Patent Application
20240000661
The present invention relates to the general technical field of glass containers, in particular for the packaging of pharmaceutical or diagnostic substances.
In the field of pharmaceutical glass primary packaging, the purpose is to propose containers, in particular of the vial type, that have an excellent chemical compatibility with the product or preparation they are intended to contain. Indeed, the aim is to prevent any harmful interaction between a species from the glass forming the container and the product contained by the latter.
In this context, the pharmacopoeias identify three main different types of glass containers, which may be acceptable for a pharmaceutical use according to the nature of the considered preparation. These containers are classified according to their level of chemical resistance, i.e. according to the resistance shown by the glass, of which they are formed, to the transfer of water-soluble inorganic substances in determined conditions of contact between the surface of the considered glass container and the water. A distinction is made between the borosilicate glass containers, said of “Type I”, which have intrinsically an excellent chemical resistance and which thus suit for most pharmaceutical substances and preparations, and the conventional soda-lime-silica glass containers, said of “Type III”, whose chemical resistance is far less advantageous. That way, the use of these latter is limited to non-aqueous vehicle preparations for parenteral use, to the powders for parenteral use (except freeze-dried preparations) and to the preparations for non-parenteral use. A distinction is also made between so-called “Type II” glass containers, which are conventional soda-lime-silica glass containers, like the Type III ones, but whose inner face has been subjected to a specific surface treatment in order to significantly improve their hydrolytic resistance. Type II glass containers thus have an intermediate chemical resistance between those of the Type II glass containers and the Type I glass containers, which make them suitable for packaging most of the acid and neutral aqueous preparations.
In view of the above, Type I glass is considered, in pharmaceutical industry, as the most chemically resistant glass. It is therefore the glass of choice for storing the most aggressive or the most unstable solutions. However, in some particular cases, even Type I glass formulation proves insufficiently chemically resistant for storing pharmaceutical solutions. The Type I glass surface may be corroded and attacked, therefore releasing significant concentrations of extractable species from the glass. It is commonly accepted that, for example, the storage of Water for Injection (WFI) is difficult, even in Type I glass containers. As regards the release of glass extractables in solution, and in addition to sodium, certain trace elements such as barium, zinc, aluminium, boron, lead, etc. can pose significant health problems. These elements are indicated in the ICHQ3D (“International Conference on Harmonization”) information documentation as potentially presenting a risk to the patient's health if administered by parenteral injection.
That is why it has been contemplated to cover the inner face of the glass wall of the borosilicate glass containers with a barrier coating, for example made of pure silica SiO2 or silicone-based, in order to further improve the chemical resistance thereof. Nevertheless, the implementation of such a barrier coating makes the manufacturing of the containers more complex and more expensive. Moreover, it does not always provide the containers with a sufficient chemical resistance, depending on the nature of the substances they are intended to contain.
As a result of the foregoing, the objects assigned to the present invention aim to remedy the technical shortcomings and problems identified hereinabove, and to propose a new glass wall container having an excellent chemical resistance while being relatively inexpensive to manufacture.
Another object of the invention aims to propose a new glass wall container that is moreover particularly easy to manufacture.
Another object of the invention aims to propose a new glass wall container that is safe in terms of health.
The objects assigned to the invention are achieved by means of a container comprising a glass wall delimiting an accommodation cavity for a substance, in particular for a pharmaceutical or diagnostic substance, said glass wall having an inner face located facing said accommodation cavity, said container being characterized in that said wall is made of borosilicate glass, said inner face forming a bare glass surface intended to come into direct contact with said substance, said glass wall having an atomic fraction of sodium, as measured by X-ray induced photoelectron spectrometry, that is lower than or equal to 2.0 at. % up to a depth of at least 300 nm from the surface of the inner face.
The objects assigned to the invention are also achieved by means of a raw container intended to form such a container according to the invention, said raw container comprising a glass wall delimiting an accommodation cavity, said glass wall having an inner face located facing said accommodation cavity, said wall being made of borosilicate glass, said inner face forming a glass surface provided with sodium sulphate grains shaped and arranged in a substantially uniform manner on said surface, thus forming a substantially homogeneous translucent white bloom, said raw container being intended to undergo a washing of the surface of the glass wall inner face in order to eliminate said bloom.
Other features and advantages of the invention will appear in more detail upon reading of the following description, with reference to the appended drawing briefly described hereinafter, given by way of purely illustrative and non-limiting examples.
WAYS TO IMPLEMENT THE INVENTION
The invention relates to a container 1 comprising a glass wall 2 delimiting an accommodation cavity 3 for a substance (or product) intended to be packaged, stored, within the container 1. The container 1 according to the invention thus forms a primary packaging for said substance. The glass wall 2 of the container 1 has an inner face 4, located facing the accommodation cavity 3, and an opposite outer face 5. Preferably, the container 1 according to the invention forms a vial or a bottle, as in the preferential embodiment illustrated as an example in
In the sense of the invention, the word “glass” refers to a mineral glass. More particularly, the wall of the container 1 is generally made in mass of borosilicate glass. The glass forming the wall 2 of the container 1 therefore advantageously comprises, on average, in mass, between 60% and 80% of silicon oxide SiO2, between 0% and 3.5% of calcium oxide CaO, between 4% and 11% of sodium oxide Na2O, between 1% and 8% of potassium oxide K2O, between 0.5% and 4% of barium oxide BaO, between 7% and 14% of boron oxide B2O3, and 2% and 8% of aluminium oxide Al2O3. More advantageously, the glass of the wall 2 of the container 1 comprises, on average, in mass, between 65% and 69% of silicon oxide SiO2, between 0% and 1.5% of calcium oxide CaO, between 6% and 9% of sodium oxide Na2O, between 1.5% and 5% of potassium oxide K2O, between 1.5% and 3% of barium oxide BaO, between 11% and 13% of boron oxide B2O3, and 5% and 7% of aluminium oxide Al2O3. The glass of the glass wall 2 may moreover contain additional elements such as zinc, iron, etc., preferably as traces.
The glass of the wall 2 of the container 1 is preferably transparent or translucent, in the visible domain for human eye. It may be indifferently either a colourless glass or a coloured glass (“yellow” or “amber” glass, for example), notably to protect substance contained in the container 1 against the effects of light, in particular in certain wavelength ranges (UV, etc.).
Preferably, the container 1 according to the invention is made of moulded glass, and not of drawn glass (i.e. manufactured from a preform, such as a tube, made of drawn glass). In a manner known per se, such a moulded glass container 1 can be obtained by a “blow-and-blow” or “press-and-blow” process, for example using an IS machine. Indeed, it has been observed that a drawn glass container suffers intrinsically, due to its forming method, from an increased risk of delamination (that is to say a risk of detachment of glass flakes or particles from the surface of the inner face of the container wall by interaction of the glass with the substance contained in the container) with respect to a moulded glass container, and in particular when the glass is borosilicate glass. Now, the presence of free particles of glass in a substance, in particular a pharmaceutical substance intended to be administered to a human being or to an animal, may have very serious health consequences.
In accordance with the invention, the inner face 4 of the wall 2 of the container 1 forms a bare glass surface intended to come into direct contact with said substance. In other words, the inner face 4 of the glass wall 2 is devoid of any continuous surface layer exogenous to the glass of the wall 2, which would have been deposited on the inner face 4 in order to separate the latter from the substance that the accommodation cavity 3 of the container 1 is intended to contain. More precisely, the inner face 4 of the glass wall 2 is devoid of any additional barrier coating, exogenous to the glass of the wall 2, designed to prevent the migration of one or more chemical species or elements contained in the glass of the glass wall 2 to said substance, and vice versa. The inner face 4 of the wall 2 of the container 1 is therefore in particular devoid of surface layer that would be formed of an oxide, a nitride or an oxynitride of an element chosen among the group consisted of silicon Si, aluminium Al, titanium Ti, boron B, zirconium Zr, tantalum Ta, or a mixture of these latter, and/or also formed of an organic material, as for example one or several polysilosanes (silicone), etc. Even so, it is not excluded that the container 1 can have at the surface of its inner face 4, and in particular upstream from a filling of the accommodation cavity 3 with said substance, one or more chemical species exogenous to the glass of the wall 2, insofar as theses species do not form a coating layer intended to protect the glass of the wall 2 and the substance contained in the accommodation cavity 3 against any chemical interaction between them. So devoid of barrier coating deposited on the inner face 4 of its glass wall 2, the container 1 according to the invention is thus relatively easy and inexpensive to manufacture.
According to the invention, and although the glass wall 2 of the container 1 is generally formed, as already described hereinabove, of a borosilicate glass, the wall 2 has a very particular atomic profile of sodium in the vicinity of the surface of its inner face 4, and over a particular depth under said surface, which provides the container 1 with very interesting properties in terms of chemical resistance of the glass of said wall 2 with respect to the substance intended to be contained in said container 1. In particular, said glass wall 2 of the container according to the invention has an atomic fraction of sodium that is lower than 2.0 at. % up to a depth of at least 300 nm (+/−1 nm) from the surface of the inner face 4 of the wall 2. Thus, from the surface of the inner face 4 of the glass wall 2, and up to a depth of at least 300 nm, the glass of the wall 2 has an atomic fraction of sodium that does not exceed 2.0 at. %.
This atomic fraction, as well as all the atomic fractions which will be discussed below, is measured, analysed, by X-ray induced photoelectron spectrometry (XPS). Advantageously, the atomic fractions discussed in the present disclosure of the invention are measured by X-ray induced photoelectron spectrometry (XPS), with a detection angle of 90° (+/−1°) with respect to the surface of the inner face 4, using an XPS spectrometry hardware and software system comprising a monochromatic Al Kalpha X-ray source, with a diameter of analysed area between 50 μm and 1 000 μm (and for example 400 μm), and with a deep abrasion of the surface of the inner face 4 under a flow of argon ions, with an energy preferentially between 0.5 keV and 5 keV (and for example 2 keV), with a speed of erosion preferentially between 5 nm/min and 10 nm/min (and for example of 8.5 nm/min). Well known as such, such an XPS measurement can be made for example using a spectrometry hardware and software system Thermo Scientific™ K-Alpha™ sold by the ThermoFischer company, with a monochromatic Al Kalpha X-ray source, a diameter of analysed area of typically 400 μm, and with a deep abrasion of the surface under a flow of argon ions, with an energy of 2 keV, with a speed of erosion (measured on a layer of SiO2) of 8.5 nm/min, for example.
The value of atomic fraction of sodium, up to a depth of at least 300 nm, being thus at most equal to 2 at. %, it is still more advantageous that said atomic fraction of sodium is lower than or equal to 1.8 at. %, preferably lower than or equal to 1.6 at. %, preferably lower than or equal to 1.4 at. %, and still preferably lower than or equal to 1.5 at. %, up to a depth of at least 300 nm from the surface of the inner face 4.
The profile of atomic fraction of sodium of the glass of the wall 2 over such a depth of 300 nm is not necessarily strictly homogeneous at any depth between 0 nm and 300 nm. In particular, given the generally gradual nature over time of an attack on the glass by a substance contained in the accommodation cavity 3, it is advantageous in terms of chemical resistance of the glass that the atomic fraction of sodium is, on average, of a value that decreases from the inside, i.e. from the very heart, of the glass wall 2 towards the surface of the inner face 4 of the latter.
Preferably, said atomic fraction of sodium of the glass of the wall 2 is lower than or equal to 1.6 at. %, preferably lower than or equal to 1.5 at. %, preferably lower than or equal to 1.4 at. %, preferably lower than or equal to 1.3 at. %, and still preferably lower than or equal to 1.2 at. %, up to a depth of at least 200 nm (+/−1 nm) from the surface of the inner face 4.
As an alternative or a complement, said atomic fraction of sodium of the glass of the wall 2 is lower than or equal to 1.0 at. %, preferably lower than or equal to 0.9 at. %, and still preferably lower than or equal to 0.8 at. %, up to a depth of at least 100 nm (+/−1 nm) from the surface of the inner face 4.
As an alternative or a complement, said atomic fraction of sodium of the glass of the wall 2 is lower than or equal to 0.8 at. %, and preferably lower than or equal to 0.7 at. %, up to a depth of at least 30 nm (+/−1 nm) from the surface of the inner face 4. As an alternative or a complement, said atomic fraction of sodium of the glass of the wall 2 is lower than or equal to 0.5 at. %, preferably lower than or equal to 0.4 at. %, preferably lower than or equal to 0.3 at. %, and still preferably lower than or equal to 0.2 at. %, up to a depth of at least 10 nm (+/−1 nm) from the surface of the inner face 4. Therefore, the glass of the wall 2 of the container 1 has, in a particularly advantageous manner, a concentration or atomic fraction of sodium that is particularly low in the immediate vicinity of the surface of the inner face 4 of said wall 2, advantageously between 0.0 at. % and 0.8 at. %, and even more advantageously between 0.0 at. % and 0.5 at. %.
In comparison, the atomic fraction of sodium of the glass of a conventional borosilicate glass container (Type I glass container) is typically equal to 6 at. % on average over all the whole depth of the glass wall, whereas the atomic fraction of sodium of the glass of a conventional soda-lime-silica glass container (Type III glass container) and of the glass of a conventional Type II glass container (treated Type III glass container) is typically between 6 at. % and 15 at. % on average over the whole depth of the glass wall.
As an alternative or a complement, the container 1 can advantageously have certain particular features in terms of ratio of an atomic fraction of one or more other atomic elements in the glass (in particular sodium, calcium and aluminium) to an atomic fraction of silicon, which contribute to a particular patterning of the glass network in the vicinity of the surface of the inner face 4, tending to still improve the glass resistance with respect to the substance intended to be contained in the accommodation cavity 3 of the container 1.
In particular, the glass wall 2 of the container 1 has advantageously a ratio of an atomic fraction of sodium to an atomic fraction of silicon, said atomic fractions being measured by X-ray induced photoelectron spectrometry as mentioned hereinabove, that is lower than or equal to 0.100, preferably lower than or equal to 0.090, and preferably lower than or equal to 0.080, up to a depth of at least 300 nm (+1-1 nm) from the surface of the inner face 4.
As an alternative or a complement, the glass wall 2 advantageously has a ratio of an atomic fraction of sodium to an atomic fraction of silicon, measured by X-ray induced photoelectron spectrometry, that is lower than or equal to 0.070, preferably lower than or equal to 0.060, and still preferably lower than or equal to 0.050, up to a depth of at least 200 nm (+/−1 nm) from the surface of the inner face 4. As an alternative or a complement, the glass wall 2 advantageously has a ratio of an atomic fraction of sodium to an atomic fraction of silicon, measured by X-ray induced photoelectron spectrometry, that is lower than or equal to 0.050, preferably lower than or equal to 0.040, and still preferably lower than or equal to 0.030, up to a depth of at least 100 nm (+1-1 nm) from the surface of the inner face 4.
As an alternative or a complement, the glass wall 2 advantageously has a ratio of an atomic fraction of sodium to an atomic fraction of silicon, measured by X-ray induced photoelectron spectrometry, that is lower than or equal to 0.040, preferably lower than or equal to 0.030, and still preferably lower than or equal to 0.020, up to a depth of at least 30 nm (+/−1 nm) from the surface of the inner face 4. As an alternative or a complement, the glass wall 2 advantageously has a ratio of an atomic fraction of sodium to an atomic fraction of silicon, measured by X-ray induced photoelectron spectrometry, that is lower than or equal to 0.030, preferably lower than or equal to 0.020, preferably lower than or equal to 0.010, and still preferably lower than or equal to 0.005, up to a depth of at least 10 nm (+1-1 nm) from the surface of the inner face 4.
The comparison between atomic fractions of sodium and silicon is here interesting in that it reflects a comparison of an atomic concentration of modifier ion (in this case, sodium) and an atomic concentration of former ion (in this case, silicon). The advantageous ratios proposed hereinabove thus reflects the fact that, in the vicinity of the inner face 4 of the glass wall 2, the glass is particularly rich in former ions, which contributes to its chemical resistance.
As an alternative or a complement, the glass wall 2 advantageously has a ratio of an atomic fraction of calcium to an atomic fraction of silicon, still measured by X-ray induced photoelectron spectrometry, that is lower than or equal to 0.040, preferably lower than or equal to 0.030, and preferably lower than or equal to 0.020, up to a depth of at least 300 nm (+/−1 nm) from the surface of the inner face 4. As an alternative or a complement, the glass wall 2 advantageously has a ratio of an atomic fraction of calcium to an atomic fraction of silicon, measured by X-ray induced photoelectron spectrometry, that is lower than or equal to 0.030, and preferably lower than or equal to 0.020, up to a depth of at least 200 nm (+/−1 nm) from the surface of the inner face 4. As an alternative or a complement, the glass wall 2 advantageously has a ratio of an atomic fraction of calcium to an atomic fraction of silicon, measured by X-ray induced photoelectron spectrometry, that is lower than or equal to 0.010, and preferably substantially zero, up to a depth of at least 10 nm (+/−1 nm) from the surface of the inner face 4.
As an alternative or a complement, the glass wall 2 advantageously has a ratio of an atomic fraction of aluminium to an atomic fraction of silicon, measured by X-ray induced photoelectron spectrometry, that is lower than or equal to 0.030, and preferably lower than or equal to 0.020, up to a depth of at least 300 nm (+/−1 nm) from the surface of the inner face 4. However, it is surprisingly advantageous that the glass wall 2 has an atomic fraction of aluminium, measured by X-ray induced photoelectron spectrometry, that is higher than or equal to 3 at. %, and preferably higher than or equal to 3.5 at. %, up to a depth of at least 300 nm (+/−1 nm) from the surface of the inner face 4. Indeed, it seems that such an aluminium content is favourable to a densification of the glass network in the vicinity of the inner face 4 of the glass wall 2, tending to further improve the glass resistance with respect to the substance intended to be contained in the accommodation cavity 3 of the container 1.
The migration of boron ions and/or barium ions coming from the borosilicate glass of the container 1 to the substance intended to be contained in the latter may be a problem both for integrity of said substance over time and from the health point of view for the final user of said substance. Therefore, in order to provide the container 1 with excellent performances in terms of control of the boron ion elution rate, the glass wall 2 has preferably an atomic fraction of boron, measured by X-ray induced photoelectron spectrometry, that is lower than or equal to 20.0 at. %, and preferably lower than or equal to 15.0 at. %, up to a depth of at least 300 nm (+/−1 nm) from the surface of the inner face 4. As an alternative or a complement, the glass wall 2 advantageously has an atomic fraction of boron, measured by X-ray induced photoelectron spectrometry, that is lower than or equal to 15.0 at. %, and preferably lower than or equal to 10.0 at. %, up to a depth of at least 30 nm (+/−1 nm) from the surface of the inner face 4.
In order to provide the container 1 with excellent performances in terms of control of the barium ion elution rate, the glass wall 2 has preferably an atomic fraction of barium, measured by X-ray induced photoelectron spectrometry, that is lower than or equal to 1.5 at. %, preferably lower than or equal to 1.4 at. %, preferably lower than or equal to 1.3 at. %, preferably lower than or equal to 1.2 at. %, preferably lower than or equal to 1.1 at. %, and preferably lower than or equal to 1.0 at. %, up to a depth of at least 300 nm (+/−1 nm) from the surface of the inner face 4. As an alternative or a complement, the glass wall 2 advantageously has an atomic fraction of barium, still measured by X-ray induced photoelectron spectrometry, that is lower than or equal to 0.9 at. %, preferably lower than or equal to 0.8 at. %, still preferably lower than or equal to 0.7 at. %, up to a depth of at least 30 nm (+1-1 nm) from the surface of the inner face 4.
After having undergone a filling and ageing protocol as defined in chapter 660 of the USP (U.S. Pharmacopoeia) or in chapter 3.2.1. of the European Pharmacopoeia (i.e. 1h at 121° C. in an autoclave, filled with ultra-pure water), the container 1 thus has a total quantity of extractables (species extracted from the glass) per surface unit that is advantageously lower than 15×10−2 μg·cm−2, and even more advantageously lower than 10×10−2 μg·cm−2 (for example, between 7×10−2 and 9×10−2 μg·cm−2), among which
Such properties in terms of quantities of extractables are inventions in their own rights. Thus, is an invention in its own right a container 1 comprising a glass wall 2 delimiting an accommodation cavity 3 for a substance, in particular for a pharmaceutical or diagnostic substance, said glass wall 2 having an inner face 4 located facing said accommodation cavity 3, said wall 2 being made of borosilicate glass, said inner face 4 forming a bare glass surface intended to come into direct contact with the substance, said container 1 having a total quantity of extractables (species extracted from the glass) per surface unit that is lower than 15×10−2 μg·cm−2, and preferably lower than 10×10−2 μg·cm−2 (for example, between 7×10−2 and 9×10−2 μg·cm−2), after having undergone a filling and ageing protocol as defined in chapter 660 of the USP (U.S. Pharmacopoeia) or in chapter 3.2.1. of the European Pharmacopoeia (i.e. during 1 h at 121° C. in an autoclave, filled with ultra-pure water).
Is also an invention in its own right a container 1 comprising a glass wall 2 delimiting an accommodation cavity 3 for a substance, in particular for a pharmaceutical or diagnostic substance, said glass wall 2 having an inner face 4 located facing said accommodation cavity 3, said wall 2 being made of borosilicate glass, said inner face 4 forming a bare glass surface intended to come into direct contact with the substance, said container 1 having a quantity of extracted sodium that is lower than 5×10−2 μg·cm−2, and preferably lower than 4×10−2 μg·cm−2 (for example, between 1.5×10−2 and 3.0×10−2 μg·cm−2), after having undergone a filling and ageing protocol as defined in chapter 660 of the USP (U.S. Pharmacopoeia) or in chapter 3.2.1. of the European Pharmacopoeia (i.e. during 1 h at 121° C. in an autoclave, filled with ultra-pure water).
Is also an invention in its own right a container 1 comprising a glass wall 2 delimiting an accommodation cavity 3 for a substance, in particular for a pharmaceutical or diagnostic substance, said glass wall 2 having an inner face 4 located facing said accommodation cavity 3, said wall 2 being made of borosilicate glass, said inner face 4 forming a bare glass surface intended to come into direct contact with the substance, said container 1 having a quantity of extracted aluminium that is lower than 2×10−2 μg·cm−2, and preferably lower than 1×10−2 μg·cm−2 (for example, between 0.3×10−2 and 0.8×10−2 μg·cm−2), after having undergone a filling and ageing protocol as defined in chapter 660 of the USP (U.S. Pharmacopoeia) or in chapter 3.2.1. of the European Pharmacopoeia (i.e. during 1 h at 121° C. in an autoclave, filled with ultra-pure water).
Is also an invention in its own right a container 1 comprising a glass wall 2 delimiting an accommodation cavity 3 for a substance, in particular for a pharmaceutical or diagnostic substance, said glass wall 2 having an inner face 4 located facing said accommodation cavity 3, said wall 2 being made of borosilicate glass, said inner face 4 forming a bare glass surface intended to come into direct contact with the substance, said container 1 having a quantity of extracted barium that is lower than 1.5×10−2 μg·cm−2, and preferably lower than 1×10−2 μg·cm−2 (for example, between 0.1×10−2 and 0.5×10−2 μg·cm−2), after having undergone a filling and ageing protocol as defined in chapter 660 of the USP (U.S. Pharmacopoeia) or in chapter 3.2.1. of the European Pharmacopoeia (i.e. during 1 h at 121° C. in an autoclave, filled with ultra-pure water).
Is also an invention in its own right a container 1 comprising a glass wall 2 delimiting an accommodation cavity 3 for a substance, in particular for a pharmaceutical or diagnostic substance, said glass wall 2 having an inner face 4 located facing said accommodation cavity 3, said wall 2 being made of borosilicate glass, said inner face 4 forming a bare glass surface intended to come into direct contact with the substance, said container 1 having a quantity of extracted zinc that is advantageously lower than 0.8×10−2 μg·cm−2, and even more advantageously lower than 0.5×10−2 μg·cm−2 (for example, between 0.0×10−2 and 0.2×10−2 μg·cm−2).
Advantageously, these results may be observed by inductively coupled plasma emission spectrometry (ICP-OES) analysis, for example using a hardware and software system ICP-OES PerkinElmer® Optima™ 7300 DV, with a Meinhard cyclone spray chamber and argon purge (white release values subtracted—acidified solutions 2% suprapure HNO3—without dilution. Acquisition time 20 seconds. Quantification by measuring the area under the peak with background correction at 2 points. Systematic rinsing between samples).
In view of the above, the container 1 with a glass wall 2 according to the invention has excellent characteristics in terms of controlling the phenomenon of elution of species present in the glass, which means a particularly strong chemical resistance, and makes said container 1 particularly suitable for receiving into its accommodation cavity 3 a substance that is particularly sensitive to said species and/or particularly aggressive to glass. Therefore, the container 1 according to the invention can advantageously be used for storing
Advantageously, but without being limited thereto, a container 1 according to the invention can be obtained, in a manner that is particularly simple, inexpensive, efficient and safe in terms of health and environment, from a container (or primary container) of the Type I moulded borosilicate glass vial type, by subjecting the latter to a dealkalization treatment of the glass in the vicinity of the surface of the inner face of its glass wall by introduction into the accommodation cavity of the container, using an injection head located remote from the opening of the container and out of the latter, whereas said glass wall is at a temperature of about 600° C., of a liquid dose of ammonium sulphate (NH4)2SO4 dissolved in water. Preferably, the concentration of ammonium sulphate in the liquid dose will be chosen close or just below the saturation concentration. The volume of said liquid dose may obviously vary according to the size, and in particular the nominal volume, of the considered container.
The following, non-limiting, examples illustrate certain particularly interesting properties of containers 1 according to the invention in terms of performance in controlling the risks of elution of certain chemical species from the glass.
Example 1—A first series of containers according to the invention has been manufactured from primary containers of the Type I moulded borosilicate glass vial type, of 20 mL nominal capacity. These primary containers have been subjected to a dealkalization treatment of the glass in the vicinity of the surface of the inner face of their glass wall by introduction into the accommodation cavity of the primary containers, using an injection head located remote from the opening of the primary containers and out of these latter, whereas the glass wall of the primary containers was at a temperature of about 600° C., of a liquid dose of ammonium sulphate (NH4)2SO4 dissolved in water, in a concentration close or just below the saturation concentration (volume of the liquid dose: 80 μL).
Table 1 below compiles results obtained for one of the containers according to Example 1, by X-ray induced photoelectron spectrometry (XPS) as described hereinabove, in terms of atomic fraction (in at. %) and ratio of atomic fractions of certain species of the wall glass, at different depths from the surface of the inner face of this wall.
Example 2—A second series of containers according to the invention has been manufactured from primary containers of the Type I moulded borosilicate glass vial type, of 10 mL nominal capacity. These primary containers have been subjected to a dealkalization treatment of the glass in the vicinity of the surface of the inner face of their glass wall by introduction into the accommodation cavity of the primary containers, using an injection head located remote from the opening of the primary containers and out of these latter, whereas the glass wall of the primary containers was at a temperature of about 600° C., of a liquid dose of ammonium sulphate (NH4)2SO4 dissolved in water, in a concentration close or just below the saturation concentration (volume of the liquid dose: 80 μL).
Table 2 below compiles results obtained for five containers R1 to R5 according to Example 2, by inductively coupled plasma emission spectrometry (ICP-OES) as described hereinabove, in terms of quantities of species extracted from the glass (expressed in μg/L), after having subjected said containers to a filling and ageing protocol as defined in chapter 660 of the USP (U.S. Pharmacopoeia) or in chapter 3.2.1. of the European Pharmacopoeia (i.e. 1 h at 121° C. in an autoclave, filled with ultra-pure water). The results obtained for containers R1 to R5 are compared with results obtained in the same conditions for five containers R1′ to R5′ of the conventional Type I glass vial type, of 10 mL nominal capacity. The observed quantities of extracted species are far lower in the case of the containers according to the invention than the quantities of extracted species for the known Type I glass containers.
Example 3—A third series of containers according to the invention has been manufactured from primary containers of the Type I moulded borosilicate glass vial type, of 20 mL nominal capacity. These primary containers have been subjected to a dealkalization treatment of the glass in the vicinity of the surface of the inner face of their glass wall by introduction into the accommodation cavity of the primary containers, using an injection head located remote from the opening of the primary containers and out of these latter, whereas the glass wall of the primary containers was at a temperature of about 600° C., of a liquid dose of ammonium sulphate (NH4)2SO4 dissolved in water, in a concentration close or just below the saturation concentration (volume of the liquid dose: 80 μL).
Table 3 below compiles results obtained for five containers R6 to R10 according to Example 3, by inductively coupled plasma emission spectrometry (ICP-OES) as described hereinabove, in terms of quantities of species extracted from the glass (expressed in μg/L), after having subjected said containers to a filling and ageing protocol as defined in chapter 660 of the USP (U.S. Pharmacopeia) or in chapter 3.2.1. of the European Pharmacopeia (i.e. 1 h at 121° C. in an autoclave, filled with ultra-pure water). The results obtained for containers R6 to R10 are compared with results obtained in the same conditions for five containers R6′ to R10′ of the conventional Type I glass vial type, of 20 mL nominal capacity. The observed quantities of extracted species are far lower in the case of the containers according to the invention than the quantities of extracted species for the known Type I glass containers.
Example 4—A fourth series of containers according to the invention has been manufactured from primary containers of the Type I moulded borosilicate glass vial type, of 50 mL nominal capacity. These primary containers have been subjected to a dealkalization treatment of the glass in the vicinity of the surface of the inner face of their glass wall by introduction into the accommodation cavity of the primary containers, using an injection head located remote from the opening of the primary containers and out of these latter, whereas the glass wall of the primary containers was at a temperature of about 600° C., of a liquid dose of ammonium sulphate (NH4)2SO4 dissolved in water, in a concentration close or just below the saturation concentration (volume of the liquid dose: 50 μL).
Table 4 below compiles results obtained for three containers R11 to R13 according to Example 4, by inductively coupled plasma emission spectrometry (ICP-OES) as described hereinabove, in terms of quantities of species extracted from the glass (expressed in μg/L), after having subjected said containers to a filling and ageing protocol as defined in chapter 660 of the USP (U.S. Pharmacopoeia) or in chapter 3.2.1. of the European Pharmacopoeia (i.e. 1 h at 121° C. in an autoclave, filled with ultra-pure water). The results obtained for containers R11 to R13 are compared with results obtained in the same conditions for three containers R11′ to R13′ of the conventional Type I glass vial type, of 50 mL nominal capacity. The observed quantities of extracted species are far lower in the case of the containers according to the invention than the quantities of extracted species for the known Type I glass containers.
Table 5 below compiles results obtained for three other containers R14 to R16 according to Example 4, in comparison with results obtained in the same conditions for three containers R14′ to R16′ of the conventional Type I glass vial type, of 50 mL nominal capacity, in terms of surface hydrolytic resistance Rh. Hydrolytic resistance Rh is here measured in a known manner, by titration of an aliquot part of the extraction solution (titrated volume: 100 mL) obtained with a solution of hydrochloric acid (HCL N/100), after having subjected said containers to a filling and ageing protocol as defined in chapter 660 of the USP (U.S. Pharmacopoeia) or in chapter 3.2.1. of the European Pharmacopoeia (i.e. 1 h at 121° C. in an autoclave, filled with ultra-pure water). The 90% capacity of the containers is here of 54 mL.
It is observed that the containers R14 to R16, according to the invention, have a hydrolytic resistance Rh that is far better (i.e. far lower) than that of the known Type I glass containers R14′ to R16′. As a reminder, for such a capacity, the regulatory limit of hydrolytic resistance Rh for a Type III glass container is of 4.8 ml HCl N/100, and that of a Type II glass container is of 0.5 ml HCl N/100, for a titrated volume of 100 mL.
Example 5—A fifth series of containers according to the invention has been manufactured from primary containers of the Type I moulded borosilicate glass vial type, of 100 mL nominal capacity. These primary containers have been subjected to a dealkalization treatment of the glass in the vicinity of the surface of the inner face of their glass wall by introduction into the accommodation cavity of the primary containers, using an injection head located remote from the opening of the primary containers and out of these latter, whereas the glass wall of the primary containers was at a temperature of about 600° C., of a liquid dose of ammonium sulphate (NH4)2SO4 dissolved in water, in a concentration close or just below the saturation concentration (volume of the liquid dose: 120 μL).
Table 6 below compiles results obtained for five containers R17 to R21 according to Example 5, by inductively coupled plasma emission spectrometry (ICP-OES) as described hereinabove, in terms of quantities of species extracted from the glass (expressed in μg/L), after having subjected said containers to a filling and ageing protocol as defined in chapter 660 of the USP (U.S. Pharmacopoeia) or in chapter 3.2.1. of the European Pharmacopoeia (i.e. 1 h at 121° C. in an autoclave, filled with ultra-pure water). The results obtained for containers R17 to R21 are compared with results obtained in the same conditions for five containers R17′ to R21′ of the conventional Type I glass vial type, of 100 mL nominal capacity. The so-observed quantities of extracted species are far lower in the case of the containers according to the invention than the quantities of extracted species for the known Type I glass containers.
Example 6—A sixth series of containers according to the invention has been manufactured from primary containers of the Type I moulded borosilicate glass vial type, of 50 mL nominal capacity. These primary containers have been subjected to a dealkalization treatment of the glass in the vicinity of the surface of the inner face of their glass wall by introduction into the accommodation cavity of the primary containers, using an injection head located remote from the opening of the primary containers and out of these latter, whereas the glass wall of the primary containers was at a temperature of about 600° C., of a liquid dose of ammonium sulphate (NH4)2SO4 dissolved in water, in a concentration close or just below the saturation concentration (volume of the liquid dose: 120 μL).
Table 7 below compiles results obtained for three series of three containers R22 to R30 according to Example 6, by comparison with three series of three conventional Type I glass containers R22′ to R30′, in terms of quantities of species extracted from the glass (expressed in ppb), and that for different tests described in chapter 1660 of the USP (U.S. Pharmacopoeia):
The results of the above Examples 1 to 6 thus show that the containers 1 according to the invention have performances in terms of chemical resistance that are far higher than those of conventional Type I containers, these latter having however intrinsically a far better chemical resistance than Type Ill or Type II glass containers. The quantities of glass species that are liable to be released by the containers 1 according to the invention are particularly low, in particular as regards sodium, aluminium, boron, barium, or also zinc. Thus, the use of containers 1 according to the invention makes it possible to store and preserve particularly aggressive and/or unstable substances in excellent conditions. It moreover generally allows extending the storage life and therefore the lifespan of substances, and in particular pharmaceutical or diagnostic-use substances.
The invention also relates, as such, to a raw container comprising a glass wall delimiting an accommodation cavity, said glass wall having an inner face located facing said accommodation cavity. Said semi-finished, raw container is intended to form a container 1 according to the invention, as described hereinabove. Therefore, the glass wall of said raw container prefigures that of the container 1 according to the invention. According to the invention, said glass wall of the raw container is made of borosilicate glass, according to the definition already given hereinabove, and advantageously has the same physical-chemical properties in terms of atomic fractions and ratio of atomic fractions as those, described hereinabove, of the glass wall 2 of the container 1 according to the invention.
According to the invention, the inner face of the glass wall of the raw container forms a glass surface that is devoid of sodium sulphate (Na2SO4) grains, which advantageously constitute a residue of dealkalization treatment of the glass in the vicinity of the surface of the inner face of the glass wall, preferably using ammonium sulphate ((NH4)2SO4). Said raw container is thus advantageously obtained from a container with a wall made of a typically Type I, borosilicate glass, preferably moulded glass, which has been subjected to a dealkalization treatment to obtain the above-described physical-chemical characteristics, and which has, due to this dealkalization treatment, sodium sulphate grains at the surface of the inner face of its glass wall. Said sodium sulphate grains thus form a powder residual deposit, which can be removed, by a suitable washing of the surface of the inner face of the glass wall, before the accommodation cavity of the container is finally filled with a substance, and in particular with a pharmaceutical or diagnostic substance.
In accordance with the invention, said sodium sulphate grains are shaped and arranged in a substantially uniform manner on the glass surface of the inner face, thus forming on said surface a bloom that is white (or whitish, slightly milky in appearance), translucent and substantially homogeneous, at least to the naked eye (i.e. from a macroscopic point of view) and under illumination using light in the range visible to the human eye. Typically, said sodium sulphate grains have a generally spherical shape. Said sodium sulphate grains advantageously have an average size between 50 nm and 1,500 nm. For example, said grains may be gathered into two populations, i.e. a population of small grains that have an average size advantageously between 50 nm and 200 nm, and a population of large grains that have an average size advantageously between 500 nm and 1,500 nm. Said sodium sulphate grains are advantageously distributed over the glass surface of the inner face with an average surface density from 0.2 grains/μm2 to 3 grains/μm2, and preferably from 0.2 grains/μm2 to 1.5 grains/μm2 (grains per square micrometer). For example, the grains may be gathered on the one hand into a population of small grains, as mentioned hereinabove, which are distributed over the glass surface of the inner face with an average surface density advantageously from 0.2 grains/μm2 to 2.5 grains/μm2, and even more advantageously from 0.5 grains/μm2 to 1.5 grains/μm2, and on the other hand a population of large grains, as already mentioned hereinabove, which are distributed over the glass surface of the inner face with an average surface density advantageously from 0 grains/μm2 to 0.5 grains/μm2, and even more advantageously from 0 grains/μm2 to 0.1 grains/μm2. These size and surface density characteristics may be observed, for example, with a scanning electron microscope (SEM).
Formed by such sodium sulphate grains uniformly distributed over the surface of the inner face, the white bloom is thus substantially uniform, therefore substantially free of more or less marked, opaque spots. Preferably, the outer face of the glass wall of the raw container, opposite to said inner face, forms a surface that is substantially devoid of sodium sulphate grains (with the possible exception of a few scattered grains). However, as an alternative, it remains conceivable that the surface of said outer face can also be provided with sodium sulphate grains, in which case these latter are shaped and arranged in a substantially uniform manner on the surface of the outer face, thus also forming a bloom that is white (or whitish, slightly milky in appearance), translucent and substantially homogeneous, at least to the naked eye (i.e. from a macroscopic point of view) and under illumination using light in the range visible to the human eye.
Said raw container is intended to undergo a washing of the surface of the inner face (and, as the case may be, of the outer face) of the glass wall in order to eliminate therefrom said bloom of sodium sulphate grains, before the accommodation cavity of the so-obtained container is finally filled with a substance, and in particular a pharmaceutical or diagnostic substance. Thus, the washing of the semi-finished, raw container makes it possible to eliminate the white bloom from the surface of the glass wall and to advantageously obtain the container 1 of the invention, as described hereinabove.
Thanks to such a characteristic of homogeneity, uniformity, of the bloom formed by the sodium sulphate grains, the glass wall of the raw container according to the invention may be easily and efficiently inspected, for potential glass defect, to the naked eye or using a conventional machine for automatic optical inspection, and that without it is thereby necessary to proceed to any post-treatment of the glass wall (such as, in particular, a washing, an elimination of the sulphate grains, from the surface of the glass wall) previously to such an inspection. The quality control of the container is thus particularly reliable, while being simpler and less expensive to implement. This ensures that the container is reliably controlled, making it particularly safe.
Particularly advantageously, but without being limited thereto, a raw container according to the invention can be obtained, in a simple and efficient manner, from a container (or primary container) of the Type I moulded borosilicate glass vial type, by subjecting the latter to a dealkalization treatment of the glass in the vicinity of the surface of the inner face of its glass wall by introduction into the accommodation cavity of the container, using an injection head located remote from the opening of the container and out of the latter, whereas said glass wall is at a temperature of about 350° C., and preferably between 350° C. and 800° C., of a liquid dose of ammonium sulphate (NH4)2SO4 dissolved in water. Preferably, the concentration of ammonium sulphate in the liquid dose will be chosen close or just below the saturation concentration. The volume of said liquid dose may obviously vary according to the size, and in particular the nominal volume, of the considered container.
It results therefrom that the containers according to the invention are not only particularly effective in terms of chemical resistance, but are also particularly reliable, at a reasonable manufacturing cost.
Possibility of Industrial Application
The invention finds its application in the field of glass containers, and in particular for the packaging of pharmaceutical or diagnostic substances.
| Number | Date | Country | Kind |
|---|---|---|---|
| FR2100222 | Jan 2021 | FR | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/FR2021/052428 | 12/22/2021 | WO |
