investigating the effects of the chemical composition on ... · hydrolytic and corrosion resistance...

10.5731/pdajpst.2019.010066Access the most recent version at doi: 185-20074, 2020 PDA J Pharm Sci and Tech

Serena Panighello and Odra Pinato Glass Corrosion: A Case Study for Type I VialsInvestigating the Effects of the Chemical Composition on

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RESEARCH

Investigating the Effects of the Chemical Composition onGlass Corrosion: A Case Study for Type I Vials

SERENA PANIGHELLO* and ODRA PINATO

SG Lab Analytics, Nuova Ompi, Piombino Dese, Italy © PDA, Inc. 2020

ABSTRACT: Glass is the favorite material for parenteral packaging because of its physico-chemical properties. Type I

borosilicate glass is worldwide use at this scope, but it may have some issues related to breakage, corrosion and delami-

nation that might compromise the drug quality, safety and efficacy. These issues can be mitigated and avoided starting

from the appropriate selection of the most suitable raw material at the early stage of the glass container design. In this

study, Type I borosilicate glass vials manufactured using two glass tubes having different chemical compositions, were

studied and compared in terms of their resistance to corrosion. Testing design was applied with the aim to select the

best practice approach comparing different storage simulation conditions: ageing treatment through autoclaving and

stability testing (real-time and accelerated). Clear differences were found between the different glass types in terms of

hydrolytic and corrosion resistance that highlighted the relation between chemical composition and glass chemical du-

rability. Non-negligible differences were also observed using different storage conditions.

KEYWORDS: Glass primary packaging, Surface chemistry, Glass corrosion, Glass delamination, Stability studies,

Hydrolytic resistance.

Introduction

Glass is one of the oldest human-made materials that

since ancient Egyptian times has been considered the

ideal choice to store medications or other precious

liquids. Nowadays, glass is still widely used as the pri-

mary packaging for pharmaceuticals thanks to its unique

combination of physicochemical proprieties, such as

transparency, strength, and chemical durability (1, 2).

The expression chemical durability is conventionally

used to denote the resistance of a glass toward attack by

aqueous solutions or atmospheric agents (3, 4), but no

explicit measure for the chemical durability is defined

(2, 3, 5). However, different tests such as those for the

hydrolytic resistance [ISO 720, ISO 4802-1 and 4802-2,

United States Pharmacopeia (USP) <660>, and Euro-

pean Pharmacopoeia (Ph Eur) 3.2.1] are usually carried

out to provide information regarding the intrinsic dura-

bility of a specific glass only in contact with water. To

further increase the knowledge regarding key contribu-

tion factors to glass corrosion/delamination, USP

<1660> provides advice on the evaluation of the inner

surface durability for glass containers in direct contact

with different pharmaceutical products.

According to the current Ph Eur and USP, glass tubes

for pharmaceutical use are classified into Type I (boro-

silicate) and Type III (soda lime) glasses. The chemical

composition of these glasses is well-known and defined

in various standards (6).

Type I borosilicate glass containers are the most suita-

ble for use in contact with parenteral preparation

according to the Ph Eur and USP. Type I borosilicate

definition comprises different chemical compositions

that can have an impact on the glass performances

postforming process. Thus, are Type I glasses the same

in terms of glass–drug interaction?

How Does the Chemical Composition of Glass Relate to

the Degradation Process?

The interaction of borosilicate glass with aqueous sol-

utions occurs according to a complex reaction that is

directly dependent on its chemical composition.

* Corresponding Author: SG Lab Analytics, Nuova

Ompi, via Molinella 17, 35017 Piombino Dese (PD),

Italy; e-mail: [email protected]

doi: 10.5731/pdajpst.2019.010066

Vol. 74, No. 2, March--April 2020 185

on June 14, 2020Downloaded from

In general, the degradation model is based on the generation

of a chemically and structurally distinct superficial altered

zone, which is often divided into a diffusion zone (ion-

exchange/leaching) and a gel zone (3, 7). The former is

related to the glass being attacked by acids or acidic aque-

ous solutions and can be considered a pure ion-exchange

between alkaline ions of the glass and H+ (or H3O+) ions of

the acidic agent (8). The acid attack on the glass, linked to

the diffusion mechanism, decreases as a function of the

square root of the contacting time (t½); consequently, the

chemical durability of glass improves with time. Simultane-

ously to the attack reactions that take place, water molecules

are incorporated into the surface, forming a thin gel layer.

This gel layer forms a superficial interface that delays or

prevents further chemical attack inside the glass body.

The outstanding chemical durability of some borosili-

cate glasses is owing to their particular structure. They

have a silica matrix in which a second phase of sodium

borosilicate is dispersed. The reactivity toward acidic

solutions is similar to that of the silica lattice because

the borosilicate phase is practically impenetrable

owing to the high-pressure required to force liquid

water within very narrow capillary channels (5, 8, 9).

The attack from alkaline solutions is determined by another

mechanism. In this case, the OH� ion plays a determining

role; it reacts with the lattice breaking the oxygen bridges.

The glass alkaline attack is not a selective first-order reac-

tion (the rate of reaction is proportional to the OH� ions

concentration). The amount of glass brought into solution

during the corrosion process increases linearly over time.

The prevalence of one of these mechanisms is also a

function of the glass chemical composition and the

environmental conditions (e.g., temperature and rela-

tive humidity).

The hydrated or gel layer generates superficial stress

tensions between the corroded layer and the pristine

glass. When the hydrated layer is thick enough, glass

flakes or lamellae can be released from the surface

(10–15). This form of glass corrosion, generally

referred to as delamination in pharmaceutical glass

literature, results in the appearance of visible glass

particles, generally known as flakes (lamellae).

Corrosion Propensity of Pharmaceutical Glass

The corrosion propensity of pharmaceutical glass is

affected by the combination of several factors, starting

from the manufacturing process to the storage of the

final product. These factors include the type of glass

used (e.g., with a different coefficient of thermal

expansion: exp. 33 and exp. 51, different B2O3 content,

and so forth) and surface treatments (e.g., ammonium

sulfate, siliconization, or special coatings), but also for-

mulation and pH of the filling media. In addition, all

the external stresses exerted during the manufacturing

processes (washing, depyrogenation, sterilization) and

the storage conditions (time, temperature, humidity)

have a significant impact on the degradation phenom-

enon (16–20).

In the glass primary packaging, autoclave (AC) stress

treatment is defined and used to simulate the aging pro-

cess and as a stress treatment for the study of glass

chemical durability, as prescribed by Ph Eur 3.2.1 and

USP <660>.

For pharma application, autoclaving is routinely used

as standard terminal sterilization method; on the con-

trary, the glass world exploits its straightforward and

low time-consuming features for both extraction and

aging procedures. On the other hand, the pharmaceu-

tical vocabulary does not refer to the term “aging”

but rather to “stability” using storage facilities (e.g.,

climatic chambers). ICH Q1A guidelines clearly

state that stability testing has the specific purpose to

provide evidence on how the quality of a drug sub-

stance or product varies with time under the influ-

ence of a variety of environmental factors such as

temperature, humidity, and light, and to establish a

retest period for the drug substance or a shelf life for

the drug product and recommended storage condi-

tions (21).

Up to now, the commitment of the glass packaging

world was and is “to be in compliance” with the phar-

macopeias’ requirements in terms of glass durability.

It should be noted that, to meet the new pharmaceuti-

cal needs and demands, a harmonization of terminolo-

gies (e.g., the mixing up of “aging” and “stability”

terms) and an improvement in testing approaches are

desirable.

Based on these premises, all the predictive studies

regarding the interaction between the primary packag-

ing and the drug product should be driven by the stabil-

ity assessment with the common intent to preserve the

integrity of the drug and, thus, its quality, safety, and

efficacy.

186 PDA Journal of Pharmaceutical Science and Technology


In the present case study, 2R glass vials manufactured

using two glass tubes having different chemical compo-

sition and different hydrolytic resistance are compared

in terms of their resistance to corrosion after filling them

with a real drug formulation (nonbuffered ionic strength

solution, which is one of the placebo solutions of drugs

currently on the market; e.g., vaccines) and real drug

quantity (0.7mL is representative of real drug formula-

tion). As well, high surface area to volume (SA/V) ratio

provides accelerated glass surface reactions in the rele-

vant vial lower area.

Beyond the role of the raw material chemical composi-

tion, aging and stability approaches will be also compared

in terms of glass primary packaging, physicochemical

performances, and suitability, to obtain preliminary infor-

mation as a guideline for further wider studies about the

chemical resistance of pharmaceutical glasses with differ-

ent filling media.

Material and Methods

Instrumentation

Visual Inspection: For the visual assessment of the so-

lution quality, after each stability time-point, a suitable

apparatus for visible particles was used according to Ph

Eur 2.9.20 Particulate contamination: Visible Particles.

The outer surface of every container was accurately

cleaned; subsequently, every vial was gently swirled up,

avoiding the formation of air bubbles and observed for

about 5 s in front of a white panel under illumination by

a cold white light. The procedure was repeated in front

of a black panel.

Confocal Differential Interference Contrast Micro-

scopy: Differential interference contract (DIC) micros-

copy is normally used in the biological field and consti-

tutes an excellent method for generating contrast by

converting specimen optical path gradients into ampli-

tude differences that can be visualized by the human

eye.

The use of this specific tool for the analysis of glass

vials without any glass sample cutting is well explained

by Wen et al. (22). Compared with scanning electron

microscopy (SEM) analysis, DIC microscopy can

examine the entire vial sidewall by translation and rota-

tion of the sample vial on the stage.

The analysis of the inner surface of the vials was per-

formed by a Zeiss Axio imager M2m microscope

equipped with a Circular Polarized Light-Differential

Interference Contrast (C-DIC) slider 6� 20 for EC

EPN 5–20�, using a 10� long working distance

objective.

Once the glass vial was laid horizontally on the sample

holder and the area to investigate was identified, a

micrograph was taken and recorded with a digital cam-

era (Axio camera). Three main glass surface areas were

analyzed, as reported in Figure 1a. In Type I pharma-

ceutical glass vials, the shoulder and the wall-near-bot-

tom are critical areas for corrosion because high-

temperature flames are applied during the conversion

process.

Inductively Coupled Plasma Analysis: Inductively

coupled plasma optical emission spectroscopy (ICP-

OES) was performed on the extracted solution of each

vial to quantitatively determine the concentration of

the leached-out glass elements. The ICP-OES instru-

ment is a Thermo Scientific iCAP7400. To estimate

the content of Al, B, Ca, and Si in the extracted solu-

tion, four levels of calibration curves using the internal

standard method for each analyte were determined.

Limit of quantification (LoQ) values were 0.05mg/L

for Al, B, and Ca and 0.2 mg/L for Si.

Figure 1

Three-dimensional image reconstruction of the vial

with the three main analyzed areas. (a) for light

microscopy (DIC); (b) for SEM.



The chemicals used are reported below:

� H2O Milli-Q, produced by MILLIPORE-IQ 7000

system, Merck;

� Concentrated nitric acid, Sigma-Aldrich;

� Y standard solution 1000mg/L, Inorganic Ventures;

� Al standard solution 1000mg/L, Inorganic Ventures;

� B standard solution 1000mg/L, Inorganic Ventures;

� Si standard solution 1000mg/L, Inorganic Ventures;

� Ca standard solution 1000mg/L, Inorganic Ventures.

The reference solutions used to calculate the calibra-

tion curve were prepared by dilution of certified ready-

to-use standard stock solution at 1000mg/L for each

analyte and for the internal standard (yttrium; final con-

centration, 1.0 mg/L).

The correlation coefficient (r ≥ 0.99) and the accuracyon two quality check solutions after calibration and ev-ery 10 samples for each analyte were calculated to testthe system reliability.

The elemental concentration results were then pre-

sented as element oxides through the stoichiometric ra-

tio between each element and its oxide.

SEM: SEM analysis was performed using a ZEISS

Sigma field emission scanning electron microscope with

1.5 nm of maximum resolution. SEM technique is based

on a focused electron beam used as a probe to inspect

the surfaces of almost any kind of solid material, and

different integrated detectors can be used to collect the

generated particles to evaluate sample morphology.

The morphological investigation of the inner vial sur-

face was performed over the three areas described in

Figure 1b.

Samples

2R glass vials provided by Nuova Ompi Srl were

selected for this study. Because the forming process is

an essential step in the generation of glass pharma con-

tainers, a proprietary process called low delamination

propensity (LDP) was chosen to investigate the glass du-

rability based on the composition of the selected raw

materials. This process is based on the smoothing of dif-

ferent aspects related to the conversion process, such as

speed, burners’ flame temperature, and annealing stage,

that decrease the manufacturing process impact.

The propensity of a vial to delaminate is tested with an

analytical protocol based on a stress treatment [Auto-

clave cycle (AC) cycle of 1 h at 121 ˚C] in contact with

a high ionic strength solution, pH 8.

The evaluation criteria are selected through a compari-

son study between standard and LDP process vials, and

they are based on the parameters normally used to eval-

uate delamination phenomenon: morphological analy-

sis and glass extracted elements (i.e., Si, Al, and B).

These specific vials that underwent the abovemen-

tioned procedure were used with the aim to limit all the

conversion process factors that can affect the corrosion

propensity of pharmaceutical glass and, thus, to better

study the impact of the chemical composition.

The vials were produced with two different glass tubes

named A and B. Glass chemical composition of the

clear glass vials is reported in Table I.

The main differences on the chemical composition are

related to the fluxes, so-called because co-adjuvants of

the melting process, and to the stabilizer agents such

as calcium, barium, aluminum, and boron oxides.

Glass B shows a slightly higher amount of fluxes with

a combination of Na2O and K2O and a higher content

of different stabilizer agents—B2O3 (10 wt %), Al2O3

(7.5 wt %), and CaO + BaO (2 wt %)—compared with

Glass A.

TABLE I

Glass Chemical Composition Expressed as Elemental Oxides (wt %) from Supplier A and Supplier B

Chemical Composition (wt %) SiO2 B2O3 Al2O3 Na2O K2O CaO+ BaO Other Elements

Glass A 74 9.5 6.5 7.8 <0.1 1.5 0.7

Glass B 72 10 7.5 6.0 1.9 2.0 0.6



Experimental Design

A total of 150 samples per category (2R vials with A

and B chemical composition) were filled with an ionic

placebo solution of 0.3% NaCl formulation, pH around

6.0. The filling volume was 0.7mL; that is about

17.5% of a 2R vial brimful volume.

Samples were submitted to real-time and accelerated

stability testing conditions and to AC and then ana-

lyzed at different time-points, as reported in Table II.

AC stress treatment is aimed to simulate an aging

effect on a filled glass container. Lyle represented the

effects of time and temperature on the chemical attack

of glass by an equation similar to the Arrhenius one:

aLogN ¼ Logh� bT þ c, where N = attack, h = time, T =

absolute temperature, and a, b, and c are experimen-

tally determined constants. According to the overre-

ported Lyle equation (23), an AC cycle of 60 min at

121 ˚C simulates a storage time of 2 y at room-tempera-

ture (23, 24). The accelerated conditions were selected

in accordance with the Arrhenius equation.

Per each time-point on both empty and filled vials,

morphological analysis was carried out by light micros-

copy with DIC tool and SEM. ICP-OES analysis of the

extracted solutions was performed before and after sta-

bility time-points and AC stress treatment.

Results and Discussion

Visual Inspection

The method to check for the presence of visible partic-

ulate contamination is well explained on the USP

<790>/Ph Eur 2.9.20. It consists of a simple procedure

that gives guidelines for the visual assessment of the

parenteral solution’s quality.

The presence of particles was tested before and after

stability and AC stress treatment for A and B glasses.

No particle was observed by visual inspection in all the

categories.

However, it should be stated that there are limitations

to visual inspection, such as wrong discrimination

between air bubbles and particles or the necessity to

use other techniques to characterize the particles, such

as light obscuration or microflow imaging.

Morphological Results

DIC images (DIC microscopy images of the wall-near-

bottom area are reported as supplementary material)

showed that the inner surface of Glass A vials dis-

played inhomogeneities (white dots) on the shoulder

and wall-near-bottom areas even before filling and

stress treatments. The middle body surface was homo-

geneous and smooth.

There is an increase on the density and distribution of

these inhomogeneities from T0 to time-point AT36 and

AC. Instead, samples of Glass B showed fewer inho-

mogeneities on the wall-near-bottom surface at T0

compared with Glass A, but a higher degree of imper-

fections after stability and AC stress treatment.

The preexisting inhomogeneities are attributed to alkali

borate-rich regions generated during the parting and

smoothing of the vial bottom forming process. It is

worth noting that with DIC microscopy observation, it

TABLE II

Storage Conditions Descriptiona

ID Time Point Description Conditions Simulated Time (mo)

T0 Freshly filled — 0

RT5 5mo 25 ˚C6 2 ˚C; 40% HR 5

RT12 12mo 25 ˚C6 2 ˚C; 40% HR 12

RT24 24mo 25 ˚C6 2 ˚C; 40% HR 24

AT12 5weeks 60 ˚C6 2 ˚C; 40% HR 12

AT24 10weeks 60 ˚C6 2 ˚C; 40% HR 24

AT36 15weeks 60 ˚C6 2 ˚C; 40% HR 36

AC Autoclave stress treatment Cycle: 60min at 121 ˚C 24aRT, real-time; AT, accelerated time; AC, autoclave cycle.



is difficult to discriminate between bulges (alkali

borate-rich regions) and pits. The latter are typical of

“pitting corrosion” that can occur when corrosion has a

preferential starting point either on or just below the

surface (12, 25). An interesting point is that the form-

ing of craters and pits occurs generally after water or

acid attack to the enriched alkali and boron areas of the

surface (26, 27).

SEM investigation was performed to characterize, at

higher magnification, the morphology of the inner sur-

face of the vial samples at different time-points, focus-

ing the analysis on the inspected regions, as shown in

Figure 2 and 3.

Morphological evaluation of glass vial inner surfaces

by SEM revealed that in general the midbody area for

Figure 2

Representative SEM images of Glass A samples at 10,0003 magnification at different time-points of the wall-

near-bottom area.



both the categories is not affected by corrosion, and it

is smooth and homogeneous. The main degraded area

is the wall-near-bottom one, in agreement with DIC

microscopy inspection.

Before filling and stress treatment, the inner surface of

Glass A vials showed sporadic bulges and shallow

craters on the shoulder and wall-near-bottom areas.

After contact with the placebo solution, these inhomo-

geneities became micropits. The size of the pits did

not really increase through the different time-points,

but rather the microroughness increased, as it is well

visible on the SEM images at higher magnification

(Figure 4).

Figure 3

Representative SEM images of Glass B samples at 10,0003 magnification at different time-points of the wall-

near-bottom area.



Furthermore, it should be noted that the shoulder area,

not directly in contact with the filling solution, showed

micropitting corrosion as well.

An increase of corrosion was observed in the vicinity of

the filling volume line, more pronounced for Glass B

vials (Figure 4). The low filling volume has an influence

on the results owing to the different wetted wall areas,

which are typically not homogeneous but more affected

in case of autoclaving, less in real-time storage.

Hydrolytic Resistance Results

The hydrolytic resistance of the samples was meas-

ured according to the current ISO 4802-1 Hydrolytic

resistance of the interior surfaces of glass containers

(28). Titration values, expressed in milliliters of

0.01 N HCl, for samples of Glass A are higher (mean

value = 0.79) than samples of Glass B (mean value =

0.56).

ICP-OES Results

The results of the extraction study for each time-point

are reported in Table III and Figure 5.

Thirty vials per sample time-point were treated.

Because of the low filling volume (0.7mL), three sam-

ples were pooled together to obtain a total of 10 sam-

ples per each time-point.

Figure 4

Further selected SEM images with different magnifications [(a) 50003, (b) 10,0003, (c) 25,0003, (d) 25,0003,

(e) 10,0003, (f) 25,0003] of Glass A and Glass B samples.



It can clearly be seen that Glass A shows a lower con-

centration of Al, B, and Si than Glass B, except for Al

and Ca in AC treatment that show slightly higher con-

centrations in Glass A.

Throughout the 5 and 12mo of real-time storage,

Glass A reveals the lowest amount of total extract-

ables (maximum about 5 mg/L) at RT5. Glass B

exhibits the highest amount (around 45mg/L) at

AT36.

Figure 5 highlights differences between the two extrac-

tion methods. Real-time aging shows a lower amount

of extractables compared with accelerated aging. After

12mo of storage with accelerated conditions, the num-

ber of elements measured in the solution is higher com-

pared with 12mo at real-time aging (the content of

SiO2 extracted is three times higher).

By a comparison between AC and AT24, Glass A

shows more aluminum and silicon extracted from the

TABLE III

ICP-OES Summarized Resultsa

T0 AC RT5 RT12 RT24 AT12 AT24 AT36

Al2O3 Glass A Average <LoQ 1.14 <LoQ <LoQ 0.08 0.26 0.26 0.30

SD NA 0.10 NA NA 0.01 0.04 0.06 0.07

Glass B Average <LoQ 0.98 <LoQ <LoQ 0.05 0.40 0.35 0.38

SD NA 0.32 NA NA 0.01 0.10 0.09 0.13

B2O3 Glass A Average <LoQ 4.11 1.29 1.63 2.28 4.44 6.24 7.06

SD NA 0.25 0.12 0.21 0.27 0.30 0.48 0.68

Glass B Average <LoQ 8.55 2.97 4.22 5.62 9.55 13.23 13.83

SD NA 0.73 0.91 1.07 1.50 3.34 4.70 4.33

SiO2 Glass A Average <LoQ 21.85 3.43 4.15 7.15 14.03 18.37 20.73

SD NA 1.08 0.24 0.40 0.61 1.33 1.20 2.01

Glass B Average <LoQ 24.28 5.78 7.29 10.82 22.18 28.28 30.18

SD NA 2.81 1.73 1.86 2.70 7.86 10.70 9.57

CaO Glass A Average 0.43 1.24 0.30 0.41 0.54 1.09 1.21 1.37

SD 0.17 0.13 0.02 0.04 0.04 0.09 0.07 0.14

Glass B Average 0.43 0.77 0.25 0.34 0.46 0.81 0.99 1.05

SD 0.15 0.05 0.05 0.07 0.11 0.20 0.25 0.24aThe concentration of the oxides is reported in mg/L. LoQ Al, B, Ca = 0.05; LoQ Si = 0.2. NA, not applicable; RT, real

time; AT, accelerated time; AC, autoclave cycle.

Figure 5

Histograms of the main extracted glass oxides (mg/L) for glasses A and B at different time-points.



AC stress treatment; instead, Glass B shows only more

aluminum extracted from the AC stress treatment.

The results after AC stress treatment are similar for both

the categories, except for extracted boron, which is

higher on Glass B, as reported in Figure 5. The effects

of this treatment on the investigated samples seem to be

independent from their chemical composition.

The different extraction process between stability and

AC is because of the intrinsic features of the glasses

but even owing to the thickness of the dissolved layer,

more marked for AC treatment (11, 29).

The rate of extraction of silica at any time is strongly

related to the concentration of the extracted boron in

both the glasses, as shown in Figure 6 (linear correla-

tion has r2 = 0.9945 and 0.9918 for Glass A and B,

respectively). Thus, the amount of glass elements

brought into solution during the corrosion process

increases linearly with time (29, 30). The SiO2/B2O3

ratio is constant along time and higher for Glass A.

Moreover, Glass B data show a higher dispersion than

Glass A.

Even though real time correlates with the accelerated

time-points, it seems that the rate of extraction

between real time and accelerated has a different

behavior. Throughout 5, 12, and 24mo of real-time

storage, the silicon and boron gradient of extraction is

lower than 12, 24, and 36mo of accelerated time

storage.

AC stress treatment values of both A and B glasses

show a different behavior that does not match the linear

trend of stability time-points (data not shown).

The following mathematical model, as a discrete func-

tion, seems to better represent the behavior of the dif-

ferent types of glass here considered:

Xi¼ n

i¼ 0

½SiO2�i ¼ ktn (1)

where n represents the nth measurement at time tn.

“Cumulative silica” is the first member of eq 1: It rep-

resents the sum of all the silica concentrations meas-

ured at the different ti time values from i = 0 to i = n.

This model is particularly useful because the experi-

mental data fit perfectly with the linear eq 1 (Figure 7)

and, hence, the k value can well represent the efficiency

of the silica release.

It is worth noting that the slope of the line for Glass B

is higher than that of Glass A, even though their initial

values at T0 are equal. It could indicate that Glass B

samples are affected by a more aggressive corrosion

process because they are less chemically resistant than

the ones of Glass A. A similar difference can be

Figure 6

Plot of SiO2 vs B2O3 extracted at different time-

points (real and accelerated time).

Figure 7

Plot of cumulative SiO2 (mg/L) vs different time-

points (mo) at two different stability conditions. In

blue, the average data from Glass B (filled square =

accelerated/simulated time; empty square = real-

time). In red, the average data from Glass A (filled

circle = accelerated/simulated time; empty circle =

real-time).



observed within real-time data; it should be noted that

real-time stability seems to be less aggressive than the

accelerated one for the investigated samples.

Glass corrosion should be related to the chemical com-

position: Glass A has a higher content of SiO2, not al-

kali-mixed (only NaO2) and more CaO than Glass B.

The presence of K2O can decrease the superficial phys-

icochemical stability of the glass (30) and thus weaken

the glass when the leaching (ion-exchange) process

has already occurred. It should be noted that the

different species of alkaline ions show different

behaviors with respect to the leaching phenomenon,

depending on temperature and radius of the cations

(4): In borosilicate glasses, alkaline elements occupy

the interstitial sites closing the silica matrix. K+ ion

has a larger ionic radius with a consequent weaker

attractive force exerted on it by the oxygen, compared

with Na+ (31, 32).

Conclusions

Glass vials manufactured using two glass tubes having

different chemical compositions were studied and com-

pared in terms of their resistance to corrosion after fill-

ing with a nonbuffered ionic strength solution (0.3%

NaCl).

To get more insight on the relation between the glass

composition and corrosion phenomenon and to try to

mitigate the effect of all the factors that generally influ-

ence glass degradation, the vials were manufactured

according to Ompi LDP process.

To give prominence to the importance of selecting the

most suitable raw material at the early stage of glass

container design, two different glass suppliers (A and

B) were selected.

Aging and stability testing approaches were compared

in terms of hydrolytic and corrosion resistance for a

glass in contact with an ionic strength solution. The

morphological assessment of corrosion was studied

through DIC and SEM microscopy-based techniques.

Glass B showed a better hydrolytic resistance than

Glass A by EP titration values and by the morphology

of the inner surface of the vials before filling, where

more inhomogeneities, that are bulges of borates, were

observed on the surface of Glass A. The hydrolytic re-

sistance of Glass B could be related to its chemical

composition, in particular to the higher content of alu-

mina and mixed of alkali (Na2O and K2O).

The scenario is different when an ionic strength solution

is used, in a slow reaction with a high SA/V ratio. Glass

B samples showed a more corroded inner surface, in

terms of microroughness, than Glass A samples. Also,

ICP-OES results of Glass A samples showed lower con-

tents of Al, B, and Si extracted than samples of Glass B

in all the different storage/stress conditions. Based on

the cumulative extracted SiO2, the corrosion process

seems the same for both the glasses, but Glass B shows

a lower chemical resistance than Glass A.

It is well-known that increasing SA/V ratios efficiently

provide accelerated glass surface reactions in the rele-

vant vial lower area, but the use of elevated tempera-

ture, as when applying the AC stress treatment, does

not always and univocally simulate the real-time

effects (29).

In the present study, samples were submitted to an AC

cycle of 1 h at 121 ˚C, and the analytical results did not

show representative differences in terms of glass corro-

sion between the categories (Glass A and Glass B).

Acceleration of glass by a high-temperature AC system

does not accurately represents the surface changes

occurring during low-temperature glass exposure.

Real-time and accelerated stability testing showed non-

negligible differences between their respective effects.

The accelerated aging results in a worst-case scenario

compared with the real-time stress test, and the auto-

claving procedure is the topmost stress program.

This scenario shows that the chemical durability of a

glass is dependent on the chemical composition and the

kinetic and thermodynamic features of the entire sys-

tem (4). Real-time stability testing provides the most

reliable data to test the integrity of the package mate-

rial and the integrity at the interface between glass and

a drug product.

Durability tests that are usually performed, for example

to extend the shelf life of a product or service condi-

tions, should consider detailed information about the

glass chemical composition and the variation of glass

local structure with composition and preparation condi-

tions, to predict corrosion behavior.

Comparing different behaviors of the raw materials in

terms of glass durability can help in the important



selection phase of the most suitable glass container

before production.

Nevertheless, further analysis is rather needed to

understand in depth the relationship between chemical

durability and corrosion, and all the other factors that

could somehow damage the chemical surface of the

pharmaceutical glass.

Acknowledgments

The authors would like to thank Emanuel Guadagnino

and Maria Chiara Frare for constructive discussion in the

preparation of the manuscript, as well as Nicolo

Mazzucco and Nicola Bessegato for the analytical and

technical support during SEM and ICP-OES analyses.

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Appendix: Supplementary Material

Figure S1

Representative DIC-OM images of the wall-near-bottom area, Glass A samples at 1003 magnification at differ-

ent time-points.

Figure S2

Representative DIC-OM images of the wall-near-bottom area, Glass B samples at 1003 magnification at differ-

ent time-points.



Figure S3

SEM images of Glass A samples at the wall-near-bottom area (10,0003 magnification).



Figure S4

SEM images of Glass B samples at the wall-near-bottom area (10,0003 magnification).



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