and aseptically fill the tray with the filtrate (liquid layer)
11 mm), and placed on a shelf in a freeze dryer drying tank, and freeze dried. During the freeze-drying process, pre-freezing was performed by raising the temperature at a rate of 1 ° C / min when the product temperature dropped to -50 ° C, and holding this temperature for 40 minutes when the shelf temperature reached -17 ° C. Primary drying is temperature -15 ~
The degree of vacuum and the shelf temperature were adjusted to maintain 7 ° C, and the secondary drying was performed for 3 hours at a product temperature of 60 ° C and a degree of vacuum of 0.1 to 0.05 mmHg. The time required for the entire drying process was 33 hours. A part of the freeze-dried cake obtained was taken out and examined by X-ray diffraction. II
It was a type crystal.

Example 2 600 g of meclofenoxate hydrochloride was dissolved in distilled water for injection to make the total amount 1. This is the Menplan filter (0.
22 μm), and aseptically fill the tray with the filtrate (liquid layer)
11 mm), and placed on a shelf in a freeze dryer drying tank, and freeze dried. During the freeze-drying process, pre-freezing was performed by raising the temperature at a rate of 1 ° C / min when the product temperature dropped to -50 ° C, and holding this temperature for 40 minutes when the shelf temperature reached -16 ° C. Then, after cooling to -50 ° C again, the shelf temperature and the degree of vacuum are controlled, and the product temperature is -50 to -7.
Primary drying was carried out at a temperature of 60 ° C, and secondary drying was carried out at a product temperature of 60 ° C and a vacuum degree of 0.1 to 0.05 mmHg. The time required for the entire drying step was 36 hours, and the resulting freeze-dried cake was meclofenoxate hydrochloride type II crystals.

Example 3 300 g of meclofenoxate hydrochloride was dissolved in distilled water for injection to make the total amount 1. This is the Menplan filter (0.
22 μm), and aseptically fill the tray with the filtrate (liquid layer)
11 mm), and placed on a shelf in a freeze dryer drying tank, and freeze dried. During the freeze-drying process, pre-freezing was carried out by raising the temperature at a rate of 1 ° C / min when the product temperature dropped to -50 ° C, and holding this temperature for 30 minutes when the shelf temperature reached -15 ° C. Primary drying is the product temperature-
The degree of vacuum and the shelf temperature were adjusted so as to maintain 15 to -7 ° C, and the secondary drying was performed for 3 hours at a product temperature of 60 ° C and a degree of vacuum of 0.1 to 0.05 mmHg. The time required for the entire drying step was 21 hours, and the obtained freeze-dried cake was meclofenoxate hydrochloride type II crystal.

Comparative Example 1 In the same manner as in Example 1, 60% of meclofenoxate hydrochloride was prepared.
% (W / v) solution 1 was prepared, and after aseptic filtration, the filtrate was filled in a tray (liquid layer 11 mm) and placed on a shelf in a freeze dryer drying tank. Pre-freezing did not adopt the conditions shown in Example 1, but vacuum evacuation was started and the shelf temperature was raised when the product temperature dropped to -50 ° C. When a normal pre-freezing pattern was adopted, during primary drying, The product foamed and melted at a product temperature of -30 to -25 ° C and could not be lyophilized.

Comparative Example 2 In the same manner as in Example 3, 30% of meclofenoxate hydrochloride was used.
% (W / v) solution 1 was prepared, and after aseptic filtration, the filtrate was filled in a tray (liquid layer 11 mm) and placed on a shelf in a freeze dryer drying tank. For pre-freezing, the conditions shown in Example 3 were not adopted, and a normal pre-freezing pattern was used in which vacuum evacuation was started and the shelf temperature was raised when the product temperature fell to -50 ° C.
For the primary drying, adjust the vacuum degree and shelf temperature to maintain the product temperature of -32 to -25 ° C, and for the secondary drying, the product temperature of 60 ° C and the vacuum degree of 0.1 to 0.05mmH
g for 3 hours. 28 hours for the whole drying process,
The freeze-dried cake obtained was meclofenoxate hydrochloride I.
It was a mixture of type II crystals and type II crystals.

In the primary drying process, the same product temperature as in Example 3 (-15 to-)
When kept at 7 ° C., it was thawed and could not be freeze-dried.

[Brief description of drawings]

The drawing shows a typical pattern when a 60% (w / v) aqueous solution of meclofenoxate hydrochloride was lyophilized according to the method of the present invention.

Claims (8)

[Claims] 1. A method for freeze-drying a high-concentration aqueous solution of meclofenoxate hydrochloride at a concentration of 30% (w / v) or higher, wherein the high-concentration aqueous solution of meclofenoxate hydrochloride is cooled to form a solid solution in the preliminary freezing process. Then, when the product temperature is gradually raised to -26 to -4 ° C, the heating is interrupted until the colorless semitransparent solid solution is changed to a white opaque frozen eutectic crystal. Freeze-drying method of highly concentrated aqueous solution of sart. 2. The concentration of the meclofenoxate hydrochloride aqueous solution is
The freeze-drying method according to claim 1, which is 30 to 70% (w / v). 3. The freeze-drying method according to claim 1 or 2, wherein the heating is stopped when the product temperature reaches -18 to -8 ° C. 4. The freeze-drying method according to claim 3, wherein heating is interrupted when the product temperature reaches -17 to -15 ° C. 5. The freeze-drying method according to claim 1, wherein the temperature rising rate is 0.5 to 2 ° C./min. 6. The freeze-drying method according to claim 5, wherein the rate of temperature rise is 1 ° C./min. 7. The freeze-drying method according to any one of claims 1 to 6, wherein the shelf temperature at the time of interruption of heating is kept at -15 ° C or lower. 8. The freeze-drying method according to claim 1, wherein heating is interrupted for 30 to 60 minutes.