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Efficient and sustainable glass surfaces for pharmacy – HEALTHYGLASS

Protect sensitive pharmaceutical substances from aggressive interaction with glass containers

Despite the strong inertness of primary glass packaging against medicinal drugs and excipient solutions, the challenge of protecting the container from the active molecule and excipient solution that is to be stored still remains. Interactions of reactive excipient solutions with the drug container can alter the glass surface and even produce glass flakes through delamination that causes storage and great sanitary concerns, especially in the case of substances administered intravenously.

Efficient and sustainable glass surfaces for pharmacy

HEALTHYGLASS will determine innovative silicon oxide and oxynitrides (SiOxNy) coatings applied on the internal surface of pharmaceutic vials, in order to obtain efficient and sustainable barrier properties. The targeted function of these coatings is to limit the interaction between the stored drug and the glass vial, and thus allow to new advanced pharmaceutic molecules, especially in oncology, which are sensitive or aggressive towards the glass, to be commercialized.

The improvement of the hydrolytic resistance of glass is induced by the partial replacement of O anions by N anions, producing denser amorphous silicon oxynitride (SiOxNy) coatings which meet the specifications of pharmaceutical applications. The deposition at high rate of SiOxNy coatings on complex surfaces, at atmospheric pressure and at moderate temperatures (< 570 ° C) has never been carried out. We use new reactive chemistries, based on one or two precursor combinations and produce SiOxNy films with adjustable N contents and at temperatures compatible with glass vials. The resulting evolution of the silicate network is widely studied through physicochemical, structural and mechanical characterization protocols. A multidisciplinary approach is taken, combining materials science, analytical chemistry and process engineering in a way that involves the simultaneous development of resistant barrier films through CVD experiments, reactive gas phase analysis, development of kinetic models and the numerical simulation of the deposition process. The investigation of coatings both at the atom lattice scale and at the macroscopic scale is used in the analysis and the in-depth understanding of the deposition and the functional mechanisms. The experimental information obtained through this approach is used to enrich the kinetic models of the literature and to define completely new deposition mechanisms. Computational Fluid Dynamics (CFD) calculations are used to understand the peculiarities of film formation in confined spaces and complex 3D parts, to obtain predictions in terms of gas and solid phase composition, as well as to explore solutions for the optimization of deposition processes.

SiO2 CVD coatings from a TEOS-O2 / O3 chemistry are deposited at a temperature compatible with the glass vials. A kinetic model provides information on the mechanisms and identifies optimized deposition conditions. However, these coatings do not pass the aqueous corrosion tests, requiring the investigation of alternative deposition routes in order to densify the network with the incorporation of nitrogen. Coatings processed from HMDS-TEOS-O2/O3 chemistry contain carbon rather than nitrogen, resulting from the incomplete decomposition of the HMDS precursor, which reduces the corrosion resistance of the films. SiOxNy films are produced from the original TDMSA-O2 chemistry, but at a slightly higher temperature than the targeted one. The correlation between the level of incorporation of N and the densification of the network is established. Films at 7 at.% N are virtually unaffected by corrosion testing. Additional densification is induced by increasing the deposition temperature, which improves the incorporation of N and decreases the concentration of hydrated species in the network. An apparent kinetic model is developed for this CVD process of SiOxNy films by an original methodology combining structural analysis of the films by ellipsometry and nuclear techniques, of the gas phase and by numerical simulations of the process by a computational fluid mechanics (CFD) code. Local profiles of deposition rate and composition of the coating on flat substrates and in hollow bodies are established. A new, more reactive trisilylamine derivative, TSAR, developed and supplied by Air Liquide is effective for CVD of SiOxNy at temperatures as low as 520 ° C, compatible with pharmaceutical glass. These coatings provide excellent corrosion resistance. The CVD of SiOxNy barrier coatings from TSAR appears to be a unique alternative for the hydrolytic protection of pharmaceutical vials.

Numerous scientific questions raised by the exploration of at least four deposition chemistries for the deposition of SiO2 and SiOxNy films remain to be explored. The study of the aqueous corrosion mechanisms of pharmaceutical glass and of the applied coatings is one of them.
SiOxNy films produced from TSAR-O2 demonstrate efficient nitrogen incorporation at temperatures compatible with Type I pharmaceutical glass and other heat sensitive substrates. Thus, it is of great interest to evaluate their hydrolytic resistance in the USP < 660> and <1660> pharmacopoeia tests. Deposition on the internal surface of bottles has been finalized and the USP tests are in progress, with the aim of fully meeting the main objective of the ANR project. The preliminary results are in line with expectations. The high deposition rates observed from this chemistry also make it attractive for industrial processing. The development of a kinetic model implemented in a numerical simulation code of the process would facilitate its implementation on a larger scale or on other types of substrates.
Additional upgrades to the TSAR-O2 CVD process for the production of SiOxNy films are being considered. In addition, the deposition pathways developed from TEOS, TEOS / HMDS, TDMSA and TSAR could be applied to other industrial fields, notably new energies. The four chemistries used also open up new prospects for single or multilayer film applications in optoelectronics based on monolithic Si and in selective pollution control, by activating the retention properties linked to certain chemical affinities (heavy metals, endocrine disruptors ).

• K. C. Topka et al. Large temperature range model for the atmospheric pressure chemical vapor deposition of silicon dioxide films on thermosensitive substrates. Chemical Engineering Research and Design, 2020, 161, 146-158.
• B. Diallo et al. Network hydration, ordering and composition interplay of chemical vapor deposited amorphous silica films from tetraethyl orthosilicate. Journal of Materials Research and Technology, 2021, 13, 534-547.
• K. C. Topka et al. Tunable SiO2 to SiOxCyH films by ozone assisted chemical vapor deposition from tetraethylorthosilicate and hexamethyldisilazane mixtures. Surface and Coatings Technology, 2021, 407, 126762.
• L. Decosterd et al. An innovative GC-MS, NMR and ESR combined gas phase investigation during chemical vapor deposition of silicon oxynitrides films from tris(dimethylsilyl)amine. Physical Chemistry Chemical Physics, 2021, 23, 10560–10572.
• M. Puyo et al. Beyond surface nanoindentation: combining static and dynamic nanoindentation to assess intrinsic mechanical properties of CVD amorphous silicon oxide (SiOx) and silicon oxycarbide (SiOxCy) thin films. Thin Solid Films, 2021, 735, 138844.
• K. C. Topka et al. An innovative kinetic model allows insight in the moderate temperature chemical vapor deposition of silicon oxynitride films from tris(dimethylsilyl)amine. Chemical Engineering Journal, Volume 431, Part 3, 1 March 2022, 133350.
• K. C. Topka et al. Critical level of nitrogen incorporation in silicon oxynitride films: transition of morphology, structure and corrosion performance. to be submitted in February 2022.

HEALTHYGLASS will determine innovative, thermally activated chemical vapor deposition (CVD) processes of amorphous silicon oxide (SiO2) oxynitrides (SiOxNy) and oxycarbides (SiOxCy) on the internal surface of pharmaceutic vials, and will define their appropriate composition and structural characteristics in order to obtain efficient and sustainable barrier properties.
The targeted function of these coatings is to limit the interaction between the stored drug and the glass vial, and thus allow to new advanced pharmaceutic molecules, especially in oncology, which are sensitive or aggressive towards the glass, to be commercialized. The generated innovation by the project in terms of materials solutions and deposition processes will thus allow pharmaceutic companies to dispose of high tech, chemical resistant vials, whose internal coating can be adapted to the characteristics of the stored drugs.
There is limited information in the literature on the deposition of SiO2, SiOxNy and SiOxCy films with respect to the specifications defined by the project, namely atmospheric pressure and moderate deposition temperature (<570 °C), leading to dense and chemically inert films deposited on confined surfaces at high growth rate. The project team has recently tuned a deposition process of SiO2 at the internal surface of vials from mixtures of tetraethyl orthosilicate (TEOS) and oxygen. However, these films presented insufficient corrosion resistance in severe tests recommended by the US Pharmacopeia. In the frame of this project SiO2, SiOxNy and SiOxCy will be processed from TEOS and O3 based chemical systems including reactive compounds which activate radical mechanisms to enrich the films with nitrogen and carbon. CVD of SiO2 will be first investigated as starting point prior focusing on SiOxNy and SiOxCy which present remarkable barrier properties due to the densification of the network obtained from the partial replacement of O anions by highly coordinated N and C ones.
State of the art protocols for the physico-chemical, structural and mechanical characterization, including microscopy, ellipsometry, nuclear and vibrational spectroscopies, atom probe tomography and nanomechanics tests, will provide information on these complex systems, including their surface and their interface with the glass substrate. The quantification of the connectivity of the silicate network, the structural disorder, the distortion of the Si environment, and the distribution of the oxynitrides and oxycarbide species will be monitored by solid state 29Si and 13C NMR, combined with XPS and µ-FTIR. High resolution 1H NMR and the very recent and challenging Dynamic Nuclear Polarization will reveal the hydrated species which are present on or by the surface.
The hydrolytic resistance and the durability of the coatings will be evaluated by sterilization cycles preconized by the European and US Pharmacopeias. The most promising coatings will be tested in more severe conditions, e.g. ageing over a period of several weeks in basic and acid pH solutions. The releasing and corrosion mechanisms will be investigated and correlations among process conditions, structure and barrier properties will be established.
HEALTHYGLASS will establish process/structure/properties/performance correlations which will lead to outstanding progress at fundamental level and will pave the way towards the application of these multifunctional and durable materials in complementary sectors concerned by the functionalization of complex surfaces such as micro- and nano-electronics, plastics, medical devices and implants, or gas sensors.

Project coordination

Constantin Vahlas (Centre Inter-universitaire de Recherche et d’Ingénierie des Matériaux)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


CIRIMAT Centre Interuniversitaire de Recherche et d'Ingenierie des Matériaux
CEMHTI CNRS_Conditions Extrêmes et Matériaux: Haute Température et Irradiation UPR3079 CNRS
CIRIMAT Centre Inter-universitaire de Recherche et d’Ingénierie des Matériaux
LGC Laboratoire de Genie Chimique (LGC)

Help of the ANR 584,425 euros
Beginning and duration of the scientific project: February 2018 - 42 Months

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