JP2014237562A - Borosilicate glass for medicament container - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a borosilicate glass for medicaments which, without containing large amounts of TiOand LiO, has excellent chemical durability and hydrolysis resistance, and a low operation point.SOLUTION: The borosilicate glass comprises: SiOof 65 to 78 mass%; AlOof 5 to 10 mass%; BOof 3 to 18 mass%; CaO of 0 to 5 mass%; BaO of 0.1 to less than 2.0 mass%; NaO of 0 to 10 mass%; KO of 0 to 5 mass%; and ZrOof 0.1 to 7 mass%.

Description

  The present invention relates to borosilicate glass for pharmaceutical containers used for glass for tubes such as vials and ampoules and syringes for syringes.

Borosilicate glass for pharmaceutical containers such as vials and ampoules is required to have the following characteristics.
(A) High chemical durability and hydrolysis resistance so as not to contaminate the chemicals to be filled. (B) Damage due to thermal shock is unlikely to occur during the manufacturing process of glass tubes and processing into vials, ampoules, etc. (C) low working point so that processing into vials, ampoules, etc. can be performed at low temperature (d) resistance to devitrification so that devitrification does not occur when forming into glass tubes, etc. High permeability The standard borosilicate glass for pharmaceutical containers satisfying these required characteristics is composed of SiO ₂ , B ₂ O ₃ , Al ₂ O ₃ , NaO ₂ , K ₂ O, BaO, and CaO as constituent components. And a small amount of fining agent.

JP 2011-16713 A Patent No. 4215176

  In recent years, development of chemicals to be filled has progressed, and chemicals with higher medicinal effects are being used. Accordingly, borosilicate glass for pharmaceutical containers constituting vials and ampoules is required to have higher chemical durability and hydrolysis resistance than ever before.

Under such circumstances, for example, Patent Document 1 and Patent Document 2 propose glass in which ZrO ₂ is added in order to improve chemical durability and hydrolysis resistance.

However, when a large amount of ZrO ₂ is added, the viscosity increases and the working point becomes high. Therefore, in Patent Document 1, an increase in viscosity is suppressed by adding TiO ₂ . However, when a large amount of TiO ₂ is added, not only an increase in production cost is caused, but also the glass is colored and the transmittance in the visible region is lowered.

Patent Document 2 proposes a glass to which Li ₂ O is added to reduce the viscosity of the glass, but this may cause an increase in production cost and refractory erosion during melting.

An object of the present invention is to provide a borosilicate glass for a pharmaceutical container that has good chemical durability and hydrolysis resistance and has a low working point even if it does not contain a large amount of TiO ₂ or Li ₂ O. It is.

The borosilicate glass for pharmaceutical containers of the present invention is SiO ₂ 65 to 78%, Al ₂ O ₃ 3 to 10%, B ₂ O _{3 3 to} 18%, CaO 0 to 5%, BaO 0.1 to 0.1% by mass. less than _{2%, Na 2 O 0~10%} , K 2 O 0~5%, characterized in that it contains ZrO 2 0.1 to 7%.

According to the above configuration, since the containing ZrO _2, it is possible to obtain chemical durability and resistance to hydrolysis of good pharmaceutical container borosilicate glass. Further, since BaO is contained as an essential component, it becomes easy to set the working point to 1230 ° C. or lower.

In the present invention, the content of Li ₂ O is preferably 0 to 0.4% by mass.

  According to the above configuration, refractory erosion during glass melting can be effectively prevented, and raw material costs can be reduced.

In the present invention, the content of TiO ₂ is preferably 0 to 0.4% by mass.

  According to the said structure, while being able to prevent coloring of glass effectively, it becomes possible to reduce raw material cost.

In the present invention, in an acid resistance test according to DIN (German Industrial Standard) 12116, the mass loss per area is preferably 1.3 mg / dm ² or less.

In the present invention, in the alkali resistance test according to ISO (International Organization for Standardization) 695, the mass loss per area is preferably 125 mg / dm ² or less.

  In the present invention, in the powder test method of the hydrolysis resistance test according to EP (European Pharmacopoeia) 7.0, the consumption of 0.02 mol / L hydrochloric acid per unit glass mass is 0.03 mL or less. It is preferable.

In the present invention, it is preferable to have a work point of 1230 ° C. or lower. The working point is a temperature at which the viscosity of the glass is 10 ⁴ dPa · s.

In the present invention, it is preferable to have a liquid phase viscosity of 10 ^5.5 dPa · s or more.

  According to the above configuration, devitrification is less likely to occur during molding into a glass tube, and a glass tube can be produced with a high yield.

  The glass tube for a pharmaceutical container of the present invention is characterized by comprising the above-described borosilicate glass for a pharmaceutical container.

  Hereinafter, the reason why the composition range of each component is limited as described above will be described. In the following description, unless otherwise specified,% display means mass%.

SiO ₂ is one of the elements constituting the glass network. Its content is 65-78%, preferably 65-76%, more preferably 67-74%. When the content of SiO ₂ is too small decreases chemical durability, it can not meet the acid resistance required for the borosilicate glass for pharmaceutical containers. On the other hand, if the content of SiO ₂ is too large liquidus viscosity lowers, easily occurs devitrification in the manufacturing process.

Al ₂ O ₃ is a component that suppresses devitrification of the glass and improves chemical durability. The content is 3 to 10%, preferably 5 to 10%, more preferably less than 5.5 to 9%, and still more preferably 5.7 to 8%. If the content of Al ₂ O ₃ is too small, the above effect cannot be obtained. On the other hand, the viscosity of the glass is increased when the content of Al ₂ O ₃ is too large, it is impossible to obtain a working point to target.

B ₂ O ₃ not only lowers the melting point of the glass but also increases the liquid phase viscosity and suppresses devitrification. Furthermore, it is known to contribute to the improvement of hydrolysis resistance. Therefore, the content of B ₂ O ₃ is ₃ to 18%, preferably 5.5 to 16%, more preferably 10.1 to 13%, and still more preferably 11 to 12.5%. Meltable and content is too small of B ₂ O ₃ is deteriorated. On the other hand, B ₂ when the content of O ₃ is too much resistance to hydrolysis and chemical durability is lowered.

  CaO has the effect of improving the solubility of the glass and improving the chemical durability. The content is 0 to 5%, preferably 0 to 3%, more preferably 0 to 2%. When there is too much CaO content, it will become easy to devitrify glass, and chemical durability will deteriorate.

  BaO has the effect of reducing the viscosity of the glass. Its content is less than 0.1 to 2%, preferably 0.1 to 1.9%, more preferably 0.1 to 0.5%. When there is too little content of BaO, the viscosity of glass will increase and the target working point cannot be obtained. Moreover, when there is too much content of BaO, a liquid phase viscosity will fall and there exists a possibility of devitrifying glass at a manufacturing process.

Na ₂ O also has the effect of lowering the viscosity of the glass in the same manner as BaO. The content of Na ₂ O is 0 to 10%, preferably 3 to 10%, more preferably 5 to 8%. Content of Na 2 _O is too large, the linear thermal expansion coefficient of increased significantly thermal shock resistance is deteriorated.

K ₂ O also has the effect of reducing the viscosity of the glass, like BaO and Na ₂ O. The content of K ₂ O is 0 to 5%, more preferably 0 to 3%. The content of K 2 _O is too large when the linear thermal expansion coefficient of increased significantly thermal shock resistance is deteriorated.

ZrO ₂ has the effect of improving chemical durability and hydrolysis resistance. The content of ZrO ₂ is 0.1 to 7%, preferably 0.51 to 7%, more preferably 1 to 5%. If the content of ZrO ₂ is too small, chemical durability, particularly alkali resistance cannot be improved, and improvement in hydrolysis resistance cannot be expected. On the other hand, when the content of ZrO ₂ is too large, the viscosity of the glass is significantly increased, and it becomes difficult to obtain a working point of 1230 ° C. or lower. Moreover, there is a possibility of devitrifying the glass in the manufacturing process.

  In the present invention, various components other than the above can be added.

For example _Cl as a fining agent, _Sb 2 _{O 3,} a SnO 2, _Na 2 SO ₄ and the like may also contain one or more kinds. The total content of these fining agents is 3% or less, preferably 1% or less, more preferably 0.5% or less. Among these fining agents, it is preferable to use Cl for the reason that the melting temperature is less harmful to the human body. When Cl is used, its content is preferably 3% or less, particularly preferably 0.1 to 1%.

If the amount is small, Li ₂ O or TiO ₂ can be added.

Li ₂ O has the effect of lowering the viscosity of the glass and increasing the coefficient of linear thermal expansion in the same manner as BaO. However, when Li ₂ O is added, the refractory is easily eroded when the glass is melted. It also leads to an increase in production costs. Therefore, the content of Li ₂ O is preferably 0 to 0.4%, 0 to less than 0.1%, 0 to 0.05%, particularly preferably 0 to 0.01%. it is desirable to use other alkaline oxides other than _{2 O.}

TiO ₂ has the effect of reducing the viscosity of the glass. However, since it has an absorption wavelength in the ultraviolet region, excessive addition colors the glass and lowers the transmittance in the visible region. Therefore, the content of TiO ₂ is preferably 0 to 0.4%, 0 to less than 0.1%, particularly preferably 0 to less than 0.05%.

  Moreover, it is preferable that the borosilicate glass for pharmaceutical containers of this invention has the following characteristics.

In the acid resistance test according to DIN12116, weight loss per unit area 1.3 mg / dm ² or less, particularly preferably 1.2 mg / dm ^2. When the amount of mass loss is greater than 1.3 mg / dm ^{2, when} a bottle container such as an ampoule or a vial is prepared, filled with chemicals, and stored, the amount of elution of the glass component is greatly increased, causing alteration of the chemical components. There is a fear.

In the alkali resistance test according to ISO695, the mass reduction amount per unit area is preferably 125 mg / dm ² or less, particularly 121 mg / dm ² . If the amount of mass loss is greater than 125 mg / dm ^{2, when} a bottle container such as an ampoule or vial is prepared, filled with chemicals, and stored, there is a risk that the amount of elution of glass components will increase significantly, causing alteration of chemical components. is there.

  In the powder test method of the hydrolysis resistance test according to EP 7.0, the consumption of 0.02 mol / L hydrochloric acid per unit glass mass is preferably 0.05 mL or less, particularly preferably 0.03 mL or less. If hydrochloric acid consumption is greater than 0.1 mL, glass bottles such as ampoules and vials are created, filled with chemicals, and stored, and the elution of glass components, particularly alkali components, may increase significantly, causing chemical component alteration. There is.

  The working point is preferably 1230 ° C. or less, particularly preferably 1220 ° C. or less. When the working point is high, the processing temperature when producing a glass container such as an ampoule or a vial from the glass tube increases, and the evaporation amount of the alkali component in the glass increases remarkably. The evaporated alkali component adheres to the inner surface of the glass container and elutes during storage of the chemical solution or during autoclaving after the chemical solution is filled, causing deterioration of the chemical component or an increase in the pH of the chemical solution.

The liquid phase viscosity is 10 ^5.5 dPa · s or more, preferably 10 ^6.0 dPa · s or more, more preferably 10 ^6.4 dPa · s or more. When the liquid phase viscosity is lower than 10 ^5.5 dPa · s, devitrification is likely to occur during sleeve molding by the Danner method, and productivity is deteriorated.

  The liquidus temperature is an important parameter for evaluating the devitrification property of glass. When the liquidus temperature is high, glass devitrification tends to occur in the production process and the processing process. Therefore, it is preferable that the borosilicate glass for pharmaceutical containers having sufficient devitrification resistance has a liquidus temperature of 1020 ° C. or lower.

The linear thermal expansion coefficient is an important parameter in the thermal shock resistance of glass. In order to obtain a sufficient thermal shock resistance, the glass has a linear thermal expansion coefficient of 58 × 10 ⁻⁷ / ° C. or less, particularly 48 to 54 × 10 ⁻⁷ / ° C. in a temperature range of 30 to 380 ° C. preferable.

  Next, a method for producing the glass tube for a pharmaceutical container of the present invention will be described. The following description is an example using the Danner method.

  First, a glass batch is prepared by blending glass raw materials so as to have the above glass composition. Next, the glass batch was continuously charged into a melting furnace at 1550 to 1700 ° C., melted and clarified, and then the obtained molten glass was wound around a rotating refractory while blowing air from the tip of the refractory, Glass is pulled out from the tip portion into a tubular shape. The drawn tubular glass is cut into a predetermined length to obtain a glass tube for a pharmaceutical container. The glass tube thus obtained is used for manufacturing vials and ampoules.

  In addition, you may manufacture the glass tube for pharmaceutical containers of this invention not only with the Danner method but using the conventionally well-known arbitrary methods. For example, the bellows method and the downdraw method are also effective methods for producing the glass tube for a pharmaceutical container of the present invention.

  Hereinafter, the present invention will be described based on examples.

  Table 1 shows examples of the present invention (sample Nos. 1 to 3), and Table 2 shows comparative examples (samples Nos. 4 and 5).

  Each sample was prepared as follows.

  First, a batch of 500 g of glass was prepared and melted at 1650 ° C. for 4 hours using a platinum crucible. In order to remove bubbles in the melt, stirring was performed twice during melting. After melting, an ingot was prepared, processed into a shape necessary for measurement, and subjected to various evaluations.

As is clear from the table, each sample of the example to which ZrO ₂ was added showed good chemical durability and hydrolysis resistance. Each sample was confirmed to have a working point of 1230 ° C. or lower.

  The linear thermal expansion coefficient was measured in a temperature range of 30 to 380 ° C. with a self-differential thermal dilatometer using a glass sample molded into a rod shape of about 5 mmφ × 50 mm.

  The strain point, annealing point, softening point and working point were measured by the fiber elongation method.

  The liquid phase temperature was measured by filling a crushed glass sample in a platinum boat of about 120 × 20 × 10 mm and placing it in an electric furnace having a linear temperature gradient for 24 hours. Then, the crystal precipitation location was identified by microscopic observation, the temperature corresponding to the crystal precipitation location was calculated from the temperature gradient graph of the electric furnace, and this temperature was defined as the liquidus temperature.

  The liquid phase viscosity is calculated by calculating the glass viscosity curve from the strain point, annealing point, softening point, working point and Fulcher's viscosity calculation formula, and calculating the viscosity of the glass at the liquid phase temperature from this viscosity curve. Was the liquid phase viscosity.

The acid resistance test was performed according to DIN12116, with the sample surface area set to 50 cm ² and the amount of 6 mol / L hydrochloric acid as the eluent to 800 mL. The detailed test procedure is as follows. First, a glass sample piece having a total surface area of 50 cm ² with a mirror polished finish on all surfaces was prepared. As a pretreatment, the sample was hydrofluoric acid (40 mass%) and hydrochloric acid (2 mol / L) at a volume ratio of 1: 9. It was immersed in the solution so mixed and stirred with a magnetic stirrer for 10 minutes. Next, the sample piece was taken out and subjected to ultrasonic cleaning for 2 minutes in ultrapure water three times, and then ultrasonic cleaning for 2 minutes in ethanol was performed twice. Next, the sample piece was dried in an oven at 110 ° C. for 1 hour and cooled in a desiccator for 30 minutes. The mass m ₁ of the sample piece thus obtained was measured to an accuracy of ± 0.1 mg and recorded. Subsequently, 800 mL of 6 mol / L hydrochloric acid was placed in a beaker made of quartz glass, heated using an electric heater until boiling, and a sample piece suspended with a platinum wire was added and held for 6 hours. In order to prevent a decrease in the liquid volume during the test, the opening of the lid of the container was plugged with a gasket and a cooling pipe. Thereafter, the sample piece was taken out and subjected to ultrasonic cleaning for 3 minutes in ultrapure water three times, and then ultrasonic cleaning for 2 minutes in ethanol was performed twice. Further, the washed sample piece was dried in an oven at 110 ° C. for 1 hour and cooled in a desiccator for 30 minutes. The mass m ₂ of the sample thus treated was measured to an accuracy of ± 0.1 mg and recorded. Finally, the amount of mass reduction per unit area was calculated from the masses m ₁ and m ₂ mg of the sample before and after being added to boiling hydrochloric acid and the total surface area Acm ^{2 of the} sample by the following formula 1, and used as the measured value in the acid resistance test. .

[Formula 1] Mass reduction per unit area = 100 × (m ₁ −m ₂ ) / 2 × A

The alkali resistance test was performed by a method according to ISO695. The detailed test procedure is as follows. First, a glass sample piece having a total surface area of 15 cm ² having a mirror-polished finish on all surfaces was prepared. As a pretreatment, the sample was hydrofluoric acid (40 mass%) and hydrochloric acid (2 mol / L) at a volume ratio of 1: 9. It was immersed in the solution so mixed, and stirred with a magnetic stirrer for 10 minutes. Next, the sample piece was taken out and subjected to ultrasonic cleaning for 2 minutes in ultrapure water three times, and then ultrasonic cleaning for 2 minutes in ethanol was performed twice. The sample was then dried in a 110 ° C. oven for 1 hour and cooled in a desiccator for 30 minutes. The mass m _{1 of} the sample thus obtained was measured to an accuracy of ± 0.1 mg and recorded. Subsequently, 800 mL of a solution prepared by mixing a 1 mol / L sodium hydroxide aqueous solution and a 0.5 mol / L sodium carbonate aqueous solution in a volume ratio of 1: 1 in a stainless steel container is boiled using an electric heater. The sample piece suspended with a platinum wire was put in and held for 3 hours. In order to prevent a decrease in the liquid volume during the test, the opening of the lid of the container was plugged with a gasket and a cooling pipe. Thereafter, the sample piece is taken out and immersed in a beaker containing 500 mL of 1 mol / L hydrochloric acid three times, followed by ultrasonic cleaning for 2 minutes in ultrapure water three times, and ultrasonic cleaning for 1 minute in ethanol. We went twice. Further, the washed sample piece was dried in an oven at 110 ° C. for 1 hour and cooled in a desiccator for 30 minutes. The mass m _{2 of} the sample thus treated was measured to an accuracy of ± 0.1 mg and recorded. Finally, the amount of mass reduction per unit area was calculated from the masses m ₁ and m ₂ mg of the sample before and after being put into the boiling solution and the total surface area Acm ^{2 of the} sample by Equation 1, and used as a measurement value in the alkali resistance test.

  In the hydrolysis resistance test, the sample was pulverized using an mortar and pestle made of alumina, and a method according to the powder test method of EP 7.0 was used. The detailed test procedure is as follows. The surface of the sample was thoroughly wiped with ethanol, and the sample was pulverized with an alumina mortar and pestle, and then classified using three sieves made of stainless steel, 710 μm, 425 μm, and 300 μm. What remained on the sieve was pulverized again and subjected to the same sieving operation. The sample powder remaining on the 300 μm sieve was washed with ultrapure water and placed in a glass container such as a beaker. Thereafter, ultrapure water was added and stirred, and the operation of pouring out only the supernatant was performed three times. Thereafter, the same operation was performed twice with ethanol to wash the sample powder, dried in an oven at 110 ° C. for 30 minutes, and cooled in a desiccator for 30 minutes. The obtained sample powder was weighed with an accuracy of 10 g ± 0.0001 g using an electronic balance, placed in a 250 mL flask, and 50 mL of ultrapure water was added. After sealing, the flask was placed in an autoclave and kept at 121 ° C. for 30 minutes. The temperature was raised at 1 ° C./min from 100 ° C. to 121 ° C., and the temperature was lowered at 2 ° C./min from 121 ° C. to 100 ° C. After cooling to 95 ° C., the sample was removed into a conical beaker. The inside of the flask was washed with 30 mL of ultrapure water and poured into a conical beaker three times. About 0.05 mL of methyl red was dropped into the liquid after the test, and neutralization titration was performed with 0.02 mol / L hydrochloric acid, and the consumption of hydrochloric acid was recorded.

  The borosilicate glass for pharmaceutical containers and the glass tube for pharmaceutical containers of the present invention are useful as materials for pharmaceutical containers such as vials and ampules and syringes.

Claims (9)

_SiO 2 65 to _78% by _{mass%, Al 2 O 3 3~10%} , B 2 O 3 3~18%, CaO 0~5%, BaO less than _0.1~2%, Na 2 O 0~10% Borosilicate glass for pharmaceutical containers, containing 0 to 5% of K ₂ O and 0.1 to 7% of ZrO ₂ Pharmaceutical container borosilicate glass according to claim 1, wherein the Li 2 _O content is 0 to 0.4% in mass%. The borosilicate glass for a pharmaceutical container according to claim 1 or 2, wherein the content of TiO ₂ is 0 to 0.4% by mass. In the acid resistance test according to DIN12116, pharmaceutical container borosilicate glass according to any one of claims 1 to 3 weight loss per unit area is characterized by comprising a 1.3 mg / dm ² or less. In the alkali resistance test according to ISO695, pharmaceutical container borosilicate glass according to claim 1, weight loss per unit area is characterized by comprising a 125 mg / dm ² or less.   In the powder test method of the hydrolysis resistance test according to EP 7.0, the consumption amount of 0.02 mol / L hydrochloric acid per unit glass mass is 0.03 mL or less. The borosilicate glass for pharmaceutical containers according to any one of the above.   The borosilicate glass for pharmaceutical containers according to any one of claims 1 to 6, which has a working point of 1230 ° C or lower. The borosilicate glass for a pharmaceutical container according to any one of claims 1 to 7, which has a liquid phase viscosity of 10 ^5.5 dPa · s or more. A glass tube for a pharmaceutical container, comprising the borosilicate glass for a pharmaceutical container according to any one of claims 1 to 8.