2025 Volume 73 Issue 2 Pages 94-102
The pharmaceutical industry relies heavily on the safe and efficient packaging of drugs and injection glass vials play a pivotal role in this regard. Ensuring the quality and consistency of these vials is essential for safeguarding the potency of pharmaceutical formulations. In this study, the recent breakthroughs achieved in the manufacturing of injection glass vials by implementing advanced surface-processing technologies were examined. We developed potential injection glass vials using the novel vial-inner-surface treatment (VIST) technology to homogenize the inner surface of the vials. Compared with common vials, the elution of alkali contents and conductivity of these injection glass vials were reduced because of the VIST technology, resulting in the formation of smooth and homogeneous inner surfaces. In addition, drug adsorption onto the inner surface of the VIST vials was considerably lowered than that onto common vials. These results suggest that VIST vials are of excellent quality and could become the standard injection glass vials.
The pharmaceutical industry relies heavily on the safe and efficient packaging of drugs and injection glass vials play a pivotal role in this regard.1) Ensuring the quality and consistency of these vials is essential for safeguarding the potency of pharmaceutical formulations.2)
Injection glass vials are made of borosilicate glass composed of silicon dioxide and anhydrous boric acid. Borosilicate glass is characterized by a low coefficient of thermal expansion, high hardness, and water resistance. Compared with soda glass and lead glass, borosilicate glass is more resistant to heat, cold, and corrosion caused by chemicals. In addition, it is impermeable to oxygen and other gases; thus, oxidation is prevented.
Delamination in injection glass vials refers to the separation of layers within the glass material, typically on the inner surface of a vial.2–7) This phenomenon can occur because of various factors, including interactions between the glass surface and the vial’s contents, such as pharmaceutical formulations or sterilization agents.5) Chemical reactions or leaching of ions from the glass into the contents can weaken the bonds between the layers and lead to delamination.8) Other potential causes of delamination include inadequately cleaning or treating the surfaces of glass vials prior to filling, which can leave residues or contaminants that promote delamination.8) Improper storage conditions, such as exposure to high temperatures or humidity, can accelerate delamination.
The challenges associated with delamination occurring in injection glass vials are significant because the quality and safety of pharmaceutical products may be compromised.1,7,9) Delamination can result in particulate contamination of the drug solution, affecting the drug’s efficacy and potentially causing adverse reactions in patients. Addressing these challenges requires a multifaceted approach, including 1) the implementation of process control, such as low-temperature processing, 2) coating of the inner surface of the vial,10–12) 3) treatment of the inner surface with chemicals such as sulfuring agents, and 4) alteration of the glass composition. However, achieving improvements by implementing process control requires operators, process control tools, and confirmation through statistical sampling. In addition, etching performed using sulfur treatment, acids, alkalis, etc., does not fundamentally improve the glass surface and, thus, poses a risk of false safety. In addition, coating techniques require revalidation because the glass surface chemistry is different from the surface chemistry of Type I glass.6,13) In addition, glass-composition changes that are outside the scope of specifications require revalidation and stability tests because safety is not established.
Therefore, deterioration occurring in the inner glass surface during the manufacturing process must be repaired without relying on operators’ skills, modifying the inner surface of the vial, and using new materials to prevent delamination in injection glass vials and improve the stability of the contained pharmaceutical products. In this study, we developed potential injection glass vials by using the “vial-inner-surface treatment” (VIST) technology to homogenize the inner surface of the vials (Fig. 1). Generally, the inner surfaces of common vials deteriorate because of volatilized Na, B, and other components that adhere to the inner surfaces. Thus, we rinsed the inner surface of the vials to remove such volatile components and heated the vials to a temperature higher than the glass transition point to homogenize the deteriorated layer on the inner surface; the vials were then slowly cooled to room temperature. In this study, we evaluated the quality of VIST vials as injection glass vials compared with that of sulfur-treated vials and common vials.
Scanning electron microscopy (SEM) analysis of the inner surface of injectable glass vials is useful for detecting microscopic surface structures and microscopic defects, and foreign matter in the vial and for evaluating the effects of coatings. As shown in Fig. 2, we examine the inner surfaces of common, sulfur-treated, and VIST vials by employing SEM. The common vials exhibit tiny cracks throughout the inner surfaces (Fig. 2A). In the sulfur-treated vials, the inner surface is corroded by acid, indicating that the surface is not completely smooth (Fig. 2B). By contrast, the inner surfaces of the VIST vials are extremely homogeneous, even in the SEM images at 30000× magnification (Fig. 2C). These results suggest that the inner surface of VIST vials may be smoother than that of sulfur-treated or normal vials. Since the SEM observation results are qualitative, it will be necessary to conduct quantitative studies on the unevenness of the inner surface of the vials using techniques such as laser microscopy.
To investigate the distribution of various elements on the glass surfaces of the common and VIST vials, the time-of-flight secondary ion mass spectrometry (TOF-SIMS) measurements in the positive and negative ion modes were performed. The depth of detection in the TOF-SIMS measurements was less than a few nanometers, which enabled the analysis of the elemental distribution on the inner surface of the vials. Here, TOF-SIMS analysis in sulfur-treated vials was not conducted because their inner surfaces were coated with a sulfur agent and could not be compared with VIST vials and common vials. Figure 3 shows the TOF-SIMS mapping of the inner surfaces of the common and VIST vials in the positive ion mode. In both the common and VIST vials, some unevenness in the distribution of various components on the inner surfaces is observed. The distributions of Al, B, Si, and Ba are similar on the inner surfaces of the common vials (Fig. 3A). In addition, the distribution of Ca is similar to that of Mg in the common vials (Fig. 3A). On the inner surfaces of the VIST vials, the distribution of Na is similar to that of K (Fig. 3B). Furthermore, the distributions of Al, B, and Si on the inner surfaces are similar in the VIST vials (Fig. 3B). In the case of TOF-SIMS mapping in the negative ion mode, a large bias in the distributions of Ca and Cl is observed on the common-vial inner surfaces compared with on the VIST-vial inner surfaces (Fig. 4). As shown in Fig. 5, the amount of each element present on the vial surface is estimated based on the peak intensity of the MS obtained by performing TOF-SIMS (Supplementary Figs. S1 and S2). The amounts of Na, Al, K, O, and CN are lower in the VIST vials than in the common vials. These results suggest that the VIST treatment drastically reduces the number of glass components.
Normalized values (the ratio of each peak’s intensity to the total intensity of all observed peaks) for the total positive and negative ion intensities were used: positive ion mode (A) and negative ion mode (B).
The elemental compositions and chemical states of the common and VIST vial surfaces were investigated by performing X-ray photoelectron spectroscopy (XPS). In the XPS analysis, the inner surfaces of the common and VIST vials were irradiated with soft X-rays in an ultrahigh vacuum, and the photoelectrons emitted from the surfaces were detected using an XPS analyzer. Under these conditions, because the distance that photoelectrons travel in a material is several nanometers, the depth of detection on the inner surface of a vial is also several nanometers. Elemental information on the inner surfaces of the vials was obtained from the binding energy values of the bound electrons, and information on the valence and bonded states was obtained from the energy shift of each peak. The peak area ratio was used for quantification. Table 1 lists the elemental compositions of the inner surfaces of the common and VIST vials. Many elements are found in addition to the main components of the glass (oxygen and silicon) in both the common and VIST vials (Supplementary Fig. S3). Notably, the amount of impurities, such as boron, sodium, and aluminum, on the inner surfaces of the VIST vials is considerably lower than that of the common vials (Table 1). In addition, the elemental compositions of the inner surfaces of the vials are converted to the amounts of the oxides of the metal elements present (Fig. 6). The amount of SiO2 is higher in the VIST vials than in common vials. Meanwhile, the amounts of B2O3 and Al2O3 are drastically lower in the VIST vials than in common vials. This is thought to be due to the decrease in the amount of other constituents of metal ions on the inner surface of the vial by the VIST treatment, resulting in an increase in the relative amount of Si oxide (SiO2), the main component of the vial. These results suggest that the VIST treatment lowers the amounts of oxidative impurities on the vial's inner surface.
| Si | B | Na | Al | K | Ca | Ba | |
|---|---|---|---|---|---|---|---|
| Common vial | 22.35 | 6.84 | 3.91 | 2.65 | 0.98 | 0.42 | 0.14 |
| VIST vial | 30.75 | 1.11 | 2.88 | 1.55 | 0.66 | n.d. | n.d. |
n.d.: not detected.
The elemental composition of the inner surfaces of the vials was converted to the amounts of the oxides of metal elements present.
We conducted an alkali elution study to measure the amount of alkaline components, such as sodium, barium, and calcium, leaching from the glass vials. Alkali elution studies are crucial because the leaching of alkaline components can affect the chemical stability and safety of injectable drugs. Leaching can cause changes in the pH or introduce impurities, which can compromise the efficacy and safety of the medication. As shown in Fig. 7, the amount of alkali eluted from the VIST vials is substantially lower than that from the common vials. In addition, we identify each eluted element, including alkalis and other glass components, from the vials (Fig. 8). The amounts of Na, B, Al, Si, Ca, and Ba eluted from the sulfur-treated and VIST vials are lower than those from the common vials (Figs. 8A–8F). In particular, the elution of glass components from the VIST vials is extremely low, and the elution of silicon is almost negligible (Fig. 8D); these results indicate that the VIST vials are of excellent quality.
The glass vials were filled with 2 and 10 mL of water and sterilized in an autoclave (121 °C) for 1 h. The solution was then titrated with 0.01 M HCl to obtain a pH value of 5.5. Each value represents the mean ± S.D. of 3 to 6 experiments. *p < 0.05 versus common vial (Scheffe’s test). †p < 0.05 versus VIST-vial (Scheffe's test).
The glass vials were filled with 2, 10, 15, and 30 mL of water. The samples were then sterilized in an autoclave (121 °C) for 1 h. The eluted elements were identified using ICP or AAS. Each value represents the mean ± S.D. of 5e experiments. *p < 0.05 versus common vial (Scheffe's test). †p < 0.05 versus VIST-vial (Scheffe’s test).
A pharmacopoeia sets strict standards for storing water for injection and specifies the amount of ionic impurities that can leach from the container. Water conductivity is used to evaluate the number of ions dissolved in a glass vial because it is highly dependent on the number of ions (e.g., sodium, calcium, and chlorine). Pure water conducts little electricity; however, the dissolution of ions in water increases conductivity. Therefore, we measured the water conductivity of the vials after various sterilization conditions (121 °C for 1, 2, and 4 h). As depicted in Fig. 9, the water conductivity in the common vials is high as the sterilization time increases. It exceeds the pharmacopoeia settings of 25 μS in 2 mL and 5 μS in 15 mL. In contrast, the water conductivity in the VIST vials is less than these values (Fig. 9). These results indicate that the VIST vials are injection glass vials that meet the criteria for conductivity tests.
After the vials were filled with distilled water equivalent to 90% of their full capacity, they were sealed tightly with a silicone rubber stopper and sterilized in an autoclave (121 °C). After sterilization for 1, 2, and 4 h, the vials were cooled to room temperature, and the dielectric constants of the solutions were measured. Each value represents the mean ± S.D. of 5 experiments, *p < 0.05 versus common vial (t-test).
Residual silanol groups (Si–OH) on the inner surfaces of glass vials often cause problems in cationic drug stability and quality owing to drug adsorption. Therefore, we evaluated the inhibitory effect of the VIST on drug adsorption onto the inner surfaces of the vials using amitriptyline as a cationic model compound. Amitriptyline (0.1 mg/mL) in water was poured into the vials and maintained at 4 °C for 6 h. The amounts of drug adsorbed onto the inner surfaces of the vials were extracted and quantified as reported previously.14,15) As shown in Fig. 10, the amount of amitriptyline adsorbed onto the inner surfaces of the VIST vials was significantly lower than that of the common vials and sulfur-treated vials. These results suggest that VIST vials are superior storage containers for injection drugs owing to the low adsorption of cationic drugs on the glass surface.
Adsorption of amitriptyline was examined by performing HPLC after incubation for 6 h at 4 °C. Each value represents the mean ± S.D. of 3 experiments. *p < 0.05 versus common vials (Scheffe’s test).
Silanol groups (Si–OH) on glass surfaces are highly reactive and interact with various chemical species, including pharmaceutical compounds. The mechanism underlying such interactions typically involves hydrogen bonding or electrostatic interactions, depending on the drug properties and specific environment. Silanol groups can form hydrogen bonds with drugs containing functional groups capable of hydrogen bonding, such as hydroxyl (–OH), carbonyl (C=O), and amine (–NH2) groups. The hydrogen atoms in the silanol group are partially positively charged, whereas the oxygen atom is partially negatively charged; thus, the oxygen atom is a suitable partner for hydrogen bond formation. This interaction can lead to the adsorption of the drug onto the glass surface, potentially affecting drug stability, solubility, and bioavailability. In aqueous environments, silanol groups can ionize to form silanolate anions, particularly at higher pH levels. The negatively charged sites on the glass surface attract and bind positively charged drug molecules or ions via electrostatic attraction. Therefore, in this study, amitriptyline, a cationic model compound, adsorbed onto the common vial (Fig. 10). On the other hand, in the VIST technique, metal elements adhering to the inner surface are removed during vial production by using a citric acid solution. The vial is then annealed by heating and slowly cooling to homogenize the vial surface (Fig. 1). VIST vials display smoother inner surfaces and significantly fewer metallic elements, such as sodium, aluminum, and potassium, than the common vials (Figs. 2–5). In addition, the decrease in the amounts of constituent elements such as boron, sodium, and potassium indicates that the number of residual silanol groups (Si–OH) decreases during the annealing process (Table 1). Hence, the presence of silanol groups on the inner surface of the VIST vials is thought to be less than in the common vial, resulting in reduced adsorption of the cationic model drug amitriptyline. The reason why the inhibitory effect of amitriptyline adsorption in the sulfur-treated vials was lower than in the VIST vials (Fig. 10) is presumably due to the uneven inner surface coating of the sulfur-treated vials (Fig. 2).
In addition to hydrogen bonding and electrostatic interactions, weaker van der Waals forces may contribute to the interactions between silanol groups and drug molecules. These forces arise from temporary dipoles induced in the molecules and facilitate adsorption, particularly for nonpolar or weakly polar drugs. These interactions can influence the behavior of drugs in pharmaceutical formulations, affecting the drug release profile, stability, and overall efficacy. Understanding the nature of these interactions is crucial for designing parenteral formulations, particularly when glass containers or surfaces are involved in drug storage or administration. Therefore, further elaborate studies are needed to analyze in detail the effects of drug type, solution type, pH change, and storage temperature on the drug adsorption tests on VIST vials.
In this study, we revealed that VIST vials showed homogeneous inner surfaces compared with sulfur-treated vials and common vials. In addition, the elution of alkali contents and conductivity were drastically reduced in the VIST vials compared to sulfur-treated vials and common vials, owing to the formation of smooth and homogeneous inner surfaces. In addition, the adsorption of amitriptyline onto the inner surface of VIST vials was lower than that of sulfur-treated vials and common vials. These results reveal that VIST vials are of excellent quality and could become the standard injection glass vials.
The common vials, sulfur-treated vials, and VIST vials were fabricated by Daiwa Special Glass Co., Ltd. (Osaka, Japan) using glass tubes (Nippon Electric Glass Co., Ltd., Shiga, Japan).
SEM Analysis of Vial Inner SurfaceThe vials were ultrasonically cleaned for 30 s, then rinsed with distilled water and dried at 150 °C for 30 min. They were then cut to the appropriate size for measurement, washed with distilled water, and dried at 150 °C for 30 min. The inner surfaces of the common, sulfur-treated, and VIST vials were observed using SEM (VHX-D500, KEYENCE, Osaka, Japan).
Distribution of Surface ElementsThe vial samples were prepared in the same manner as for SEM analysis. To investigate the distribution of various glass components on the glass surfaces of the common and VIST vials, TOF-SIMS measurements (TOF.SIMS5 IONTOF GmbH, Münster, Germany) were performed. The inner walls of the vials (3–5 mm from the bottom) were examined. The TOF-SIMS measurement conditions were as follows: primary ion gun was Bi+ (25 kV), pulse width of 7.0 ns, mass range of 0–500 m/z, number of scans was 128, and secondary ion polarity was positive or negative.
Analysis of Vial-Inner-Surface CompositionThe vial samples were prepared in the same manner as for SEM analysis. The elemental compositions and chemical states of the common and VIST vial surfaces were investigated using XPS (Quantera SXM, ULVAC-PHI, Inc., Kanagawa, Japan). The inner walls of the vials (3–5 mm from the bottom) were examined. The XPS measurement conditions were as follows: excitation X-ray was monochromatic Al Kα1,2 (1486.6 eV), X-ray diameter 200 μm, and take-off angle of 45°. The Si 2p main peak (SiO2) was set at 103.3 eV.
Alkali Elution Study and Analysis of Elements Eluted from the VialsThe alkali elution study was performed according to the regulations of the Japanese Pharmacopoeia. The common and VIST vials were filled with water up to the full capacity and placed on the autoclave tray. The autoclave with an open vent cock was heated at a regular rate such that steam vigorously emitted from the vent cock after 20–30 min, and the vigorous emission of steam was maintained for an additional 10 min. The vent cock was then closed, and the temperature was raised from 100 to 121 °C at a rate of 1 °C/min. The temperature was maintained at 121 ± 1 °C for 1 or 4 h. Subsequently, the autoclave was cooled to 100 °C at a rate of 0.5 °C/min to prevent vacuum formation; the autoclave was vented during this time. After the temperature in the autoclave reached 95 °C, the hot samples were removed and cooled to room temperature within 30 min while avoiding thermal shock.
Titration was performed within 1 h of vial removal from the autoclave. The liquids obtained from the vials were combined and mixed. An aliquot of each sample was then transferred into a conical flask. The solutions were then titrated with 0.01 M HCl to obtain a pH value 5.5. For the blank, the same volume of water was transferred into a second conical flask and then titrated with 0.01 M HCl to reach a pH value of 5.5. In addition, elements eluted from vials of various sizes (2, 10, 15, and 30 mL) were analyzed by using inductively coupled plasma (ICP)-optical emission spectroscopy (Model SPS 3500; Hitachi High-Tech Corp., Tokyo, Japan) or atomic absorption spectroscopy (AAS; Model AA-7800, Shimadzu Corp., Kyoto, Japan) for the identification of Na, B, Al, Si, Ca, and Ba.
Water ConductivityAfter the common and VIST vials were filled with water equivalent to 90% of their full capacity, they were tightly sealed with a silicone rubber stopper and sterilized in an autoclave (121 ± 1 °C). After sterilization for 1, 2, and 4 h, the vials were allowed to cool to room temperature, and the water conductivities of the solutions at 25 ± 1 °C were measured with a conductivity meter (Model AB-6; Organo Corp., Tokyo, Japan).
Drug Adsorption StudyThe amounts of drugs adsorbed onto the inner surfaces of the vials were quantified. Amitriptyline, which is a cationic compound, was dissolved in water (0.1 mg/mL). Subsequently, 2 mL of the solution was poured into the vials and maintained at 4 °C for 6 h. The sample solutions were then removed and gently rinsed twice with water. The drugs that remained on the barrels after rinsing were collected by filling the barrels with 0.5 mL of an acetonitrile/water (1/1 (v/v)) solution and then vortexing and sonicating in an ultrasonic bath for 15 min at room temperature.
A calibration curve with various concentrations of amitriptyline was established using a reverse-phase HPLC system (i-Series LC-2030C, Shimadzu Corp.) equipped with a UV detector and COSMOSIL 5C18-MS-II instrument (4.6 mm ID ×150 mm, Nacalai Tesque, Kyoto, Japan). The column temperature was set at 40 °C. Mobile phase A was 0.1% formic acid in water, and mobile phase B was 0.1% formic acid in acetonitrile. Next, 100 μL of each sample solution was injected into the HPLC system and eluted with isocratic mobile phases A (70%) and B (30%) for 20 min at a flow rate of 0.5 mL/min. The UV absorbance was monitored at 254 nm. The amounts of amitriptyline adsorbed onto the inner surfaces of the vials were determined under the same analytical conditions as those used for the calibration curve. The areas under the curves of the peaks were calculated using the LabSolutions software (Shimadzu Corp.). The amounts of adsorbed drugs per square meter of the inner surface areas of the vials were calculated.
StatisticsAll experiments were performed in triplicate for each series of measurements, and each series was repeated at least thrice. The experimental results were presented as mean ± standard deviation (S.D.). Significance levels for comparisons between samples were determined by conducting T-tests or Scheffe’s test. The level of statistical significance was set at p < 0.05.
This work was funded by Daiwa Special Glass Co., Ltd. and Taisei Kako Co., Ltd.
Norikazu Miyamoto is an employee of Daiwa Special Glass Co., Ltd.
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