TWI829850B - Manufacturing method of high-purity pharmaceutical container and high-purity pharmaceutical container - Google Patents

Abstract

[Problem] To provide a method for manufacturing a high-purity pharmaceutical container that can be used as a high-purity pharmaceutical container while minimizing the elution of contaminants such as eluates and degraded products of the resin of the pharmaceutical, and can be used for a long time. [Solution] A method of manufacturing high-purity pharmaceutical containers, characterized in that in the method of manufacturing containers by blow molding polyethylene resin, the screw shape of the blow molding machine satisfies the following conditions (1) to (3) , the temperature of the molten resin (parison) extruded through the screw is in the range of 170°C to 210°C. (1) The ratio of the effective length L of the screw to the shaft diameter D of the screw (L/D ratio) is in the range of 24 to 32 (2) The groove depth of the screw in the supply part is in the range of 0.1D~0.3D (3) The ratio of the groove depth of the supply part to the groove depth of the compression part is in the range of 0.80 to 1.00

Description

Manufacturing method of high-purity pharmaceutical container and high-purity pharmaceutical container

The present invention relates to the manufacture of containers for high-purity pharmaceuticals suitable for use in the semiconductor device industry, the field of precision industrial components, and pharmaceuticals. When filling high-purity pharmaceuticals, the generation of particles and metal dissolution of the pharmaceuticals are minimal and the cleanliness is high. Excellent manufacturing method of high-purity pharmaceutical containers and high-purity pharmaceutical containers.

In recent years, with the significant development of the electronics industry, the demand for high-purity pharmaceuticals has increased. High-purity drugs are used and are indispensable in the manufacturing of electronic circuits such as large-scale and integrated LSI. Specifically, sulfuric acid, hydrochloric acid, nitric acid, etc. are used for wafer cleaning and etching, wiring and insulating film etching, mold cleaning, developer, photoresist diluent, photoresist stripping solution, and drying. Hydrofluoric acid, ammonium fluoride, hydrogen peroxide, isopropyl alcohol, xylene, TMAH, methanol, acetic acid, phosphoric acid, ammonia, PGMEA, DMSO, NMP, ECA, ethyl lactate, etc. It is known that polyethylene resin is used as a container material for these high-purity pharmaceuticals from the viewpoint of chemical resistance, impact resistance, price, etc. However, conventional containers made of polyethylene resin have a problem of contamination of contents due to contaminants such as eluates and degraded products of the resin of pharmaceuticals, and their use as containers for high-purity pharmaceuticals has limitations. That is, with the miniaturization of ultra-LSI, although the conventional metal impurity concentration is 1 PPB, it is now required to be less than 1 PPT. It is also known that particles of 0.5 μm or more are a problem, but particles of 0.2 μm or more are required to have a strict quality of 100/mL or less. Furthermore, recently, particles of 0.1 μm level have become a problem, and particles of 0.1 μm or more are required to be 100/mL or less. Stricter quality below pc/mL. Therefore, the emergence of high-purity pharmaceutical containers with excellent cleanliness that meets the metal impurity concentration and particle level is expected.

Here, although there have been proposals for a container made of polyethylene resin and molded at a temperature of 173 to 190° C. with minimal elution of impurity particles, the particle level as an indicator of cleanliness is not sufficient if it is 0.2 μm or more (see, for example, Patent Document 1 ).

There is also a method for molding a clean hollow container using pure air, but there is no description of the evaluation of particles eluted from the container (for example, see Patent Document 2). [Prior technical literature]

[Patent Document 1] Japanese Patent Application Publication No. 7-257540 [Patent document 2] Japanese Patent Application Publication No. 8-192455

[Problem to be solved by the invention]

The present invention provides a method for manufacturing a container made of polyethylene resin by blow molding, using a screw having a specific shape in a blow molding machine to mold the container, and minimizing the possibility of using it as a high-purity pharmaceutical container. A method for manufacturing a high-purity pharmaceutical container that can be used for a long time without eluting contaminants such as leached products or degraded products of the resin and discoloring the resin, and a high-purity pharmaceutical container. [To solve the problem]

The inventors of the present invention carefully examined the screw shape of a blow molding machine when manufacturing a container made of a polyethylene resin having specific properties, and found out that a container with excellent cleanliness can be obtained, leading to the achievement of the present invention.

That is, various aspects of the present invention are as follows [1] to [6]. [1] A method of manufacturing high-purity pharmaceutical containers, characterized in that, in the method of manufacturing containers by blow molding polyethylene resin, the screw shape of the blow molding machine satisfies the following conditions (1) to (3), The temperature of the molten resin (parison) extruded through the screw is in the range of 170°C to 210°C. (1) The ratio of the effective length L of the screw to the diameter D of the screw (L/D ratio) is in the range of 24 to 32 , (2) The groove depth of the screw in the supply part is in the range of 0.1D~0.3D, (3) The ratio of the groove depth of the supply part to the groove depth of the compression part is in the range of 0.80~1.00. [2] The method for manufacturing a high-purity pharmaceutical container according to the above [1], wherein the number of particles of 0.1 μm or more eluted from the high-purity pharmaceutical container obtained by blow molding is 10 particles/mL or less. [3] The method of manufacturing a high-purity pharmaceutical container as described in the above [1], wherein the polyethylene resin has the following properties (1) to (5): (1) Density (JIS K6922-1:1997) is 940 to 970kg/m ³ , (2) The melt flow rate (melt flow rate) (JIS K6922-1:1997) at 190°C and 21.6kg load is 2.0~15g/10 minutes, (3) By gel permeation chromatography The ratio (Mw/Mn) of the weight average molecular weight (Mw) and the number average molecular weight (Mn) calculated by the method (GPC) is 8 to 15. (4) The molecular weight distribution curve obtained by the gel permeation chromatography (GPC) method Among them, components with a molecular weight of 1000 or less are 0.40% by weight or less, and (5) the chlorine content is 8PPM or less relative to the polyethylene resin. [4] The method for manufacturing a high-purity pharmaceutical container according to the above [3], wherein the ash content of the polyethylene resin is 30 PPM or less relative to the resin. [5] The method for manufacturing a high-purity pharmaceutical container according to the above [3], wherein the polyethylene resin does not contain additives. [6] A high-purity pharmaceutical container obtained by the manufacturing method described in any one of the above [1] to [5].

The ratio of the screw effective length L and the screw shaft diameter D (L/D ratio) of the present invention is 24 to 32, preferably 25 to 28. If L/D is 24 or more, the polyethylene resin can be sufficiently melted and kneaded. If L/D is 32 or less, the load on the screw-driven engine capacity is not an economic problem.

The groove depth of the screw in the supply part of the present invention is 0.1D~0.3D, preferably 0.1D~0.15D. When the groove depth of the supply part is less than 0.1D, the extrusion amount is too small, so in direct blow molding, etc., the parison lowering time to form the desired parison length that matches the mold shape becomes longer, and the molding cycle becomes longer. . On the contrary, if the groove depth of the supply part exceeds 0.3D, the extrusion amount increases, so the load on the engine becomes greater, and a screw extruder engine with a larger engine capacity must be installed or the screw may be damaged.

The ratio of the groove depth of the supply part to the groove depth of the compression part of the present invention is 0.80~1.00, preferably 0.80~0.90. If the groove depth ratio is less than 0.8, the extrusion amount will increase, thereby increasing the load on the engine and possibly damaging the screw. When the groove depth ratio is greater than 1.00, the resin in the supply part and the compression part is insufficiently heated, resulting in poor plasticization and a reduction in the extrusion amount. In direct molding, etc., the length of the desired parison that conforms to the shape of the mold is reached. The parison lowering time becomes longer and the molding cycle becomes longer.

In the screw shape of the present invention, the ratio of the length of the supply part to the effective length of the screw is preferably 0.35 to 0.50. If the length ratio of the supply part is in the range of 0.35 to 0.50, sufficient preheating of the polyethylene can be provided.

In the screw shape of the present invention, the ratio of the length of the compression part to the effective length of the screw is preferably 0.30 to 0.40. If the length ratio of the compressed portion is in the range of 0.30 to 0.40, the polyethylene can be sufficiently melted and kneaded.

For the screw shape of the present invention, the ratio of the length of the measuring part to the effective length of the screw is preferably 0.20 to 0.30. If the length ratio of the measuring portion is in the range of 0.20 to 0.30, the polyethylene can be extruded with less variation in the extrusion amount (surge phenomenon).

In order to further improve the shearing effect, the screw shape may be provided with different concave and convex positions in the screw shape such as Madock's in the measuring part.

In order to efficiently supply the polyethylene to the extruder using a screw of the present invention, it is advisable to provide non-parallel inclined grooves (also called forced feeding, etc.) in the length direction of the barrel of the supply part of the extruder. .

The temperature of the molten resin (parison) extruded through the screw in the present invention is in the range of 170°C to 210°C. When the molten resin (parison) temperature is lower than 170° C., the polyethylene resin cannot be sufficiently melted and kneaded. When the temperature of the molten resin (parison) is higher than 210°C, the molten resin deteriorates, affecting the cleanliness of the molded container. The temperature of the molten resin (parison) can be controlled by the temperature of the cylinder in the screw, and can be controlled within the above range by setting it to a range of 160°C to 200°C.

The number of particles of 0.1 μm or more eluted from the high-purity pharmaceutical container manufactured according to the present invention is preferably 10 particles/mL or less. If the number of particles of 0.1 μm or more is 10 particles/mL or less, LSI can be made smaller.

The polyethylene resin used in the present invention should preferably have the following properties (1) to (5). (1) Density (JIS K6922-1) is 0.94~0.97g/m ³ (2) Melt flow rate (JIS K6922-1:1997) at 190°C and 21.6kg load is 2.0~15g/10 minutes (3 )The ratio (Mw/Mn) of the weight average molecular weight (Mw) and the number average molecular weight (Mn) determined by gel permeation chromatography (GPC) is 8 to 15 (4) Using gel permeation chromatography (GPC) ) In the molecular weight distribution curve obtained, the component with a molecular weight of 1000 or less is 0.40% by weight or less (5) The chlorine content is 8PPM or less relative to the polyethylene resin. Furthermore, the ash content contained in the polyethylene resin is 0.40% by weight or less relative to the resin. , preferably polyethylene resin below 30PPM. In addition, it is preferable that the polyethylene resin does not contain additives.

The polyethylene resin used in the present invention can be produced through a highly active catalyst such as a Ziegler catalyst or a metallocene catalyst. For example, a highly active Zigler catalyst composed of a transition metal compound such as titanium and zirconium, a magnesium compound, and an organic aluminum compound is used as a polymerization catalyst to make ethylene or ethylene and an α-olefin having 3 to 20 carbon atoms. The desired density ratio is obtained and copolymerized to produce it.

Examples of the catalyst in this case include the catalyst described in Japanese Patent No. 3319051.

Examples of α-olefins having 3 to 20 carbon atoms include propylene, 1-butene, 4-methyl-1-pentene, 3-methyl-1-butene, 1-pentene, 1-hexene, 1 -Heptene, 1-octene, 1-nonene, 1-decene, 1-undecene, 1-dodecene, 1-tridecene, 1-tetradecene, 1-pentadecene, 1 -Hexadecene, 1-heptadecene, 1-octadecene, 1-nonadecene, 1-eicosene, etc.

The polymerization method used in the production of polyethylene resin uses a polymerization method with a carbon number of 6 or more and 10 or less in order to suppress the low metal impurity concentration of drug elution and to limit the entry of low molecular polymer resin that causes the generation of fine particles. The medium, such as slurry polymerization of n-hexane, n-heptane, etc., contains a low molecular weight component with a density of 0.94~0.98 g/m ³ , and a high molecular weight component with a density of 0.92~0.95 g/m ³ , which is lower than the low molecular weight component. Two components, the weight ratio of the two components is preferably, low molecular weight component: high molecular weight component = 20:80~80:20. The two components of a low molecular weight component and a high molecular weight component are produced by, for example, a two-step polymerization method.

The polyethylene resin has the following density, melt flow rate, molecular weight distribution (Mw/Mn), melting temperature, components with a molecular weight of 1000 or less, xylene extractables at 25°C, and chlorine content.

That is, the density (JIS K6922-1:1997) of the polyethylene resin is 940 to 970 kg/m ³ , preferably 950 to 960 kg/m ³ . If the density is in the range of 940~970kg/ ^m3 , containers can be molded without problems with container cleanliness and drop strength due to particles.

The polyethylene resin has a melt flow rate (JIS K6922-1:1997) of 2.0~15g/10min at 190°C and a load of 21.6kg, preferably 5.0~10g/10min. If the melt flow rate is in the range of 2.0~15g/10 minutes, deterioration of the container surface can be suppressed.

The ratio (Mw/Mn) of the weight average molecular weight (Mw) and the number average molecular weight (Mn) of the polyethylene resin determined by gel permeation chromatography (GPC) is 8 to 15. If Mw/Mn is in the range of 8 to 15, deterioration of the container surface can be suppressed, and containers can be molded without problems with container cleanliness and drop strength due to particles.

In the molecular weight distribution curve obtained by gel permeation chromatography (GPC), it is preferable that the component with a molecular weight of 1000 or less is 0.40% by weight or less. Preferably it is 0.30 weight% or less. If the component with a molecular weight of 1,000 or less is 0.40% by weight or less, a container can be molded without problems with container cleanliness caused by fine particles.

The chlorine content of the polyethylene resin measured with a fluorescent X-ray device is preferably 8 PPM or less relative to all polyethylene resins. If the chlorine content is 8PPM or less based on the total polyethylene resin, discoloration of the container can be suppressed. Once it exceeds 8PPM relative to the entire polyethylene resin, chlorine will cause discoloration of the container, resulting in poor appearance. In addition, since the metal of the molding machine and the mold corrodes, a neutralizing agent for supplementing chlorine is necessary, and the neutralizing agent inevitably used becomes a cause of metal impurities.

The ash content contained in the polyethylene resin is preferably 30 PPM or less relative to the resin. If the ash content contained in the polyethylene resin is 30 PPM or less, the amount of ash elution into pharmaceuticals is small, so the concentration of metal impurities in pharmaceuticals can be suppressed. Ash content is the ratio of complete ashes to all resins and is expressed in PPM by weight. Complete ashes are obtained by complete ashing in an electric furnace, so they are the residues of polymerization catalysts such as Al, Mg, Ti, and Si, metal-containing additives such as neutralizers, and impurities and adhesion during the production of polyethylene resins. metal oxides of matter.

The polyethylene resin is blown into a container shape and becomes a high-purity pharmaceutical container. In particular, it is preferable to use a blow molding machine installed in a clean room and use a blow molding method that uses a filter to remove particulate air during blowing to produce clean containers.

Depending on the type of medicine, it is necessary to make a light-shielding container. A multi-layered container containing the polyethylene resin as an inner layer and at least one layer containing a light-shielding material such as an organic pigment or an inorganic pigment can also be used within the scope of maintaining cleanliness. Organic pigments or inorganic pigments are added to the polyethylene resin. [Effects of the invention]

Using the screw having the shape of the present invention can minimize contaminants such as eluates or deterioration products of the polyethylene resin and metal impurities due to pharmaceuticals when molding the container, and can provide cleanliness that can cope with the miniaturization of ultra-LSI. container.

[Example]

Hereinafter, the present invention will be described through Examples and Comparative Examples. The polyethylene resin used in the examples and comparative examples, the blow molding machine and screw shape, and the test method are as follows.

(1) Polyethylene resin density = 957g/cm ³ , melt flow rate = 8.0g/10 minutes (load: 21.6kgf, temperature: 190°C), Mw/Mn = 13, components with a molecular weight of less than 1000 = 0.26% by weight , chlorine content = 2PPM, ash content = 16PPM

(2)Blow molding machine Electric blow molding machine, MSE-50E/54M-A (manufactured by TAHARA Co., Ltd.)

(3) Screw shape The screw used in the Examples and Comparative Examples has the shape described in Table 1. [Table 1] Screw shape Effective length L (mm) Screw shaft diameter D (mm) Ministry of Supply Compression section Measurement Department L/D h3/h2 Length(mm) Groove depth h3 (mm) Length(mm) Groove depth h2 (mm) Length(mm) Groove depth h1 (mm) A 1443 50 550 5.1 500 6.2 393 4.2 28.9 0.82 B 1443 50 550 8.9 500 8.3 393 4.2 28.9 1.07

(4) Number of particles: Use a container with an internal volume of 800 mL obtained by blow molding polyethylene. In a clean room, fill the container with 800 mL of ultrapure water, cover it and leave it for 1 hour. Then measure the number of particles above 0.1 μm with a particle counter (Controller: KE-40B1, Particle sensor: KS-42A) made by RION Corporation. . The number of particles in water is expressed in particles/mL.

(5) Extrusion characteristics Using an electric blow molding machine (manufactured by TAHARA Co., Ltd.) with a screw of shape A inserted, the barrel temperature is set at 180°C to 220°C, and the rotation speed is 10 to 40 rpm. The polyethylene is extruded and measured. The extrusion amount of polyethylene relative to the screw rotation speed (kg/h). The results are shown in Table 2. In addition, the polyethylene was extruded using an electric blow molding machine (manufactured by TAHARA Co., Ltd.) with a screw of shape B inserted, the barrel temperature was set to 180°C to 220°C, and the rotation speed was 10 to 60 rpm. The polyethylene was then measured. Pressure output based on the number of screw rotations (kg/h). The results are shown in Table 3. [Table 2] Screw shape Number of rotations (rpm) Pressure capacity (kg/h) 180(℃) 200(℃) 220(℃) A 10.0 7.6 7.9 7.7 20.0 15.3 15.6 15.7 30.0 22.9 23.5 23.1 40.0 30.5 30.7 30.8 [table 3] Screw shape Number of rotations (rpm) Pressure capacity (kg/h) 180(℃) 200(℃) 220(℃) B 10.0 7.2 7.4 7.8 20.0 10.6 11.0 11.5 30.0 12.2 13.0 14.0 40.0 14.3 14.5 15.3 60.0 15.1 15.7 20.2

Example 1 The polyethylene was extruded using an electric blow molding machine (manufactured by TAHARA Co., Ltd.) with a screw of shape A inserted, the barrel set temperature was 180°C, the screw rotation speed was 26.0 rpm, and the extrusion rate was 20 kg/h. The molding cycle was 27 seconds. , forming a container with a weight of 120g and an internal volume of 800mL. The parison temperature is 184.6℃. The component with a molecular weight of 1000 or less in the molded container is 0.29% by weight. Using the obtained container, the above-described particle number measurement was performed. As shown in Table 4 and Figure 1, the number of particles above 0.1 μm is 6.2 particles/mL.

Example 2

The same molding machine as in Example 1 was used, the barrel temperature was set to 200°C, the screw rotation speed was 25.5 rpm, and the extrusion volume was 20kg/h. The polyethylene was extruded, the molding cycle was 27 seconds, and a container with a weight of 120g and an internal volume of 800mL was formed. . The parison temperature is 204.8℃. The component with a molecular weight of 1000 or less in the molded container is 0.33% by weight. Using the obtained container, the above-described particle number measurement was performed. As shown in Table 4 and Figure 1, the number of particles above 0.1 μm is 8.5 particles/mL.

Comparative example 1

The same molding machine as in Example 1 was used, the barrel temperature was set to 220°C, the screw rotation speed was 25.5 rpm, and the extrusion volume was 20kg/h. The polyethylene was extruded, the molding cycle was 27 seconds, and a container with a weight of 120g and an internal volume of 800mL was formed. . The parison temperature is 223.9°C. The component with a molecular weight of 1000 or less in the molded container is 0.41% by weight. Using the obtained container, the above-described particle number measurement was performed. As shown in Table 5 and Figure 1, the number of particles above 0.1 μm is 12.4 particles/mL.

Comparative example 2

Using an electric blow molding machine (manufactured by TAHARA Co., Ltd.) with a screw of shape B inserted, setting the temperature conditions of 180°C and 200°C, and performing the same molding cycle as in Examples 1 and 2, an attempt was made to create a container using polyethylene. Molding, as shown in Table 3, at 180°C and 200°C, even if the screw rotates at a high speed of 60rpm, the extrusion amount of the polyethylene is small and cannot reach 20kg/h, so it cannot be molded. Under the conditions of set temperatures of 180°C and 200°C and a rotation speed of 60 rpm, the parison temperatures when the polyethylene was extruded were 193.0°C and 212.2°C respectively. Therefore, at the set temperature of 220°C, the screw rotation speed is 60.0 rpm, the extrusion amount is 20kg/h, and the polymer is extruded. Ethylene, a molding cycle of 27 seconds, molding a container with a weight of 120g and an internal volume of 800mL. The parison temperature is 232.1℃. The component with a molecular weight of 1000 or less in the molded container is 0.46% by weight. Using the obtained container, the above-described particle number measurement was performed. As shown in Table 5 and Figure 1, the number of particles above 0.1 μm is 15.1 particles/mL.

without.

[Fig. 1] shows the relationship between the number of particles of 0.1 μm or more obtained by particle measurement of the containers obtained in Examples 1 to 4 and the parison temperature during molding of the container.

Claims (4)

A method for manufacturing high-purity pharmaceutical containers, characterized in that in the method of manufacturing containers by blow molding polyethylene resin, the screw shape of the blow molding machine satisfies the following conditions (1) to (3), and the screw is The temperature of the extruded molten resin (parison) is in the range of 170°C to 210°C. The screw includes a supply part and a compression part. (1) The ratio of the effective length L of the screw to the diameter D of the screw (L/D ratio ) is in the range of 24 to 32, (2) the groove depth of the screw in the supply part is in the range of 0.1D to 0.3D, (3) the ratio of the groove depth of the supply part to the groove depth of the compression part is 0.80 ~1.00, in which the polyethylene resin has the following (1) ~ (6) properties, (1) density (JIS K6922-1: 1997) is 940 ~ 970kg/m ³ , (2) at 190°C , the melt flow rate (JIS K6922-1: 1997) of 21.6kg load is 2.0~15g/10 minutes, (3) the weight average molecular weight (Mw) and number average determined by gel permeation chromatography (GPC) The ratio of molecular weight (Mn) (Mw/Mn) is 8 to 15, (4) in the molecular weight distribution curve obtained by gel permeation chromatography (GPC), the component with a molecular weight of 1000 or less is 0.40% by weight or less, (5) The chlorine content is 8PPM or less relative to the polyethylene resin, and (6) the ash content is 30PPM or less relative to the polyethylene resin. The method of manufacturing a high-purity pharmaceutical container according to claim 1, wherein the number of particles of 0.1 μm or more eluted from the high-purity pharmaceutical container obtained by blow molding is 10 particles/mL or less. The method for manufacturing a high-purity pharmaceutical container of claim 1 is characterized in that the polyethylene resin does not contain additives. A high-purity pharmaceutical container obtained by the manufacturing method described in any one of claims 1 to 3.

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