JPH10128076A - Method for membrane treatment of solvent-based solution - Google Patents

Abstract

(57) [Problem] To provide a membrane treatment method for a solvent-based solution that can easily produce a highly reliable raw material powder from which endotoxin has been completely removed. A solvent-based solution contaminated with endotoxin is treated with a membrane module having a molecular weight cutoff of 50 to 50,000 to remove endotoxin.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for treating a solvent solution contaminated with endotoxin, and is useful for purifying an active ingredient produced by synthesis or fermentation in a pharmaceutical process.

[0002]

2. Description of the Related Art In a pharmaceutical process, an active ingredient is usually produced by synthesis or fermentation, and the active ingredient is purified to obtain a raw material powder. In this case, if the active ingredient is fat-soluble, the active ingredient is separated and extracted with a solvent, and the solvent of this solvent-based solution is removed by evaporation or freeze drying to obtain the active ingredient.

[0003]

As is well known, among the pyrogens (pyrogens) that cause fever and shock when mixed into blood, endotoxin, an endotoxin of Gram-negative bacilli, causes severe symptoms even in minute amounts. Because it induces, it must not be contained even in a trace amount in the drug raw material powder, and complete removal is indispensable. Conventionally, at the end of the raw material stage, an endotoxin detection reagent (LAL reagent) is used to check for the presence or absence of endotoxin. ing. In this case, since it is difficult to identify the contamination source, the preparation is performed again from the first step, and the labor is enormous.

It is known that the above-mentioned endotoxin is remarkably excellent in heat resistance and cannot be destroyed by ordinary sterilization treatment, and that it passes through an ordinary bacteria filter. Thus, the present inventors have attempted to treat a solvent contaminated with endotoxin, for example, ethanol, with a porous membrane. If the porous membrane has a molecular weight cut-off of 50,000 or less, I learned that endotoxin can be separated from ethanol. That is, it was found that the endotoxin-inhibiting property of the porous membrane with respect to the endotoxin-containing solvent was exerted with a cutoff molecular weight of 50,000 as a boundary value. As the molecular weight cut-off of the porous membrane becomes smaller than 50,000, the passage of the solute dissolved in the solvent is also blocked by the membrane, but the molecular weight cut-off at which the solute can sufficiently pass through the membrane is obtained. If there is a sufficient width between the molecular weight and the molecular weight cut off of 50,000, endotoxin and the solute can be effectively separated. Thus, the present inventors have confirmed that this separation is possible.

[0005] An object of the present invention is to provide a membrane treatment method for a solvent-based solution which can easily produce a highly reliable raw material powder from which endotoxin has been completely removed based on the above findings.

[0006]

According to the present invention, there is provided a method for treating a solvent-based solution with a membrane, wherein the solvent-based solution contaminated with endotoxin is treated with a membrane module having a molecular weight cutoff of 50 to 50,000. Is removed.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Examples of the solvent of the solvent solution in the present invention include ethanol, methanol, isopropyl alcohol, ethyl acetate, acetone, methyl ethyl ketone and the like. In the present invention, a solvent-resistant membrane module is used, and all the members used are equivalent to, for example, ethanol, the 13th revised Japanese Pharmacopoeia General Test Method 45 "Plastic Drug Test Method". Of 9
It is desirable 00cm ² / 300ml evaporation residue when immersed 1 day at 25 ° C. in a ratio of at most 1 mg, suitable porous membrane, for example, polytetrafluoroethylene-based, polysulfone-based, polypropylene-based And a polyimide-based porous film, a polyamide-based composite film, a polyvinyl-based composite film, and the like.

[0008] As the type of the above-mentioned membrane module, it is preferable to use a type which can easily perform a pyrogen treatment with a high alkali solution. Spiral type, hollow fiber membrane type, tuber type, plate & frame type (many membrane units are stacked, holding frames are arranged at both ends, and these holding frames In the plate and frame type, the membrane units are stacked and integrated in advance to perform depyrogenation processing, and then holding frames are provided at both ends. It is possible to assemble the two frames with bolts, shorten the time from depyrogenation treatment to assembly, and easily eliminate re-contamination of endotoxin. It is advantageous.

FIG. 1 shows a plate and frame used in the present invention.
Shows an example of a membrane-type membrane separation apparatus, and includes a large number of membrane units u.
(In the membrane unit u, as shown in FIG.
Membranes 2 and 2 are attached to both sides of the container, a stock solution main passage space 41 is attached to the stock solution main passage hole 31, and a concentrated solution main passage space spacer 42 is attached to the stock solution in the main passage hole 32. The filtrate main passage spacer 43 is mounted on the filtrate main passage hole 33, and the packing 5 is mounted around the hole 33). Pressing frames 6 are arranged at both ends thereof, and these pressing frames are disposed. -The holes 6 and 6 are fastened with bolts 7 so that the raw liquid main passage holes of all the membrane units are liquid-tightly associated to form the raw liquid main passage 310, and the concentrated liquid main passage holes of all the membrane units are also connected with the liquid. The concentrated liquid main passage 320 is formed in close association, and the filtrate main passage 330 of the entire membrane unit is formed in liquid-tight association.

In this plate and frame type membrane separation apparatus, the undiluted solution is supplied to an undiluted solution inlet 3 provided in one of the holding frames.
11 ⇒ stock solution main passage 310 ⇒ stock solution communication hole 411 of stock solution main passage spacer of each membrane unit ⇒ stock solution gap flow path b between membrane units ⇒ concentrate of concentrate solution main passage spacer of each membrane unit The communication hole 421 ⇒ the concentrated liquid main passage 320 ⇒ flows through the concentrated liquid outlet 321 provided in the other holding frame, and the solvent in the concentrated liquid flows while the concentrated liquid flows through the concentrated liquid gap flow path b between the membrane units. The solvent that has permeated the membrane, that is, the filtrate, passes through the filtrate chamber a in the membrane unit → the filtrate communication hole 431 of the filtrate main passage spacer → the filtrate main passage hole 330.
⇒ It is taken out from the filtrate outlet 331 provided in one of the holding frames.

In order to assemble the above-mentioned plate & frame type membrane separation apparatus, the number of all the membrane units is set to a large number Y
(16 sheets in FIG. 1), many of the sheets are divided into n groups (2 groups in FIG. 1) and y sheets (8 sheets in FIG. 1)
Are laminated and integrated by fastening bolts 71 inserted into the ends of the support plate of the membrane unit. The integrated laminate E is depyrogenated with a high alkali, and then removed by steam treatment with an autoclave. The membrane units laminated and sterilized, sterilized and sterilized and sterilized and sterilized are stacked n times (two in FIG. 1), and holding frames 6 and 6 are arranged at both ends thereof. The plate and the membrane are fastened by the bolts 6 and 6, thereby completing the assembly of the plate and frame type membrane separation apparatus.

[0012] The processing operation method of the above-mentioned membrane module includes:
In order to stabilize the processing, a cross-flow method is usually used.
It is also possible to use a total filtration system.

In the present invention, the solvent solution contaminated with endotoxin comes into contact with the porous membrane of the membrane module, and the molecular weight cut off of this porous membrane is less than 50,000, so that the endotoxin cannot pass through the membrane. As a result, the solute of the solvent-based solution easily passes through the membrane together with the solvent (solvent) because the molecular weight cut off of the membrane is 50 or more, and as a result, endotoxin is separated from the solute.

The method for treating a film of a solvent-based solution according to the present invention comprises:
It is suitably used for the purification of raw material powder in the pharmaceutical field. In order to purify the raw material powder using the present invention, an active ingredient is produced by synthesis or fermentation, and the active ingredient is dissolved and separated and extracted in a solvent. Is treated with a membrane module of 50 to 50,000, and the solvent of the solvent solution which has passed through the membrane is removed by evaporation or freeze-drying to obtain an active ingredient. In this case, even if endotoxin is contaminated in the synthesis, fermentation step, or separation / extraction step, the endotoxin can be prevented from passing through the membrane, so that a highly reliable raw material powder from which endotoxin has been completely removed can be obtained.

[0015]

EXAMPLES In the membrane module, the membrane has a molecular weight cut off of about 50,
000, a polysulfone ultrafiltration membrane with a membrane area of 0.7 m ² , where all the components evaporate when immersed at 25 ° C. for 1 day at a rate of 33 cm ² / ml, equivalent to the “Plastic Drug Test Method” A low elution plate & frame type membrane module having a residue of 1 mg or less was used. Concentration 2 in stock solution
An ethanol solution contaminated with endotoxin at 10 ² EU / ml was used. The undiluted solution is applied to the above membrane module at an inlet pressure of 0.5 kg / cm ² , an inlet flow rate of 5 liter / min,
Processed in a cross-flow system with a 50% recovery rate,
After a period of time, the filtrate was collected and examined for endotoxin, but no endotoxin was detected. However,
Endotoxin can be detected by replacing the pyrogen-free water with Limulus ESII Single Test Wako (Lot. DMM178).
1, sensitivity 4.9 × 1/10 ³ EU / ml).

[0016]

According to the method for treating a solvent-based solution with a membrane according to the present invention, endotoxin can be completely removed from the solvent-based solution by treating the solvent-based solution contaminated with endotoxin with a membrane module. If used for refining raw material powder, highly reliable raw material powder can be obtained. In addition, the number of steps increases due to the presence of a membrane treatment step in the middle, but if endotoxin is detected at the end of the raw material, overall production efficiency will be improved compared to the conventional method, in which the preparation of all steps must be repeated. be able to.

[Brief description of the drawings]

FIG. 1 is a view showing an example of a plate and frame type membrane module used in the present invention.

FIG. 2 is a drawing showing a membrane unit of the membrane module of FIG.

[Explanation of symbols]

 u Membrane unit 6 Holding frame 7 Bolt

Claims (3)

[Claims] 1. A method of treating a solvent-based solution with a membrane, the method comprising treating a solvent-based solution contaminated with endotoxin with a membrane module having a molecular weight cut-off of 50,000 or less to remove endotoxin. 2. The molecular weight of the membrane of the membrane module is 50 to 5
2. The method for treating a film of a solvent-based solution according to claim 1, wherein the molecular weight is 0.000. 3. The method according to claim 1, wherein a plate and frame type membrane module is used as the membrane module.