A high-efficiency silicidation method for medium-borosilicate glass

Abstract

The invention discloses an efficient silicidation method for medium-borosilicate glass, and the experimental steps are as follows: spraying a silanization agent on the surface of the medium-borosilicate glass; wherein the silanization agent is a mixture of N,O-bis(trimethylsilyltrifluoroacetamide (BSTFA) and a solvent; reacting at low temperature under a nitrogen atmosphere; and cooling and cleaning. The method of the invention can modify the silanol groups on the surface of the glass into silyl groups, and enhance the hydrophobicity of the glass surface by changing the glass surface groups, thereby reducing the risk of metal ion precipitation and drug contamination inside the glass, and solving the problem of drug adsorption on the glass surface.

Description

Technical Field

[0001] The invention belongs to the technical field of silicidation technology, and in particular relates to a high-efficiency silicidation method for medium-borosilicate glass. Background Art

[0002] The primary packaging of injections is a container composed of medium borosilicate glass as the main material, such as vials, PFS prefilled syringes, cartridges, etc. Syringes and vials need to be silanized before they can be used. On the container, siliconization provides a barrier coating between the glass and the drug formulation to prevent the adsorption of the formulation ingredients on the glass surface. The hydrophobicity of the siliconized surface improves the drainage capacity of the container. In pre-injectable syringes and vials, siliconization also has another function, which is used to lubricate the syringe barrel or barrel so that the plunger can be pushed forward smoothly.

[0003] At present, the silanization treatment is mainly based on Dow Corning's dimethyl silicone oil emulsion (DC366 35% Dimethicone NFEmulsion), which is a water-dilutable emulsion containing non-ionic surfactants and 35% Dimethicone. Its main component is trimethyl-terminated polysiloxane. After dilution, it is sprayed on the inner wall of the glass container and then cured at high temperature. A layer of silicone oil coating can be formed on the glass surface, thereby improving the lubrication and waterproof properties. However, current studies have shown that the use of DC366 silicone oil as a silanization agent cannot cause polysiloxane to completely react chemically with medium-borosilicate glass. There will be a large amount of physically adsorbed DC366 silicone oil on the glass surface. Although the hydrophobicity of the glass surface has been improved to a certain extent, due to the presence of a large amount of physically adsorbed silicone oil, this will easily cause the active ingredients of the drug (peptides, proteins) to interact with the silicone oil layer, such as condensation, adsorption and shedding into the solution.

[0004] Since both peptides and proteins have the property of being adsorbed on silicone oil, for some low-dose peptide and protein injections, this adsorption effect will cause unnecessary content loss in the product. Therefore, the vials produced by the existing siliconization process will inevitably have a small amount of silicone oil leached into the drug solution because the coating modified on the glass surface will cause the adsorbed silicone oil gel to fall off under the action of external force (shear force formed by the shaking of the solution during transportation), thus causing silicone oil to contaminate the drug.

[0005] In summary, the present invention proposes a new silanization method, which uses a greener, more environmentally friendly, and low-energy chemical method to achieve complete silanization treatment of the surface of medium-borosilicate glass, so as to avoid the above-mentioned glass defects and silicone oil contamination of drugs. Summary of the invention

[0006] The purpose of the present invention is to solve the technical problems raised in the above-mentioned background technology and to provide an efficient silicidation method for medium-borosilicate glass, which can be used in glass containers to significantly reduce the risk of leaching of metal elements in the glass without causing contamination of drugs.

[0007] In order to achieve the above object, the technical solution adopted by the present invention is:

[0008] An efficient silicidation method for medium borosilicate glass comprises the following steps:

[0009] S1: spraying a silanization reagent on the surface of medium borosilicate glass; wherein the silanization reagent is a mixture of N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) and a solvent;

[0010] S2: low temperature reaction under nitrogen atmosphere;

[0011] S3: Cooling and cleaning.

[0012] Preferably, the solvent in the silanization reagent in step S1 is hexamethyldisiloxane or tetrahydrofuran (THF).

[0013] Preferably, in step S1, the volume ratio of N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) to the solvent is (1-3):(1-5).

[0014] Preferably, the atomization pressure of the spraying in step S1 is 1.0-1.5 bar.

[0015] Preferably, the coating amount of the silanization agent in step S1 is 30 μg to 50 μg / cm 2 .

[0016] Preferably, the low temperature in step S2 is 60-65°C.

[0017] Preferably, the reaction time in step S2 is 90 min to 120 min.

[0018] Preferably, the cooling and cleaning in step S3 uses toluene, anhydrous ethanol, and deionized water for ultrasonic cleaning for 5 minutes each;

[0019] Preferably, before step S1, the step further includes cleaning and drying the borosilicate glass;

[0020] Preferably, in step S1, the silanization agent is sprayed on the drug contact surface of the borosilicate glass.

[0021] The beneficial effects of the present invention are:

[0022] The method of the present invention uses BSTFA as a silanization agent, which can react at low temperature to promote the conversion of silanol groups on the glass surface into silanyl groups, and achieve BSTFA's full participation in the silanization reaction, thereby avoiding the risk of silicone oil leaching, effectively reducing the risk of silicone oil contaminating drugs, and solving the problem of drug adsorption on the glass surface. The present invention improves the physical stability of drugs such as polypeptides and proteins during long-term storage, ensuring that drugs close to the life cycle of the drug still have good efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 is a comparison chart of the water antenna angle (WCA) results of the untreated vial and Examples 1-8;

[0024] Figure 2 1 is the infrared characteristic graph of the untreated vial and the vial treated with low temperature siliconization in Example 1-8;

[0025] Figure 3 The methylene blue staining results of the untreated vials and the vials treated in Examples 1, 3, and 5 are shown;

[0026] Figure 4 pH value of water tested by an acidometer for untreated vials and vials treated in Examples 1, 3, and 5

[0027] Figure 5 The silanized vials of Comparative Examples 1 and 2 lost their surface hydrophobicity significantly after extraction, proving that a large amount of physically adsorbed silicone oil existed on their surfaces. DETAILED DESCRIPTION

[0028] In order to better understand the content of the present invention, the content of the present invention is further described below in conjunction with specific implementation methods, but the protection content of the present invention is not limited to the following embodiments.

[0029] Comparative Example 1: Using dimethyl silicone oil emulsion (DC366) as a silanization agent and performing UV curing reaction

[0030] (1) Wash a 2 mL vial with 75-80°C water for injection, then blow it with compressed air;

[0031] (2) Siliconizing the vials with a dimethyl silicone oil emulsion having a dimethyl silicone oil concentration of 2.5% (by weight), with an atomization pressure of 1.0-1.5 bar and a silicone oil coating amount of 3-5 mg / vial (the coating amount refers to the sample inspection after the silicone oil is sprayed but before drying. If the coating amount is within this range, the subsequent operation is officially carried out, and it is calculated based on the weight gain of each vial);

[0032] (3) Transfer the siliconized vials to a tunnel sterilization oven, set the temperature to 180°C, sterilize for 15 minutes, and then cool;

[0033] (4) The cooled vial was transferred to an ultraviolet light box with a power of 120 W. The ultraviolet light was turned on for 20 min to cure the vial to obtain a siliconized vial.

[0034] Comparative Example 2: Using dimethyl silicone oil emulsion (DC366) as a silanization agent and performing a high temperature reaction

[0035] (1) Wash a 2 mL vial with 75-80°C water for injection, then blow it with compressed air;

[0036] (2) Siliconizing the vials with a dimethyl silicone oil emulsion having a dimethyl silicone oil concentration of 2.5% (by weight), with an atomization pressure of 1.0-1.5 bar and a silicone oil coating amount of 3-5 mg / vial (the coating amount refers to the sample inspection after the silicone oil is sprayed but before drying. If the coating amount is within this range, the subsequent operation is officially carried out, and it is calculated based on the weight gain of each vial);

[0037] (3) Transfer the siliconized vial to a muffle furnace, set the temperature to 320°C, react at high temperature for 15 minutes, and then cool;

[0038] (4) The cooled vial was cleaned with toluene, anhydrous ethanol, and deionized water for 5 min each, and then placed in an oven at 120°C for drying.

[0039] Example 1

[0040] (1) Wash a 10 mL vial with water for injection and then purge it with N2 gas;

[0041] (2) preparing a silanization reagent by mixing BSTFA and THF in a volume ratio of 1:5; spraying the silanization reagent into the interior of a vial;

[0042] (3) Transfer the siliconized vial to an oil bath and seal it with a rubber stopper. Set the temperature to 65°C, continue to introduce nitrogen gas for 120 min, and then cool it down.

[0043] (4) Wash the cooled vial with toluene, anhydrous ethanol, and deionized water for 5 minutes each.

[0044] Oven dried at 120°C.

[0045] Example 2

[0046] (1) Wash a 10 mL vial with water for injection and then purge it with N2 gas;

[0047] (2) preparing a silanization reagent by mixing BSTFA and THF in a volume ratio of 3:5; spraying the silanization reagent into the interior of a vial;

[0048] (3) Transfer the siliconized vial to an oil bath and seal it with a rubber stopper. Set the temperature to 65°C, continue to introduce nitrogen gas for 120 min, and then cool it down.

[0049] (4) The cooled vial was cleaned with toluene, anhydrous ethanol, and deionized water for 5 min each, and then placed in an oven at 120°C to dry.

[0050] Example 3

[0051] (1) Wash a 10 mL vial with water for injection and then purge it with N2 gas;

[0052] (2) preparing a silanization reagent by mixing BSTFA and THF in a volume ratio of 1:1; spraying the silanization reagent into the interior of a vial;

[0053] (3) Transfer the siliconized vial to an oil bath and seal it with a rubber stopper. Set the temperature to 65°C, continue to introduce nitrogen gas for 120 min, and then cool it down.

[0054] (4) Wash the cooled vial with toluene, anhydrous ethanol, and deionized water for 5 minutes each.

[0055] Oven dried at 120°C.

[0056] Example 4

[0057] (1) Wash a 10 mL vial with water for injection and then purge it with N2 gas;

[0058] (2) Spray the prepared silanization reagent (the volume ratio of BSTFA to hexamethyldisiloxane Q7-9180 is 1:5) onto the inside of the vial;

[0059] (3) Transfer the siliconized vial to an oil bath and seal it with a rubber stopper. Set the temperature to 65°C, continue to introduce nitrogen gas for 120 min, and then cool it down.

[0060] (4) The cooled vial was cleaned with toluene, anhydrous ethanol, and deionized water for 5 min each, and then placed in an oven at 120°C for drying.

[0061] Example 5

[0062] (1) Wash a 10 mL vial with water for injection and then purge it with N2 gas;

[0063] (2) Spray the prepared siliconizing agent (the volume ratio of BSTFA to Q7-9180 is 3:5) onto the inside of the vial;

[0064] (3) Transfer the siliconized vial to an oil bath and seal it with a rubber stopper. Set the temperature to 65°C, continue to introduce nitrogen gas for 120 min, and then cool it down.

[0065] (4) The cooled vial was cleaned with toluene, anhydrous ethanol, and deionized water for 5 min each, and then placed in an oven at 120°C for drying.

[0066] Example 6

[0067] (1) Wash a 10 mL vial with water for injection and then purge it with N2 gas;

[0068] (2) Spray the prepared siliconizing agent (the volume ratio of BSTFA to Q7-9180 is 1:1) onto the inside of the vial;

[0069] (3) Transfer the siliconized vial to an oil bath and seal it with a rubber stopper. Set the temperature to 65°C, continue to introduce nitrogen gas for 120 min, and then cool it down.

[0070] (4) The cooled vial was cleaned with toluene, anhydrous ethanol, and deionized water for 5 min each, and then placed in an oven at 120°C for drying.

[0071] Example 7

[0072] (1) Wash a 10 mL vial with water for injection and then purge it with N2 gas;

[0073] (2) preparing a silanization reagent by mixing BSTFA and THF in a volume ratio of 1:1; spraying the silanization reagent into the interior of a vial;

[0074] (3) Transfer the siliconized vial to an oil bath and seal it with a rubber stopper. Set the temperature to 60°C, continue to introduce nitrogen gas for 120 min, and then cool it down.

[0075] (4) The cooled vial was cleaned with toluene, anhydrous ethanol, and deionized water for 5 min each, and then placed in an oven at 120°C for drying.

[0076] Example 8

[0077] (1) Wash a 10 mL vial with water for injection and then purge it with N2 gas;

[0078] (2) Spray the prepared siliconizing agent (the volume ratio of BSTFA to Q7-9180 is 1:1) onto the inside of the vial;

[0079] (3) Transfer the siliconized vial to an oil bath and seal it with a rubber stopper. Set the temperature to 60°C, continue to introduce nitrogen gas for 120 min, and then cool it down.

[0080] (4) The cooled vial was cleaned with toluene, anhydrous ethanol, and deionized water for 5 min each, and then placed in an oven at 120°C to dry.

[0081] Figure 1 is a comparison chart of the water antenna angle (WCA) results of the untreated vial and Examples 1-8;

[0082] Figure 2 1 is the infrared characteristic graph of the untreated vial and the vial treated with low temperature siliconization in Example 1-8;

[0083] Figure 3 It is a comparison diagram of the methylene blue dyeing experiment of the vials treated by low temperature siliconization and the vials not treated by the present invention;

[0084] Figure 4 The present invention implements a water resistance test of glass at 121° C. on vials treated with low-temperature siliconization and untreated vials.

[0085] Related tests

[0086] (1) The bottom of the untreated vial and the vial treated with low-temperature siliconization in Example 1-8 were tested for water contact angles to compare the improvement in the hydrophobicity of the glass surface. Figure 1 The silanization reagent BSTFA significantly improved the hydrophobicity of the vials.

[0087] (2) Fourier transform infrared spectroscopy was performed on the untreated vials and the vials treated with low temperature siliconization in Example 1-8 to characterize the changes in the main groups (silicon methyl) on the glass surface. Figure 2 Infrared spectra of Examples 1 to 8.

[0088] (3) The colorimetric staining method was used to detect the uniformity of the glass surface of the untreated vials and the vials treated with low-temperature siliconization in Examples 1, 3, and 5. The vials were rinsed twice with distilled water, filled to the brim with 0.05% methylene blue solution (Sigma-Aldrich), and allowed to equilibrate for 20 minutes. After being rinsed twice with distilled water, they were dried in an oven at 120°C and then observed. Figure 3 Column (A) shows an untreated vial, a large area of ​​which is stained with methylene blue. Columns (B), (C), and (D) show Examples 1, 3, and 5, respectively, which do not show methylene blue staining, indicating that the silanization treatment is relatively uniform.

[0089] (4) Accurately weigh 10.00 g of untreated vials and vial glass particles treated with low-temperature siliconization in Examples 1, 3, and 5, place them in a 250 mL conical flask, and accurately add 50 mL of water. Invert a beaker on the conical flask, place the conical flask in a pressure steam sterilizer, open the exhaust valve, heat at a uniform rate, allow steam to spray from the exhaust valve for 10 minutes, close the exhaust valve, continue heating, and raise the temperature to 121°C within 19 to 33 minutes. Start timing when this temperature is reached. After maintaining at 121°C for 30 minutes ± 1 minute, slowly cool and reduce the pressure, and reduce the temperature to 100°C within 38 to 46 minutes (to prevent vacuum formation). Remove from the pressure steam sterilizer and cool to room temperature. Prepare a blank solution in the same way. Use a pH meter to detect the pH value of the water, see Figure 4 .

[0090] (5) Take Comparative Examples 1 and 2, extract with n-heptane solution, add 5 ml of n-heptane into the vial, vortex stir at 1500 rpm / min for 2 h, then remove n-heptane with N2 at 100°C, and then ultrasonically clean with toluene, ethanol, and deionized water for 5 min each. And detect the change of the water contact angle on its surface. Figure 5 The silanized vials of Comparative Examples 1 and 2 lost their surface hydrophobicity significantly after extraction, proving that a large amount of physically adsorbed silicone oil existed on their surfaces. Figure 5 A is comparative example 1 (before extraction), water contact angle: 103.23°; B is comparative example 1 (after extraction), water contact angle: 46.57°; C is comparative example 2 (before extraction), water contact angle: 105.28°; D is comparative example 2 (after extraction), water contact angle: 48.53°.

Claims

1. An efficient silicidation method for medium borosilicate glass, characterized in that: The method comprises the following steps: S1: spraying a silanization reagent on the surface of medium borosilicate glass; wherein the silanization reagent is a mixture of N,O-bis(trimethylsilyl)trifluoroacetamide and a solvent; S2: low temperature reaction under nitrogen atmosphere; the low temperature is 60-65°C; S3: Cooling and cleaning.

2. The method according to claim 1, characterized in that The solvent in the silanization reagent in step S1 is hexamethyldisiloxane or tetrahydrofuran.

3. The method according to claim 1, characterized in that In step S1, the volume ratio of N,O-bis(trimethylsilyl)trifluoroacetamide to the solvent is (1-3):(1-5).

4. The method according to claim 1, characterized in that: The atomization pressure of the spraying in step S1 is 1.0-1.5 bar.

5. The method according to claim 1, characterized in that The coating amount of the silanization agent in step S1 is 30 μg to 50 μg / cm 2 .

6. The method according to claim 1, characterized in that The reaction time in step S2 is 90 min to 150 min.

7. The method according to claim 1, characterized in that The cooling and cleaning in step S3 uses toluene, anhydrous ethanol, and deionized water for ultrasonic cleaning for 5 minutes each.

8. The method according to claim 1, characterized in that: Before step S1, the borosilicate glass is also cleaned and dried.

9. The method according to claim 1, characterized in that: In step S1, a silanization agent is sprayed on the drug contact surface of the borosilicate glass.

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