Container closure systems and seal assemblies that maintain seal integrity at low storage temperatures

Abstract

A sealed pharmaceutical container (100) includes a shoulder (130), a neck (128) extending from the shoulder, and a flange (126) extending from the neck. The flange includes an outer surface (136) extending from a lower side surface (132) and a contact surface (138) extending between the outer surface and an inner surface that defines an opening (105) in the sealed pharmaceutical container. The contact surface includes an outer peripheral edge (142) disposed proximate the outer surface of the flange. The sealed pharmaceutical container includes a sealing assembly (104) including a stopper (106) extending over the contact surface of the flange and covering the opening and a cap (108) securing the stopper to the flange. The stopper includes a sealing surface secured in contact with the contact surface of the flange to form a seal between the flange and the stopper. An outer peripheral edge of the sealing surface is disposed at or radially inward of the outer peripheral edge.

Description

[0001] Cross-reference of related applications

[0002] This application is based on and incorporates in its entirety the priority interest in U.S. Provisional Application No. 63 / 179,719, filed April 26, 2021, pursuant to 35 U.SC §119. Technical Field

[0003] This specification generally relates to container closure systems, such as glass containers for storing pharmaceutical compositions. Background Technology

[0004] Typically, drug containers (such as vials and syringes) are sealed with stoppers or other closures to maintain the integrity of the contained material. Closures are usually made of synthetic rubber and other elastomers. Such materials advantageously possess high permeability resistance and elasticity, facilitating insertion into the container to seal its interior. However, the elasticity of commonly used closure materials can decrease at low temperatures. For example, synthetic rubber currently used as material closures may have a transition temperature greater than or equal to -70°C and less than or equal to -30°C. Below the transition temperature, closures made of this synthetic rubber may behave as solids and cannot elastically expand to compensate for the relatively large difference in thermal expansion coefficients between the glass and the crimping cap used to secure the closure to the container. Therefore, existing sealing assemblies for drug containers may fail at temperatures below or equal to -30°C.

[0005] Some biological materials (such as blood, serum, proteins, stem cells, and other perishable biofluids) need to be stored at temperatures below the glass transition temperature of conventional elastomers to remain usable. For example, some RNA-based vaccines may require storage at dry ice temperatures (e.g., about -80°C) or liquid nitrogen temperatures (e.g., about -180°C) to maintain their activity. Such low temperatures can cause dimensional changes in sealing components (e.g., glass or polymer containers, stoppers, aluminum caps), leading to issues with the integrity of the seals and potential contamination of the materials stored within. Summary of the Invention

[0006] A first aspect of this disclosure includes a sealable drug container comprising a shoulder, a neck extending from the shoulder, and a flange extending from the neck. The flange includes a lower surface extending from the neck, an outer surface extending from the lower surface (the outer surface defining an outer diameter of the flange), and a contact surface extending between the outer surface and an inner surface, the inner surface defining an opening in the sealable drug container. The contact surface includes an inner edge disposed near the opening and an outer peripheral edge disposed near the outer surface of the flange. The sealable drug container includes a sealing assembly comprising a plug extending above the contact surface of the flange and covering the opening, and a cap securing the plug to the flange. The plug includes a sealing surface secured to contact the contact surface of the flange to form a seal between the flange and the plug. The outer peripheral edge of the sealing surface is disposed at the outer peripheral edge of the contact surface of the flange or radially inward of the outer peripheral edge of the contact surface of the flange.

[0007] A second aspect of this disclosure includes a sealed drug container according to the first aspect, wherein the contact surface includes a conical region of the upper surface of a flange.

[0008] A third aspect of this disclosure includes a sealed drug container according to any one of the first to second aspects, wherein the contact surface has a surface roughness of less than or equal to 0.2 μm.

[0009] The fourth aspect of this disclosure includes a sealed drug container according to any one of the first to third aspects, wherein the contact surface does not include a surface height variation greater than or equal to 5.0 μm.

[0010] The fifth aspect of this disclosure includes a sealed drug container according to any one of the first to fourth aspects, wherein the flange further includes a fillet extending between the contact surface and the outer surface.

[0011] The sixth aspect of this disclosure includes a sealed drug container according to any one of the first to fifth aspects, wherein the radius of curvature of the fillet is less than or equal to 21% of the length of the contact surface of the flange.

[0012] The seventh aspect of this disclosure includes a sealed drug container according to any one of the first to sixth aspects, wherein the outer peripheral edge of the sealing surface is disposed radially inward at the transition portion between the upper sealing surface and the rounded corner.

[0013] The eighth aspect of this disclosure includes a sealed drug container according to any one of the first to seventh aspects, wherein the flange further includes a chamfer extending between the contact surface and the outer surface at an angle relative to the contact surface.

[0014] The ninth aspect of this disclosure includes a sealed drug container according to any one of the first to eighth aspects, wherein the angle is less than or equal to 30°.

[0015] The tenth aspect of this disclosure includes a sealed drug container according to any one of the first to ninth aspects, wherein the outer peripheral edge of the sealing surface is disposed radially inward at the transition portion between the upper sealing surface and the chamfer.

[0016] The eleventh aspect of this disclosure includes a sealed drug container according to any one of the first to tenth aspects, wherein the upper sealing surface extends at a flange angle relative to a plane extending through the end of the opening.

[0017] The twelfth aspect of this disclosure includes a sealed drug container according to any one of the first to eleventh aspects, wherein the flange angle is greater than or equal to 5°.

[0018] The thirteenth aspect of this disclosure includes a sealed drug container according to any one of the first to twelfth aspects, wherein the flange angle is less than or equal to 30°.

[0019] The fourteenth aspect of this disclosure includes a sealed drug container according to any one of the first to thirteenth aspects, wherein: the cap includes a metal portion rolled around a lower surface of a flange and a plastic portion holding an upper portion of the metal portion on an upper surface of a stopper, and an inner edge of the metal portion is inserted into the plastic portion such that the upper portion extends at a cap angle relative to a plane extending through an end of an opening.

[0020] The fifteenth aspect of this disclosure includes a sealed pharmaceutical container according to any one of the first to fourteenth aspects, wherein the flange angle differs from the cap angle by no more than one degree.

[0021] The sixteenth aspect of this disclosure includes a sealed drug container according to any one of the first to fifteenth aspects, wherein the stopper is compressed by a cap to provide a residual nominal strain of less than or equal to 8%.

[0022] The seventeenth aspect of this disclosure includes a sealed drug container according to any one of the first to sixteenth aspects, wherein, when the sealed drug container is cooled to a temperature less than or equal to -80°C, the sealing assembly maintains a helium leakage rate of the sealed drug container less than or equal to 1.4 x 10⁻⁶. -6 cm 3 / s.

[0023] The eighteenth aspect of this disclosure includes a sealed drug container according to any one of the first to seventeenth aspects, wherein when the sealed drug container is cooled to a temperature less than or equal to -80°C, the sealing surface maintains a contact area greater than or equal to 10% of the total surface area of ​​the contact surfaces.

[0024] The nineteenth aspect of this disclosure includes a sealable drug container comprising a shoulder; a neck extending from the shoulder; and a flange extending from the neck. The flange includes a lower surface extending from the neck; an outer surface extending from the lower surface, the outer surface defining an outer diameter of the flange; and an upper surface extending between the outer surface and an inner surface, the inner surface defining an opening in the sealable drug container. The upper surface includes a conical region extending between the opening and the outer surface, wherein the conical region does not include a surface height deviation greater than or equal to 5 μm; and a transition region extending between the conical region and the outer surface. The sealable drug container includes a sealing assembly comprising: a stopper covering the opening; and a cap that is rolled onto the lower surface of the flange, thereby compressing a sealing surface of the stopper against the conical region such that the outer peripheral edge of the sealing surface contacts the conical region.

[0025] The twentieth aspect of this disclosure includes a sealed drug container according to the nineteenth aspect, wherein the contact surface comprises an Ra value of less than or equal to 5 nm.

[0026] The 21st aspect of this disclosure includes a sealed drug container according to any one of the 19th to 20th aspects, wherein when the sealed drug container is cooled to a temperature less than or equal to -80°C, the sealing surface maintains a contact area greater than or equal to 10% of the total surface area of ​​the upper surface.

[0027] The 22nd aspect of this disclosure includes a sealed pharmaceutical container according to any one of the 19th to 21st aspects, wherein the transition region includes a rounded corner, the radius of curvature of which is less than or equal to 21% of the width of the conical portion.

[0028] The 23rd aspect of this disclosure includes a sealed drug container according to any one of the 19th to 22nd aspects, wherein the radius of curvature is less than or equal to 0.5 mm.

[0029] The 24th aspect of this disclosure includes a sealed pharmaceutical container according to any one of the 19th to 23rd aspects, wherein the transition region includes a chamfer extending at an angle relative to the conical region.

[0030] The 25th aspect of this disclosure includes a sealed pharmaceutical container according to any one of the 19th to 24th aspects, wherein the angle is less than or equal to 30°.

[0031] The 26th aspect of this disclosure includes a sealed pharmaceutical container according to any one of the 19th to 25th aspects, wherein the conical portion extends at a flange angle relative to a plane extending through the end of the opening, the flange angle being greater than or equal to 5°.

[0032] The 27th aspect of this disclosure includes a sealed drug container according to any one of the 19th to 26th aspects, wherein the flange angle is less than or equal to 30°.

[0033] The 28th aspect of this disclosure includes a sealed drug container according to any one of the 19th to 27th aspects, wherein: the cap includes a metal portion rolled around a lower surface of a flange and a plastic portion holding an upper portion of the metal portion on an upper surface of a stopper, and an inner edge of the metal portion is inserted into the plastic portion such that the upper portion extends at a cap angle relative to a plane extending through an end of an opening.

[0034] The 29th aspect of this disclosure includes a sealed pharmaceutical container according to any one of the 19th to 28th aspects, wherein the flange angle differs from the cap angle by no more than one degree.

[0035] The thirtieth aspect of this disclosure includes a sealed drug container according to any one of the nineteenth to twenty-ninth aspects, wherein the stopper is compressed by a cap to provide a residual nominal strain of less than or equal to 8%.

[0036] A thirty-fourth aspect of this disclosure includes a sealed drug container according to any of the nineteenth to thirtieth aspects, wherein, when the sealed drug container is cooled to a temperature less than or equal to -80°C, the sealing assembly maintains a helium leakage rate of the sealed drug container less than or equal to 1.4 x 10⁻⁶. -6 cm 3 / s.

[0037] The thirty-second aspect of this disclosure includes a sealed drug container according to any one of aspects nineteen to thirty-one, wherein when the sealed drug container is cooled to a temperature less than or equal to -80°C, the sealing surface maintains a contact surface of greater than or equal to 20 mm. 2 The contact area.

[0038] The thirty-third aspect of this disclosure includes a method for sealing a sealed drug container, the method comprising the steps of: providing a sealed drug container including a shoulder, a neck extending from said shoulder, and a flange extending from said neck, said flange including: a lower surface extending from the neck; an outer surface extending from the lower surface, said outer surface defining an outer diameter of the flange; and an upper surface extending between an outer surface and an inner surface of the sealed drug container, said inner surface defining an opening, said upper surface including a conical region; placing a drug composition into the sealed drug container; providing a sealing assembly including a stopper extending above the upper surface of said flange and covering said opening; pressing a metal-containing cap over the stopper and against the flange, thereby compressing the stopper against the upper surface such that the outer peripheral edge of the sealing surface of the stopper contacts the conical region; and cooling the sealed drug container to a temperature less than or equal to -45°C, wherein, after cooling the sealed drug container, the sealing surface is kept pressed so that the helium leakage rate of the sealed drug container at said temperature is less than or equal to 1.4 x 10⁻⁶. -6 cm 3 / s.

[0039] The thirty-fourth aspect of this disclosure includes a method according to the thirty-third aspect, wherein the metal-containing cap is rolled up such that the plug is compressed against the upper surface to provide a residual nominal strain of less than or equal to 8%.

[0040] The thirty-fifth aspect of this disclosure includes a method according to any one of the thirty-third to thirty-fourth aspects, wherein when the sealed drug container is cooled to the temperature, the contact area between the sealing surface of the stopper and the upper surface of the flange is greater than or equal to 10% of the total surface area of ​​the upper surface.

[0041] The thirty-sixth aspect of this disclosure includes a method according to any one of the thirty-third to thirty-fifth aspects, wherein the temperature is less than or equal to -80°C.

[0042] The thirty-seventh aspect of this disclosure includes a method according to any one of the thirty-third to thirty-sixth aspects, wherein the temperature is less than or equal to -180°C.

[0043] The thirty-eighth aspect of this disclosure includes a method according to any one of the thirty-third to thirty-seventh aspects, wherein: the upper surface further includes a transition region extending between the conical region and the outer surface of the flange, and the outer peripheral edge of the sealing surface does not contact the transition region due to the compression of the plug.

[0044] The thirty-ninth aspect of this disclosure includes a method according to any one of the thirty-third to thirty-eighth aspects, wherein the transition region includes a rounded corner with a radius of curvature of less than 1.0 mm.

[0045] The fortieth aspect of this disclosure includes the method according to any one of the thirty-third to thirty-ninth aspects, wherein the radius of curvature is less than or equal to 0.5 mm.

[0046] The forty-first aspect of this disclosure includes a method according to any one of the thirty-third to fortyth aspects, wherein the transition region includes a chamfer extending at an angle of less than or equal to 30° relative to the conical region.

[0047] The forty-second aspect of this disclosure includes a method according to any one of the thirty-third to forty-first aspects, wherein the conical region extends at a flange angle relative to a plane extending through the end of the opening, the flange angle being greater than or equal to 5°.

[0048] The forty-third aspect of this disclosure includes a method according to any one of the thirty-third to forty-second aspects, wherein: the metal-containing cap includes a metal portion rolled around a lower surface of a flange and a plastic portion holding an upper portion of the metal portion on an upper surface of a stopper, and an inner edge of the metal portion is inserted into the plastic portion such that the upper portion extends at a cap angle relative to a plane extending through an end of an opening.

[0049] The forty-fourth aspect of this disclosure includes a method according to any one of the thirty-third to forty-third aspects, wherein the flange angle differs from the cap angle by no more than one degree.

[0050] The forty-fifth aspect of this disclosure includes a method according to any one of the thirty-third to forty-fourth aspects, wherein the sealed drug container is cooled to the temperature at a rate of less than or equal to 3°C / min.

[0051] The forty-sixth aspect of this disclosure includes a glass container comprising: a shoulder; a neck extending from the shoulder; and a flange extending from the neck, the flange including: a lower surface extending from the neck; an outer surface extending from the lower surface, the outer surface defining an outer diameter of the flange; and an upper surface extending between the outer surface and an inner surface, the inner surface defining an opening in the glass container, wherein the upper surface includes: a conical region extending between the opening and the outer surface, wherein the conical region does not include a surface height deviation greater than or equal to 5 μm; and a transition region extending between the conical region and the outer surface, wherein at least one of the following is satisfied: the transition region includes a chamfer or a fillet, the chamfer extending at a chamfer angle less than or equal to 30° relative to the upper surface, and the fillet including a fillet radius r less than or equal to 0.8 mm. f ; and the conical region extends at a flange angle of 5° or greater relative to the plane, the plane extending through the end of the opening.

[0052] The forty-seventh aspect includes the glass container according to the forty-sixth aspect, wherein: the transition region includes a chamfer with a chamfer angle less than or equal to 10°.

[0053] The forty-eighth aspect of this disclosure includes a glass container according to any one of the forty-sixth or forty-seventh aspects, wherein: the transition region includes a rounded corner with a radius less than or equal to 21% of the width of the conical portion.

[0054] The forty-ninth aspect of this disclosure includes a glass container according to any one of the forty-sixth to forty-eighth aspects, wherein: the conical region extends at a flange angle relative to the plane, the angle being greater than or equal to 5° and less than or equal to 20°.

[0055] Brief description of the attached figures

[0056] The embodiments illustrated in the accompanying drawings are illustrative and exemplary in nature and are not intended to limit the subject matter defined by the claims. A detailed description of the illustrative embodiments can be understood by reading the following drawings, in conjunction with which the same structures are indicated by the same reference numerals, wherein:

[0057] Figure 1 A cross-sectional view of a sealed glass container is schematically shown according to one or more embodiments described herein;

[0058] Figure 2A According to one or more embodiments described herein, a portion of a glass container is schematically shown, which includes a rounded corner extending between the upper and outer surfaces of a flange;

[0059] Figure 2B According to one or more embodiments described herein, a portion of the plug is schematically shown compressed against... Figure 2A On the upper surface of the flange shown;

[0060] Figure 3A According to one or more embodiments described herein, a portion of a glass container is schematically shown, which includes a chamfer extending between the upper and outer surfaces of a flange;

[0061] Figure 3B According to one or more embodiments described herein, a portion of the plug is schematically shown compressed against... Figure 3A On the upper surface of the flange shown;

[0062] Figure 4A According to one or more embodiments described herein, a portion of a glass container is schematically shown, including an upper surface extending at a flange angle relative to a plane that extends through an end of an opening in the glass container;

[0063] Figure 4B According to one or more embodiments described herein, a portion of the plug is schematically shown compressed against... Figure 4A On the upper surface of the glass container shown;

[0064] Figure 5A According to one or more embodiments described herein, simulation results are shown of a portion of a stopper being compressed against the upper surface of a first glass container, the first glass container including an upper surface of a flange extending at a first flange angle relative to a plane extending through the end of an opening of the first glass container;

[0065] Figure 5B According to one or more embodiments described herein, it is shown that when cooled to a temperature of -80°C, a portion of the plug is compressed against... Figure 5A Simulation results of the upper surface of the flange of the first glass container;

[0066] Figure 5C According to one or more embodiments described herein, simulation results are shown of a portion of a stopper being compressed against the upper surface of a flange of a second glass container, the upper surface extending at a second flange angle relative to a plane that extends through the end of the opening of the second glass container;

[0067] Figure 5D According to one or more embodiments described herein, it is shown that when cooled to a temperature of -80°C, a portion of the plug is compressed against... Figure 5C Simulation results on the upper surface of the second glass container;

[0068] Figure 5E According to one or more embodiments described herein, simulation results are shown of a portion of a stopper being compressed against the upper surface of a flange of a third glass container, the upper surface extending at a third flange angle relative to a plane that extends through the end of the opening of the third glass container;

[0069] Figure 5F According to one or more embodiments described herein, it is shown that when cooled to a temperature of -80°C, a portion of the plug is compressed against... Figure 5E Simulation results on the upper surface of the third glass container;

[0070] Figure 5G According to one or more embodiments described herein, simulation results are shown of a portion of a plug being compressed against the upper surface of a flange of a fourth glass container, the upper surface extending at a fourth flange angle relative to a plane that extends through the end of the opening of the fourth glass container;

[0071] Figure 5H According to one or more embodiments described herein, it is shown that when cooled to a temperature of -80°C, a portion of the plug is compressed against... Figure 5G Simulation results on the upper surface of the fourth glass container;

[0072] Figure 6A According to one or more embodiments described herein, a graph is shown showing the change in contact area between the upper surface of a plurality of glass containers and a stopper as a function of temperature, the plurality of glass containers having 20 mm flanges including different flange angles;

[0073] Figure 6B According to one or more embodiments described herein, it is shown that when a glass container is cooled to -80°C, reference Figure 6A The curve showing the change in contact area between the glass container and the stopper as a function of the flange angle;

[0074] Figure 7A According to one or more embodiments described herein, simulation results are shown of a portion of a stopper being compressed against the upper surface of a first glass container, the first glass container including a chamfer extending at a first angle relative to the upper surface of a flange;

[0075] Figure 7B According to one or more embodiments described herein, it is shown that when cooled to a temperature of -80°C, a portion of the plug is compressed against... Figure 7A Simulation results on the upper surface of the first glass container;

[0076] Figure 7C According to one or more embodiments described herein, simulation results are shown of a portion of a stopper being compressed against the upper surface of a second glass container, the second glass container including a chamfer extending at a second angle relative to the upper surface of a flange;

[0077] Figure 7D According to one or more embodiments described herein, it is shown that when cooled to a temperature of -80°C, a portion of the plug is compressed against... Figure 7C Simulation results on the upper surface of the second glass container;

[0078] Figure 7E According to one or more embodiments described herein, simulation results are shown of a portion of a stopper being compressed against the upper surface of a third glass container, the third glass container including a chamfer extending at a third angle relative to the upper surface of a flange;

[0079] Figure 7F According to one or more embodiments described herein, it is shown that when cooled to a temperature of -80°C, a portion of the plug is compressed against... Figure 7ESimulation results on the upper surface of the third glass container;

[0080] Figure 8A According to one or more embodiments described herein, simulation results are shown of a portion of a stopper being compressed against the upper surface of a first glass container, the first glass container including a rounded corner at its outer diameter, the rounded corner having a first radius of curvature at a temperature of 25°C.

[0081] Figure 8B According to one or more embodiments described herein, simulation results are shown of a portion of a stopper being compressed against the upper surface of a second glass container, the second glass container including a rounded corner at its outer diameter, the rounded corner having a second radius of curvature at a temperature of 25°C.

[0082] Figure 8C According to one or more embodiments described herein, it is shown that when cooled to a temperature of -80°C, a portion of the plug is compressed against... Figure 8A Simulation results of the upper surface of the first glass container;

[0083] Figure 8D According to one or more embodiments described herein, it is shown that when cooled to a temperature of -80°C, a portion of the plug is compressed against... Figure 8B Simulation results on the upper surface of the second glass container;

[0084] Figure 8E According to one or more embodiments described herein, it is shown that when cooled to a temperature of -180°C, a portion of the plug is compressed against... Figure 8A Simulation results on the upper surface of the first glass container;

[0085] Figure 8F According to one or more embodiments described herein, it is shown that when cooled to a temperature of -180°C, a portion of the plug is compressed against... Figure 8B Simulation results on the upper surface of the second glass container;

[0086] Figure 9 According to one or more embodiments described herein, a graph showing the contact area between a stopper and a glass container with different corner radii is shown. Detailed Implementation

[0087] Embodiments of a sealed drug container will now be described in detail, comprising a sealing assembly that maintains the container's closure integrity at relatively low storage temperatures (e.g., less than or equal to -30°C, less than or equal to -40°C, less than or equal to -50°C, less than or equal to -60°C, less than or equal to -70°C, less than or equal to -80°C, less than or equal to -100°C, less than or equal to -125°C, less than or equal to -150°C, less than or equal to -175°C, -180°C). To facilitate maintaining the container's closure integrity at such low storage temperatures, the sealed glass container described herein may include a flange designed such that the outer peripheral edge of the sealing surface contacts the upper surface when the sealing surface of a stopper is compressed against the upper surface of the flange using a rolling process. The upper surface of the flange may include a relatively low surface roughness (e.g., including an Ra value of less than or equal to 5 nm) and is free from surface height variations and defects to facilitate a seal with the stopper. In some embodiments, the outer peripheral edge of the sealing surface may be located at the outer peripheral edge of the upper surface of the flange or radially inward from the outer peripheral edge of the upper surface of the flange, ensuring that the continuous contact area between the stopper and the flange begins from the outer peripheral edge of the sealing surface. In these embodiments, this positioning of the outer peripheral edge of the sealing surface in contact with the upper surface advantageously maintains the contact area between the stopper and the upper surface at 10% or greater than the total surface area of ​​the upper surface, thereby reducing the likelihood of seal breakage compared to existing glass containers. Without being bound by theory, it is considered that this arrangement of the outer peripheral edge of the sealing surface of the stopper facilitates more uniform compression of the stopper by capping by avoiding compression concentration at the outer diameter of the stopper.

[0088] Various structural modifications can be made to existing pharmaceutical glass containers to achieve a beneficial relative positioning between the outer peripheral edge of the stopper sealing surface and the upper surface of the flange, as described herein. For example, when the outer diameter of the flange is fixed at a standard, commonly used diameter (e.g., 13 mm, 20 mm), this relative positioning can be achieved by manufacturing the glass container such that the radial extent of the transition region between the upper and outer surfaces of the flange is reduced compared to existing pharmaceutical glass containers. In an embodiment, the radial extent of the transition region is reduced such that the radius of curvature of the fillet extending between the upper and outer surfaces of the flange is limited to less than one-third of the width of the upper surface (e.g., less than or equal to 21%) (e.g., less than or equal to 0.8 mm, less than or equal to 0.7 mm, less than or equal to 0.6 mm, less than or equal to 0.5 mm, less than or equal to 0.4 mm, less than or equal to 0.3 mm, less than or equal to 0.2 mm). In this embodiment, the radial range of the transition region is reduced such that the chamfer angle of the chamfer extending between the upper and outer surfaces is maintained at less than or equal to 30° (e.g., less than or equal to 25°, less than or equal to 20°, less than or equal to 15°, less than or equal to 10°, less than or equal to 5°). In this embodiment, when the outer diameter of the flange is fixed at a standard commonly used value, this relative positioning between the outer peripheral edge of the stopper sealing surface and the upper surface of the flange can be achieved by increasing the flange angle of the upper surface relative to a plane extending through the end of the opening of the glass container, compared to existing pharmaceutical glass containers. In this embodiment, the flange angle of the upper surface extending from the flange can be greater than or equal to 5° (e.g., 6°, 7°, 8°, 9°, 10°, 11°, 12°, 13°, 14°, 15°, 16°, 17°, 18°, 19°, 20°, and any value between these flange angles). This increased flange angle increases the surface area of ​​the upper surface, which in turn helps to place the outer peripheral edge of the sealing surface of the plug radially inward in the transition area between the upper and outer surfaces.

[0089] The pharmaceutical glass containers described herein are more advantageous than existing pharmaceutical glass containers because they maintain a seal at low storage temperatures and exhibit lower stopper compression during crimping. Existing pharmaceutical containers can be sealed using a crimping process, resulting in a residual seal force greater than 20 pounds (lbf) at the upper surface of the flange (e.g., greater than or equal to 25 pounds, resulting in stopper compression greater than 10% and less than or equal to 20%). The improved seal provided by the pharmaceutical glass containers described herein maintains container closure integrity with lower residual forces (e.g., resulting in a stopper with less than or equal to 8% residual nominal strain after crimping). This reduction in residual seal force facilitates the use of a simpler and more efficient crimping process, thereby reducing production costs.

[0090] As used herein, the term "surface roughness" refers to the Ra value or Sa value. The Ra value is a measure of the arithmetic mean of the filtered roughness profile, determined by the deviation relative to the centerline of the filtered roughness. For example, the Ra value can be determined based on the following relationship:

[0091]

[0092] Where H i It is the measured surface height, H. CL The surface height measurement corresponds to the centerline between the data points of the filtered profile (e.g., the center between the maximum and minimum surface height values). The Sa value can be determined by real extrapolation from Equation 1 here. The filtered value (e.g., the cutoff wavelength) used to determine the Ra or Sa values ​​described herein can be found in ISO 25718 (2012). Surface height can be measured using various tools, such as optical interferometers, stylus-based profilometers, or laser confocal microscopes. To assess the roughness of the surface described herein (e.g., a sealed surface or a portion thereof), the largest possible measurement area should be used to assess variations that may exist on a large spatial scale.

[0093] As used herein, the term "container closure integrity" refers to maintaining a seal at the interface between the glass container and the sealing assembly (e.g., between the sealing surface of the glass container and the stopper), said interface seal excluding gaps exceeding a threshold size to keep the likelihood of contaminant entry below a predetermined threshold or reduce the likelihood of gas permeation below a predetermined threshold, said predetermined threshold being based on the material stored in the glass container. For example, in an embodiment, if the helium leakage rate during a helium leak test described in USP<1207> (2016) is less than or equal to 1.4 x 10-1 -6 cm 3 / s, thus maintaining the container's closed integrity.

[0094] As used herein, the term "about" refers to quantities, dimensions, formulations, parameters, and other quantities and characteristics that are not precise and do not need to be precise, but can be approximated and / or larger or smaller as needed, reflecting tolerances, conversion factors, rounding, measurement errors, and other factors known to those skilled in the art. When the term "about" is used to describe the value or endpoint of a range, the specific value or endpoint referred to is also included. Regardless of whether the numerical values ​​or endpoints of a range in the specification are described as "about," two implementations are described: one modified with "about" and the other not. It should also be understood that the endpoints of each range are important both in relation to and independent of another endpoint.

[0095] The directional terms used in this article—such as up, down, right, left, front, back, top, bottom—are only for reference to the accompanying drawings and do not imply absolute orientation.

[0096] Unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the / said” used herein include plural references. Thus, for example, unless the context clearly indicates otherwise, reference to “a” component includes aspects having two or more such components.

[0097] For reference Figure 1 The cross-sectional view schematically illustrates one embodiment of a sealed pharmaceutical container 100 for storing pharmaceutical preparations. The sealed pharmaceutical container 100 includes a glass container 102 and a sealing assembly 104, the sealing assembly 104 being connected to the glass container 102 through an opening 105. The glass container 102 generally includes a body 112. The body 112 extends between an inner surface 114 and an outer surface 116 of the glass container 102, includes a central axis A, and generally surrounds an internal volume 118. Figure 1 In the illustrated embodiment of the glass container 102, the body 112 generally includes a wall portion 120 and a base portion 122. The wall portion 120 transitions into the base portion 122 via a heel portion 124. In the illustrated embodiment, the glass container 102 includes a flange 126, a neck 128 extending from the flange 126, a cylinder 115, and a shoulder 130 extending between the neck 128 and the cylinder 115. In the embodiment, the glass container 102 is symmetrical about a central axis A, wherein each of the cylinder 115, the neck 128, and the flange 126 is substantially cylindrical. The body 112 has a wall thickness T extending between an inner surface 114 and an outer surface 116. W .

[0098] In this embodiment, the glass container 102 may be made of USP <660> Type I, Type II, or Type III glass formation as defined in [the document] includes borosilicate glass compositions, such as those specified in USP [the document]. <660> The glass container 102 may be formed of a type 1B borosilicate glass composition. Alternatively, the glass container 102 may be formed of an alkaline aluminosilicate glass composition, such as those disclosed in U.S. Patent No. 8,551,898, which is incorporated herein by reference in its entirety, or of an alkaline earth metal aluminosilicate glass, such as those described in U.S. Patent No. 9,145,329, which is incorporated herein by reference in its entirety. In embodiments, the glass container 102 may include a coating, such as a heat-resistant coating disclosed in U.S. Patent No. 100,273,049, which is incorporated herein by reference in its entirety. In embodiments, the glass container 102 may be made of a soda-lime glass composition. In embodiments, the glass container 102 has a coefficient of thermal expansion greater than or equal to 0 x 10⁻⁶. -7 / K and less than or equal to 100x10 -7 / K (for example, greater than or equal to 30 × 10) -7 / K and less than or equal to 70x10 -7 It is composed of a glass composition of / K).

[0099] Although glass container 102 is Figure 1 While depicted as having a specific shape (i.e., a vial), it should be understood that the glass container 102 may have other shapes, including but not limited to... Bottles, syringes, ampoules, bottles, flasks, tubular bottles, tubes, beakers, etc. Furthermore, it should be understood that the glass containers described herein can be used for a variety of applications, including but not limited to pharmaceutical packaging and beverage containers.

[0100] The wall thickness T of glass container 102 W The thickness T can vary depending on the implementation method. In one implementation, the wall thickness T of the glass container 102 is... W The thickness can be less than or equal to 6 millimeters (mm), for example, less than or equal to 4 mm, less than or equal to 2 mm, less than or equal to 1.5 mm, or less than or equal to 1 mm. In the embodiment, the wall thickness T W The wall thickness can be greater than or equal to 0.1 mm and less than or equal to 6 mm, greater than or equal to 0.3 mm and less than or equal to 4 mm, greater than or equal to 0.5 mm and less than or equal to 4 mm, greater than or equal to 0.5 mm and less than or equal to 2 mm, or greater than or equal to 0.5 mm and less than or equal to 1.5 mm. In the embodiment, the wall thickness T W It can be greater than or equal to 0.9 mm and less than or equal to 1.8 mm. Wall thickness T W It can vary depending on the axial position inside the glass container 102.

[0101] like Figure 1As shown, flange 126 includes a lower surface 132, an outer surface 136, and an upper surface 138. The outer surface 136 may define the outer diameter of flange 126. In embodiments, the outer diameter is 13 mm, 20 mm, or between 13 mm and 20 mm. In embodiments, the upper surface 138 is a conical surface including an inner edge 140 (e.g., defining the boundary of opening 105) and an outer peripheral edge 142. In embodiments, the upper surface 138 of flange 126 includes the upper surface of glass container 102 extending between the inner edge 140 and the outer peripheral edge 142. The inner edge 140 and the outer edge 142 may mark a transition point where the outer surface of glass container 102 deviates from the conical surface by a degree exceeding the surface height variation, which is related to the surface roughness of the upper surface 138. In this embodiment, the upper surface 138 has a relatively low surface roughness (e.g., an Ra value less than or equal to 5 nm) and is free from surface defects and surface height deviations greater than or equal to 5 μm from the conical surface. This uniformity of the upper surface 138 advantageously helps maintain contact between the upper surface 138 and the stopper (e.g., stopper 106 as described herein), thereby maintaining a seal when the glass container 102 is cooled to relatively low temperatures (e.g., less than or equal to -45°C, less than or equal to -80°C, less than or equal to -180°C). In this embodiment, the sealed drug container can be cooled to the low storage temperature described herein at a rate of less than or equal to 3°C / min.

[0102] In one embodiment, flange 126 further includes a transition region 144 extending between upper surface 138 and outer surface 136. In one embodiment, within the transition region 144, the outer surface 116 of the glass container 102 deviates from the conical surface followed by upper surface 138 and the second surface (e.g., cylindrical surface) followed by outer surface 136. The transition region 144 can take various forms depending on the embodiment. In one embodiment, the transition region 144 includes a corner, such that outer surface 116 transitions directly from upper surface 138 to outer surface 136. In one embodiment, the transition region 144 includes a chamfer extending from upper surface 138 at a chamfer angle. In another embodiment, the transition region 144 includes a fillet with a radius of curvature (r). f As will be described in more detail herein, the relative positioning of the transition region 144 and the sealing surface of the stopper (e.g., stopper 106 described herein) is an important factor in ensuring that the sealed drug container 100 maintains its closure integrity at relatively low storage temperatures.

[0103] In one embodiment, each section of the upper surface 138 of the flange 126 extends at a flange angle α relative to a plane 146 extending through the end of the opening 105 of the glass container 102. In one embodiment, the plane 146 contacts the portion of the glass container 102 furthest from the base portion 122 along axis A (e.g., at its top). In one embodiment, the furthest portion includes the inner edge 140 of the upper surface 138 of the flange 126. In one embodiment, the plane 146 extends perpendicular to axis A. As described in more detail herein, a larger flange angle α results in a larger surface area of ​​the upper surface 108, which causes the transition region 144 to be further away from the inner edge 140 along the upper sealing surface 146. As described in more detail herein, such a distance between the transition region 144 and the inner edge 140 advantageously ensures that the outer peripheral edge of the sealing surface of the stopper is positioned radially inward of the transition region 144, which ensures the container's closure integrity is maintained at relatively low storage temperatures. In one embodiment, the flange angle α can vary between -2° and 30° depending on the implementation.

[0104] Still referencing Figure 1 The sealing assembly 104 includes a plug 106 and a cap assembly 108. The plug 106 may be made of a suitable elastomeric material (e.g., butyl rubber). Figure 1 In the illustrated embodiment, the stopper 106 includes an insertion portion 117 and a sealing portion 119, the sealing portion 119 including a sealing surface 121. The insertion portion 117 is inserted into the opening 105 of the glass container 102 until the sealing surface 121 contacts the upper sealing surface of the glass container 102 (e.g., the upper surface 138 of the flange 126). The sealing portion 119 is then pressed against the upper surface 138 by the press-fit cap assembly 108, thereby forming a seal between the sealing surface 121 and the upper surface 138 of the flange 126.

[0105] The illustrated cap assembly 108 includes a metal portion 148 and a plastic portion 150. The metal portion 148 is rolled around the lower surface 132 of the flange 126 such that its lower edge portion 152 contacts the lower surface 132. In this embodiment, the length of the lower edge portion 152 of the metal portion 148 that directly contacts the lower surface 132 of the flange 126 (e.g., in...) Figure 1The thickness (in the X direction shown) is greater than or equal to 1 mm to facilitate maintaining residual sealing force within the stopper 106 at storage temperatures less than or equal to -80°C. In an embodiment, the plastic portion 150 includes retaining features 154 (e.g., grooves, cavities, recesses, holes, etc.) that receive the inner edge 156 of the metal portion 148 to retain the upper portion 158 of the metal portion 148 on the upper surface 160 of the stopper 106. In an embodiment, the retaining features 154 of the plastic portion 150 are oriented such that the upper portion 158 extends at a cap angle β relative to a plane 162 that extends perpendicular to axis A. The cap angle β advantageously ensures downward compression of the upper surface 160 of the stopper 106, thereby compressing the sealing surface 121 against the upper surface 138 and contributing to seal formation.

[0106] In one embodiment, during the crimping process, the plug 106 is inserted into the opening 105, and pressure is applied to the metal portion 148 during crimping. The compression of the plug 106 creates a residual sealing force within the flange 126, which maintains compression on the plug 106 after the metal portion 148 has been crimped into place. In this embodiment, the residual sealing force can vary between 5 pounds and 25 pounds, resulting in 5% to 19% of the plug's nominal strain.

[0107] In this embodiment, aspects of the glass container 102 and the cap assembly 108 are designed to maintain the container's closure integrity at relatively low storage temperatures. For example... Figure 1 As shown, the sealing surface 121 of the stopper 106 includes an outer peripheral edge 164. In this embodiment, the outer peripheral edge 164 marks the transition portion between the sealing surface 121 and the outer surface 166 of the stopper 106. It should be understood that when the stopper 106 is compressed against the glass container 102 by the cap assembly 108, the sealing surface 121 and the outer surface 166 of the stopper 106 represent a portion of the external surface shape of the stopper 106. Therefore, reference is made herein to... Figure 1 The exact endpoints of the various surfaces of the described stopper 106 (e.g., sealing surface 121 and outer surface 166) may not perfectly correspond to the shape of the stopper 106 in its uncompressed state. That is, when in its uncompressed state, the exact shape of the stopper 106 may be similar to... Figure 1 The shapes shown are different.

[0108] In this embodiment, the glass container 102 is shaped such that when the stopper 106 is compressed against the upper surface 138 of the flange 126 by the cap assembly 108, the outer peripheral edge 164 of the sealing surface 121 is located at or radially inward of the transition region 144 extending between the upper surface 138 and the outer surface 136 of the flange 126 (e.g., relative to axis A). That is, after the sealing portion 119 is compressed between the upper portion 158 and the upper surface 138, the outer peripheral edge 164 (e.g., the radially outward portion of the sealing surface 121 from axis A) is positioned at or radially inward of the transition region 144. In this embodiment, the glass container 102 is shaped such that when the stopper 106 is compressed against the upper surface 138 of the flange 126 by the cap assembly 108, the outer peripheral edge 164 of the sealing surface contacts the upper surface 138 of the flange 126. In this embodiment, no part of the sealing surface 121 contacts the transition region 144. Without being bound by theory, it is assumed that keeping the sealing surface 121 from contacting the transition region 144 prevents deformation of the sealing portion 119, which could reduce the contact area between the sealing surface 121 and the upper surface 138 of the flange 126.

[0109] While it is possible to keep the outer peripheral edge 164 at or radially inward of the transition region 144 by reducing the radial extent of the stopper 106 (e.g., making the stopper 106 smaller), such a change to the stopper would detrimentally reduce the contact area between the upper surface 138 and the stopper 106, thereby reducing the quality of the seal. Therefore, the structure of the glass container 102 described herein advantageously maximizes the contact area between the stopper 106 and the upper surface 138 without requiring a change in the shape of the stopper 106. Furthermore, the glass container described herein is compatible with existing capping processes, eliminating the need to modify existing production lines. The structural aspects of the flange 126 will be described in more detail below.

[0110] Now for reference Figure 2A The diagram schematically shows a portion of the flange 200 of the glass container. Figure 2A The flange 200 shown is structurally comparable to the flanges described in this article. Figure 1 The flange 126 of the described glass container 102 is similar. In embodiments, flange 200 may be used instead of the flange described herein. Figure 1 The flange 126 in the sealed drug container 100. For example... Figure 2AAs shown, flange 200 includes a lower surface 202, an outer surface 204 extending from the lower surface 202, and an upper surface 206. The outer surface 204 defines the outer diameter of flange 200, which in some embodiments may be 13 mm, 20 mm, or between 13 mm and 20 mm. Upper surface 206 is a conical surface extending at a flange angle α relative to plane 214, which extends through the end of the opening in the glass container (e.g., located at the inner edge 210 of upper surface 206). Figure 2A In the illustrated embodiment, the flange angle α can be greater than or equal to 1° and less than or equal to 5°. The upper surface 206 includes an inner edge 210 and an outer peripheral edge 212. In this embodiment, the inner edge 210 defines an opening in the glass container (e.g., corresponding to the opening described herein). Figure 1 The described opening 105) is the boundary. The flange 200 also includes a transition region 208 extending between the upper surface 206 and the outer surface 204.

[0111] like Figure 2A As shown, the transition region 208 includes a corner radius r compared to existing glass containers. f Reduced fillet radius. In the implementation, the fillet radius r... f Less than or equal to 21% of the width of the upper surface 206 (e.g., the distance along the upper surface 206 between the inner edge 210 and the outer peripheral edge 212). In the embodiment, the fillet radius r f Less than 1.0mm (e.g., less than or equal to 0.8mm, less than or equal to 0.5mm, less than or equal to 0.4mm, less than or equal to 0.3mm, less than or equal to 0.2mm). Reduce the fillet radius r. f This advantageously reduces the extent to which the transition region 208 extends radially inward from the outer surface 204, thereby ensuring that the outer peripheral edge of the sealing surface of the plug is positioned radially inward in the transition region 208 and / or contacts the upper surface 206.

[0112] Figure 2B A portion of a compressed plug 216 is schematically shown, pressed against the upper surface 206 of the flange 200. In an embodiment, the compressed plug 216 corresponds to the portion described herein. Figure 1 The described cap assembly 108 compresses the plug 106. For clarity, in Figure 2B The cap assembly 108 is omitted. For example... Figure 2B As shown, the compressed plug 216 includes a sealing surface 218 that is compressed against the upper surface 206 of the flange 200. The sealing surface 218 includes an outer peripheral edge 220, which is located radially inward of the outer peripheral edge 212 of the upper surface 206. Due to the fillet radius r of the transition region 208... f Decrease (see) Figure 2A The sealing surface 218 does not contact the transition region 208, which advantageously helps to maintain the contact area between the sealing surface 218 and the upper surface 206 of the flange being greater than or equal to 10% of the total surface area of ​​the upper surface 206 (e.g., greater than or equal to 20mm in the case where the flange 200 has an outer diameter of 20mm). 2 Regardless of whether the glass container is cooled to a storage temperature of less than or equal to -80°C.

[0113] Now for reference Figure 3A The diagram schematically shows a portion of the flange 300 of the glass container. Figure 3A The flange 300 shown is structurally comparable to the flanges described in this paper. Figure 1 The flange 126 of the described glass container 102 is similar. In embodiments, flange 300 may be used instead of the flanges described herein. Figure 1 The flange 126 in the sealed drug container 100. For example... Figure 3A As shown, flange 300 includes a lower surface 302, an outer surface 304 extending from the lower surface 302, and an upper surface 306. The outer surface 304 defines the outer diameter of flange 300, which in some embodiments may be 13 mm, 20 mm, or between 13 mm and 20 mm. Upper surface 306 is a conical surface extending at a flange angle α relative to a plane 314, which extends through the end of the opening in the glass container (e.g., located at the inner edge 310 of upper surface 306). Figure 3A In the illustrated embodiment, the flange angle α can be greater than or equal to 1° and less than or equal to 5°. The upper surface 306 includes an inner edge 310 and an outer peripheral edge 312. In this embodiment, the inner edge 310 defines an opening in the glass container (e.g., corresponding to the opening described herein). Figure 1 The described opening 105) is the boundary. The flange 300 also includes a transition region 308 extending between the upper surface 306 and the outer surface 304.

[0114] like Figure 3A As shown, the transition region 308 includes a chamfer extending at a chamfer angle ν relative to the upper surface 306. In existing glass containers, the chamfer angle ν can be approximately 45°. In the illustrated embodiment, the chamfer angle ν can be less than or equal to 30° (e.g., less than or equal to 25°, less than or equal to 20°, less than or equal to 15°, less than or equal to 10°, less than or equal to 5°). Reducing the chamfer angle ν advantageously reduces the extent to which the transition region 308 extends radially inward from the outer surface 304, thereby ensuring that the outer peripheral edge of the sealing surface of the stopper is positioned radially inward in the transition region 308 and / or contacts the upper surface 306.

[0115] Figure 3BA portion of a compressed plug 316 is schematically shown, pressed against the upper surface 306 of the flange 300. In an embodiment, the compressed plug 316 corresponds to the portion described herein. Figure 1 The described cap assembly 108 compresses the plug 106. For clarity, in Figure 3B The cap assembly 108 is omitted. For example... Figure 3B As shown, the compressed plug 316 includes a sealing surface 318 that is compressed against the upper surface 306 of the flange 300. The sealing surface 318 includes an outer peripheral edge 320, which is located at the outer peripheral edge 312 of the upper surface 306 or radially inward of the outer peripheral edge 312. Due to the reduced chamfer angle ν of the transition region 308 (see...), Figure 3A The sealing surface 318 does not contact the transition area 308, which advantageously helps to maintain the contact area between the sealing surface 318 and the upper surface 306 of the flange being greater than or equal to 10% of the total surface area of ​​the upper surface 306, regardless of whether the glass container is cooled to a storage temperature less than or equal to -80°C.

[0116] Now for reference Figure 4A The diagram schematically shows a portion of the flange 400 of the glass container. Figure 4A The flange 400 shown is structurally comparable to the flanges described in this article. Figure 1 The flange 126 of the described glass container 102 is similar. In embodiments, flange 400 may be used instead of the flanges described herein. Figure 1 The flange 126 in the sealed drug container 100. For example... Figure 4A As shown, flange 400 includes a lower surface 402, an outer surface 404 extending from the lower surface 402, and an upper surface 406. The outer surface 404 defines the outer diameter of flange 400, which in some embodiments may be 13 mm, 20 mm, or between 13 mm and 20 mm. The upper surface 406 includes an inner edge 410 and an outer peripheral edge 412. In embodiments, the inner edge 410 defines an opening in the glass container (e.g., corresponding to the opening described herein). Figure 1 The flange 400 also includes a transition region 408 extending between the upper surface 406 and the outer surface 404. The transition region 408 may take various forms (e.g., chamfer, fillet, corner) depending on the implementation.

[0117] like Figure 4A As shown, the upper surface 406 of the flange 400 extends at a flange angle α relative to the plane 414, which extends through the opening (e.g., corresponding to the reference). Figure 1The described glass container 102 has an opening 105 at its end. The flange angle α of the flange 400 may be greater than the flange angles of existing glass containers. Existing glass containers may include flange angles of 1° to 5°. Figure 4B In the illustrated embodiment, the flange angle α is greater than 5° (e.g., 6°, 7°, 8°, 9°, 10°, 11°, 12°, 13°, 14°, 15°, 16°, 17°, 18°, 19°, 20°, and any value between these flange angles). In another embodiment, the flange angle α is less than or equal to 30°. If the flange angle is greater than this angle, the compression of the plug 106 is reduced due to the increased distance between the sealing surface 121 and the upper portion 158 at the outer peripheral edge 164, thereby reducing the contact area. In another embodiment, it is particularly advantageous to maintain the flange angle α at less than or equal to 10° to provide sufficient compression of the plug 106 to maintain a suitable contact area. Figure 4A The larger flange angle α of the embodiment shown advantageously increases the surface area of ​​the upper surface 406 and facilitates placing the outer peripheral edge of the plug sealing surface at the transition region 408 or radially inward of the transition region 408.

[0118] Figure 4B This schematically illustrates the content of this article. Figure 1 The stopper 106 described herein uses the method described herein. Figure 1 The cap assembly 108 is rolled and pressed against the flange 400. As shown in the figure, the flange angle α of the upper surface 406 (see figure) Figure 4A The increase in the amount of sealing surface 121 results in the outer peripheral edge 164 being located radially inward of the outer peripheral edge 412 of the upper surface 406. For example... Figure 4B As shown, the upper portion 158 of the metal portion 148 of the cap assembly 108 extends at a cap angle β relative to the plane 146, which extends perpendicularly to the central axis A (see Figure 108). Figure 1 In this embodiment, the flange angle α of the upper surface 406 differs from the cap angle β by less than one degree. It is not desirable to be bound by theory, but it is believed that the correspondence between the flange angle α and the cap angle β advantageously provides uniform compression of the sealing surface 121 against the upper surface 406, helping to maintain a relatively high contact area between the plug 106 and the flange 400, regardless of storage temperature.

[0119] refer to Figure 1-4BThe structural modifications to existing glass containers described herein (e.g., reducing chamfers, reducing fillet radii, increasing flange angles, or any combination thereof) facilitate the use of existing capping processes associated with currently used flange outer diameters (e.g., 20 mm, 13 mm). It should be understood that glass containers with flange outer diameters larger than those currently used in existing glass containers (e.g., those defined by the outer surface 136 of flange 126, see...) are also conceivable. Figure 1 For example, in the implementation method, Figure 1 The outer surface 136 of the flange 126 of the glass container 102 can define an outer diameter of 20.2 mm, 20.4 mm, 20.5 mm, 21 mm, 22 mm, or larger. In an embodiment, Figure 1 The outer surface 136 of the flange 126 of the glass container 102 can define an outer diameter of 13.2 mm, 13.4 mm, 13.6 mm, 13.8 mm, 14.0 mm, or larger. Such a larger outer diameter can be used in combination with existing flange angles and transition areas (e.g., fillets and chamfers) while maintaining the characteristics described herein. Figure 1 The beneficial relative positioning between the outer peripheral edges 164 and 142 of the upper surface 138.

[0120] Figures 5A-5H The simulation results show the plug compression as a function of the flange angle. Figure 5A and 5B Simulation results at 25°C and -80°C are shown respectively. These simulations predict the values ​​presented in this paper regarding... Figure 1 The compression of the stopper 106 is described by the cap assembly 108 (not shown) pressing the stopper 106 against a flange 500 having an upper surface 502 extending at a flange angle α1 = -3° relative to a plane 506 located at the top of the flange 500. Figure 5C and 5D Simulation results at 25°C and -80°C are shown respectively. These simulations predict the values ​​presented in this paper regarding... Figure 1 The compression of the stopper 106 described is achieved by the cap assembly 108 (not shown) pressing the stopper 106 against a flange 508, which has an upper surface 508 extending at a flange angle α2 = 0° relative to a plane 512 located at the top of the flange 508. Figure 5E and 5F Simulation results at 25°C and -80°C are shown respectively. These simulations predict the values ​​presented in this paper regarding... Figure 1The compression of the stopper 106 is described by the cap assembly 108 (not shown) pressing the stopper 106 against a flange 514 having an upper surface 516 extending at a flange angle α3 = 2.4° relative to a plane 518 located at the top of the flange 514. Figure 5G and 5H Simulation results at 25°C and -80°C are shown respectively. These simulations predict the values ​​presented in this paper regarding... Figure 1 The compression of the stopper 106 is described by the cap assembly 108 (not shown) pressing the stopper 106 against a flange 520 having an upper surface 522 extending at a flange angle α4 = 8.04° relative to a plane 524 located at the top of the flange 520.

[0121] Figures 5A-5H The simulations shown predict the compression of the stopper 106 against flanges 500, 508, 514, and 520 when the stopper 106 is rolled up by the cap assembly 108 (not shown) to provide a residual sealing force of approximately 25 pounds (e.g., greater than or equal to 24.7 pounds and less than or equal to 25.6 pounds). Finite element analysis was then performed to simulate the compression of the stopper 106 against each of the flanges 500, 508, 514, and 520 at 25°C and -80°C. Figure 5A , 5C As shown in 5E and 5G, at 25°C, flanges 500, 508, 514, and 520 maintain continuous compression regions extending over the entire length of upper surfaces 502, 510, 516, and 522, respectively. In contrast, at -80°C, the decompression of the stopper 106 results in significant breaks in the compression between the stopper 106 and flanges 500, 508, and 514 (e.g., regions with compressive forces less than 0.0001 MPa). In this embodiment, at -80°C, flange 520, including a flange angle α4 greater than 5°, maintains a continuous compression region extending over the entire length of upper surface 522. Not wishing to be bound by theory, it is believed that the continuous compression region is maintained by flange 520 due to the increased surface area of ​​upper surface 522, which advantageously results in the outer peripheral edge 164 (see...). Figure 1 The offset between the upper surface 522 and the outer surface 524 of the flange 520 (see...) Figure 5H This avoids the compression of the stopper 106 concentrated at the outer edge of the upper surface 522. These simulation results validate the effectiveness of the modifications to the existing drug container described herein.

[0122] Figure 6A and 6B Graphs 600 and 602 show the simulation results of the contact area, which is the contact area described in this paper regarding... Figure 1The described plug 106 has contact area with multiple flanges having different flange angles (e.g., different values ​​of flange angle α). Figure 6A A graph 600 shows the contact area of ​​multiple flanges as a function of storage temperature. As shown, in this embodiment, at temperatures below -100°C, flange angles greater than 5° are maintained at greater than 20 mm. 2 The contact area is greater than or equal to 10% of the total surface area of ​​the upper surface of the flange. At temperatures less than or equal to -80°C, a flange angle greater than 5° advantageously maintains a contact area of ​​greater than 40 mm with the stopper. 2 Increase the contact area to increase the likelihood of maintaining the container's closed integrity.

[0123] Figure 6B Curve 602 shows the contact area between the stopper 106 and the multiple flanges as a function of the flange angle at -80°C. As shown, the maximum contact area occurs when the flange angle is approximately 8.3°, representing the correspondence between the flange angle α and the cap angle β (see...). Figure 1 Unwilling to be bound by theory, such a flange angle α can advantageously result in uniform compression of the sealing portion 119 of the cap assembly 108 over the plug 106 (see...). Figure 1 This achieves the desired contact area without deforming the sealing portion 119. Curve 602 also shows a sharp increase in contact area as the flange angle increases from 5° to 8.3°. Without being bound by theory, it is believed that at a flange angle α = 5°, the outer peripheral edge 164 of the sealing surface 121 lies directly at the outer peripheral edge 142 of the upper surface 138 (see...). Figure 1 Therefore, the increase from 5° advantageously results in the outer peripheral edge 164 being positioned radially inward of the outer peripheral edge 142 without significantly reducing the contact area.

[0124] Figures 7A-7F The simulation results show the changes in plug compression as a function of the chamfer angle. Figure 7A and 7B Simulation results at 25°C and -80°C are shown respectively. These simulations predict the values ​​presented in this paper regarding... Figure 1 The compression of the stopper 106 is described, wherein the compression is achieved by the cap assembly 108 (not shown) pressing the stopper 106 against a flange 700, the flange 700 having an upper surface 702 and a transition region 704 including a chamfer extending at a chamfer angle ν1 = 30°. Figure 7C and 7D Simulation results at 25°C and -80°C are shown respectively. These simulations predict the values ​​presented in this paper regarding... Figure 1The compression of the stopper 106 is described, wherein the compression is achieved by the cap assembly 108 (not shown) pressing the stopper 106 against a flange 706, the flange 706 having an upper surface 708 and a transition region 710 including a chamfer extending at a chamfer angle ν2 = 10°. Figure 7E and 7F Simulation results at 25°C and -80°C are shown respectively. These simulations predict the values ​​presented in this paper regarding... Figure 1 The compression of the stopper 106 is described, wherein the compression is achieved by the cap assembly 108 (not shown) pressing the stopper 106 against the flange 712, the flange 712 having an upper surface 714 and a transition region 716 including a chamfer extending at a chamfer angle ν2 = 10°.

[0125] Figures 7A-7F The simulations shown predict the compression of the stopper 106 against flanges 700, 706, and 712 when the stopper 106 is rolled up by the cap assembly 108 (not shown) to provide a residual sealing force of approximately 25 pounds (e.g., greater than or equal to 24.7 pounds and less than or equal to 25.6 pounds). Finite element analysis was then performed to simulate the compression of the stopper 106 against each of flanges 700, 706, and 712 at 25°C and -80°C. Figure 7A , 7C As shown in Figure 7E, at 25°C, each flange maintains a continuous compression region extending along the entire length of the upper surfaces 702, 708, and 714, respectively. At -80°C, the contact area between the stopper 106 and the upper surfaces 702, 708, and 714 is inversely proportional to the magnitudes of the first, second, and third chamfer angles ν1, ν2, and ν3. That is, at -80°C, flange 712 comprises the maximum contact area with the stopper 106. Not wishing to be bound by theory, it is believed that a relatively small third chamfer ν3 facilitates contact between the outer peripheral edge 164 of the sealing surface 121 and the upper surface 714 after capping (see Figure 7E). Figure 1 This improves the seal quality between the stopper 106 and the flange 712. These simulation results validate the effectiveness of the modifications to the existing drug container described herein.

[0126] Figures 8A-8F Simulation results of plug compression for two different flanges, 800 and 806, are shown, with the two flanges having a fillet radius r. f They differ in many ways. Figure 8A and 8B The simulation results are shown, which predict the values ​​of the data in this paper at 25°C. Figure 1 The compression of the stopper 106 is achieved by the cap assembly 108 (not shown) abutting against flanges 800 and 806, which include upper surfaces 802 and 808 and have different chamfer radii r.f1 and r f2 The transition regions 804 and 810. In this simulation, r f1 Equal to 0.8mm, r f2 It equals 0.3mm. Figure 8A and 8B The simulation results are shown, which predict the following at -80°C: Figure 1 The compression of the stopper 106 is achieved by the cap assembly 108 (not shown) compressing the stopper 106 against the flanges 800 and 806. Figure 8E and 8F The simulation results are shown, which predict the following at -180°C: [The text abruptly ends here, likely due to an incomplete sentence or missing information.] Figure 1 The compression of the stopper 106 is achieved by the cap assembly 108 (not shown) compressing the stopper 106 against the flanges 800 and 806.

[0127] Figures 8A-8F The simulations shown predict the compression of the stopper 106 against flanges 800 and 806 when the stopper 106 is rolled up by the cap assembly 108 (not shown) to provide a residual sealing force of approximately 25 pounds (e.g., greater than or equal to 24.7 pounds and less than or equal to 25.6 pounds). Finite element analysis was then performed to simulate the compression of the stopper 106 against each of flanges 800 and 806 at 25°C, -80°C, and -180°C. Figure 8A and 8B As shown, at 25°C, flanges 800 and 806 maintain continuous contact areas with the plug 106, respectively covering the entire upper surfaces 802 and 808. Figure 8C and 8D As shown, at -80℃, flange 800 (with a large fillet radius r) f2 There is no continuous contact area with the stopper 106 (there is substantial contact breakage radially inward at the outer peripheral edge 164, see...) Figure 1 While flange 806 maintains a continuous contact area that essentially covers the entire upper surface 808, flange 806 maintains a continuous contact area that essentially covers the entire upper surface 808. In other words, according to simulation results, with other variables remaining constant, compared to flange 800, the fillet radius r... f2 The reduction in radius significantly improves the sealing quality at -80°C. Compared to a flange of 800, the fillet radius r... f2 The improvement from the reduction is more pronounced at -180°C. For example... Figure 8E As shown, at -180°C, the flange 800 maintains contact with the plug 106 only near its outer peripheral edge 164 (see...). Figure 1The flange 806 remains in contact across essentially the entire upper surface 808, indicating a significant improvement in sealing quality. These simulation results validate the effectiveness of the modifications to existing drug containers described herein.

[0128] Figure 9 This article shows the information about Figures 8A-8F The flanges 800 and 806 are cooled to multiple storage temperatures as shown in the simulated curves 900, wherein, in this document, regarding... Figure 1 The stopper 106 is pressed against the upper surfaces 802 and 808 by the cap assembly 108. The graph shows the change in contact area achieved by the flanges 800 and 806 with storage temperature. Figure 9 As shown, flange 800 includes a larger fillet radius r as associated with existing pharmaceutical glass containers. f2 The contact area achieved by flange 800 begins to decrease significantly at temperatures above -80°C (approximately -60°C), making flange 800 unsuitable for storage at such temperatures. In fact, for flange 800, between -80°C and -100°C, the simulated contact area appears to decrease to below 20 mm². 2 In contrast, at temperatures below -60°C, the reduction in contact area of ​​flange 806 is much smaller than that of flange 800. At temperatures as low as -180°C, flange 806 appears to maintain a contact area with stopper 106 greater than 120 mm. 2 The contact area. Therefore, by ensuring the relative positioning between the outer peripheral edges 164 of the sealing surface 121 of the plug 106 described herein (see... Figure 1 This significantly increases the likelihood of maintaining the container's closure integrity at storage temperatures as low as -160°C. Such improved sealing quality can be achieved without any modifications to the capping process.

[0129] Based on the foregoing description, it should be understood that a sealed glass container capable of maintaining its closure integrity at storage temperatures below or equal to -70°C is disclosed. The improved seal can be achieved entirely by modifying the structure of the glass container's flange without altering current capping processes. The flange angles, fillet radii, and chamfer angles of the glass pharmaceutical containers meeting the requirements described herein advantageously facilitate contact between the outer peripheral edge of the stopper's sealing surface and the upper surface of the flange, the stopper being associated with standard capping processes. Such an upper surface may be free of surface defects, thereby contributing to continuous contact with the stopper's sealing surface and improving seal quality.

[0130] Unless otherwise expressly stated, no method described herein should be construed as requiring its steps to be performed in a specific order, nor should any device be required to have a specific orientation. Therefore, if a method claim does not actually describe the order in which its steps are to be followed, or any device claim does not actually describe the order or orientation of the components, or the claims or description do not otherwise expressly state that the steps should be limited to a specific order, or do not describe a specific order or orientation of the device components, then in no way should the order or orientation be inferred. This applies to any possible non-explicit basis of expression, including: logical questions concerning the arrangement of steps, the flow of operations, the order of components, or the orientation of components; concise meanings derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0131] It will be apparent to those skilled in the art that various modifications and variations can be made to the embodiments described herein without departing from the spirit and scope of the claimed subject matter. Therefore, this specification is intended to cover modifications and variations of the various embodiments described herein, provided that such modifications and variations fall within the scope of the appended claims and their equivalents.

Claims

1. A sealed pharmaceutical container, comprising: Shoulders; The neck extending from the shoulder; and A flange extending from the neck, the flange comprising: The lower surface extending from the neck; An outer surface extending from the lower surface defines the outer diameter of the flange; and A contact surface extending between an outer surface and an inner surface, the inner surface defining an opening in a sealed drug container, wherein the contact surface includes an inner edge disposed near the opening and an outer peripheral edge disposed near the outer surface of a flange; A fillet extending between the contact surface and the outer surface, the fillet having a radius of curvature less than or equal to 21% of the length of the contact surface of the flange; and A sealing assembly comprising a plug extending above a contact surface of a flange and covering an opening, and a cap securing the plug to the flange, wherein: The plug includes a sealing surface that is fixed to contact the contact surface of the flange to form a seal between the flange and the plug. The outer peripheral edge of the sealing surface is located at the outer peripheral edge of the contact surface of the flange or radially inward at the outer peripheral edge of the contact surface of the flange.

2. The sealed drug container as claimed in claim 1, wherein, The contact surface includes a conical region of the upper surface of the flange.

3. The sealed drug container of claim 1, wherein the contact surface has a surface roughness of less than or equal to 0.2 µm.

4. The sealed drug container of claim 3, wherein the contact surface does not include a surface height variation of 5.0 µm or more.

5. The sealed drug container as claimed in claim 1, wherein, The outer peripheral edge of the sealing surface is located radially inward at the transition portion between the contact surface and the fillet.

6. The sealed drug container as claimed in claim 1, wherein, The flange also includes a chamfer that extends between the contact surface and the outer surface at an angle relative to the contact surface.

7. The sealed drug container of claim 6, wherein the angle is less than or equal to 30°.

8. The sealed drug container as claimed in claim 1, wherein, The contact surface extends at a flange angle relative to a plane that extends through the end of the opening.

9. The sealed drug container of claim 8, wherein the flange angle is greater than or equal to 5°.

10. The sealed drug container of claim 9, wherein the flange angle is less than or equal to 30°.

11. The sealed drug container as claimed in claim 8, wherein: The cap includes a metal portion rolled around the lower surface of a flange and a plastic portion holding the upper part of the metal portion to the upper surface of the stopper. The inner edge of the metal part is inserted into the plastic part, such that the upper part extends at a cap angle relative to the plane, which extends through the end of the opening.

12. The sealed drug container of claim 11, wherein the flange angle and the cap angle differ by no more than one degree.

13. The sealed drug container of claim 1, wherein the stopper is compressed by the cap to provide less than or equal to 8% of residual nominal strain.

14. The sealed drug container as claimed in claim 1, wherein, When the sealed drug container is cooled to a temperature less than or equal to -80°C, the sealing assembly maintains a helium leakage rate of less than or equal to 1.4 x 10⁻⁶. -6 cm 3 / s.

15. The sealed drug container as claimed in claim 1, wherein, When the sealed drug container is cooled to a temperature less than or equal to -80°C, the sealing surface maintains a contact area greater than or equal to 10% of the total surface area of ​​the contact surfaces.

16. A sealed pharmaceutical container comprising: Shoulders; The neck extending from the shoulder; and A flange extending from the neck, the flange comprising: The lower surface extending from the neck; An outer surface extending from the lower surface defines the outer diameter of the flange; and An upper surface extending between an outer surface and an inner surface, the inner surface defining an opening in a sealed drug container, wherein the upper surface includes: A conical region extending between the opening and the outer surface, wherein the conical region does not include a surface height deviation greater than or equal to 5 µm; and A transition region extending between the conical region and the outer surface, the transition region including a chamfer extending at an angle less than or equal to 30° relative to the conical region, or a fillet having a radius of curvature less than or equal to 21% of the width of the conical region; and A sealing assembly, the sealing assembly comprising: A plug covering the opening; and The cap is rolled and pressed against the lower surface of the flange, thereby compressing the sealing surface of the plug against the conical region, so that the outer peripheral edge of the sealing surface contacts the conical region.

17. The sealed drug container of claim 16, wherein the upper surface comprises an Ra value of less than or equal to 5 nm.

18. The sealed drug container as claimed in claim 16, wherein, When the sealed drug container is cooled to a temperature less than or equal to -80°C, the sealing surface maintains a contact area greater than or equal to 10% of the total surface area of ​​the upper surface.

19. The sealed drug container as claimed in claim 16, wherein, The transition region includes rounded corners, the radius of curvature of which is less than or equal to 21% of the width of the conical portion.

20. The sealed drug container of claim 19, wherein the radius of curvature is less than or equal to 0.5 mm.

21. The sealed drug container of claim 16, wherein the transition region includes a chamfer extending at an angle relative to the conical region.

22. The sealed drug container of claim 21, wherein the angle is less than or equal to 30°.

23. The sealed drug container of claim 16, wherein the conical portion extends at a flange angle relative to a plane extending through the end of the opening, the flange angle being greater than or equal to 5°.

24. The sealed drug container of claim 23, wherein the flange angle is less than or equal to 30°.

25. The sealed drug container as claimed in claim 23, wherein: The cap includes a metal portion rolled around the lower surface of a flange and a plastic portion holding the upper part of the metal portion to the upper surface of the stopper. The inner edge of the metal part is inserted into the plastic part, such that the upper part extends at a cap angle relative to the plane, which extends through the end of the opening.

26. The sealed drug container of claim 25, wherein the flange angle differs from the cap angle by no more than one degree.

27. The sealed drug container of claim 16, wherein the stopper is compressed by the cap to provide less than or equal to 8% of residual nominal strain.

28. The sealed drug container as claimed in claim 16, wherein, When the sealed drug container is cooled to a temperature less than or equal to -80°C, the sealing assembly maintains a helium leakage rate of less than or equal to 1.4 x 10⁻⁶. -6 cm 3 / s.

29. The sealed drug container as claimed in claim 16, wherein, When the sealed drug container is cooled to a temperature less than or equal to -80°C, the sealing surface maintains a distance of greater than or equal to 20 mm from the upper surface. 2 The contact area.

30. A method for sealing a sealed pharmaceutical container, the method comprising the following steps: A sealable drug container is provided, comprising a shoulder, a neck extending from the shoulder, and a flange extending from the neck, the flange comprising: The lower surface extending from the neck; An outer surface extending from the lower surface defines the outer diameter of the flange; and The upper surface extends between an outer surface and an inner surface of a sealed drug container, the inner surface defining an opening, the upper surface including a conical region extending between the opening and the outer surface and a transition region extending between the conical region and the outer surface, the transition region including a chamfer extending at an angle of less than or equal to 30° relative to the conical region, or a fillet having a radius of curvature less than or equal to 21% of the width of the conical region; Place the pharmaceutical composition into the sealed pharmaceutical container; A sealing assembly is provided, the sealing assembly including a plug that extends above the upper surface of the flange and covers the opening; The metal cap is rolled and pressed onto the stopper and against the flange, thereby compressing the stopper against the upper surface so that the outer peripheral edge of the sealing surface of the stopper contacts the conical area; and The sealed drug container is cooled to a temperature less than or equal to -45°C, wherein, after cooling, the sealing surface is kept pressed so that the helium leakage rate of the sealed drug container at said temperature is less than or equal to 1.4 x 10⁻⁶. -6 cm 3 / s.

31. The method of claim 30, wherein, The metal-containing cap is rolled up such that the plug is compressed against the upper surface to provide less than or equal to 8% of residual nominal strain.

32. The method of claim 30, wherein, When the sealed drug container is cooled to the temperature, the contact area between the sealing surface of the stopper and the upper surface of the flange is greater than or equal to 10% of the total surface area of ​​the upper surface.

33. The method of claim 32, wherein the temperature is less than or equal to -80°C.

34. The method of claim 32, wherein the temperature is less than or equal to -180°C.

35. The method of claim 30, wherein: As a result of the compression of the plug, the outer peripheral edge of the sealing surface does not contact the transition area.

36. The method of claim 30, wherein the fillet has a radius of curvature of less than 1.0 mm.

37. The method of claim 36, wherein, The radius of curvature is less than or equal to 0.5 mm.

38. The method of claim 30, wherein, The conical region extends at a flange angle of 5° or greater relative to a plane that extends through the end of the opening.

39. The method of claim 38, wherein: The metal-containing cap includes a metal portion rolled around the lower surface of a flange and a plastic portion holding the upper part of the metal portion on the upper surface of the stopper. The inner edge of the metal portion is inserted into the plastic portion, such that the upper portion extends at a cap angle relative to a plane that extends through the end of the opening. The flange angle and the cap angle differ by no more than one degree.

40. The method of claim 30, wherein the sealed drug container is cooled to the temperature at a rate of less than or equal to 3°C / min.

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