Déposition d'un revêtement organique par voie photochimique sur des particules employées dans le contrôle qualité des médicaments injectables

摘要

After oral absorption, intravenous injection is considered to be the second most important administration path to administer a medicine. In order to prevent incidents of granulomatosis, pulmonary emboli and venous occlusions with the patient, the automated inspection process in place makes sure that each batch of injectable medicine is free of solid contaminants with diameter exceeding 100 mum. For qualification and periodical validation of the detection system, standardized polystyrene divinylbenzene (PS-DVB) beads of different sizes are seeded inside control syringes to mimic contamination. The low surface energy of the PS-DVB frequently leads to the beads' irreversible adhesion to the inner wall of the container, which prevents them from moving freely inside the solution. As the detection principle relies on contaminant motion inside a suspension, the inspection system is unable to detect adhered beads, and the validation of the system fails. This major issue leads to the frequent replacement of control syringe sets, and since they are difficult and costly to produce, the pharmaceutical industry incurs important losses of both time and money for what should be a simple day-to-day validation step.;The main goal of this project is to solve this issue by forcing the PS-DVB beads to stay in suspension, so their motion is ensured inside a control syringe subjected to agitation. Adhesion is due to the low energy functional groups of the polystyrene, such as the C-C and C-H simple bonds and the aromatic rings. Surface grafting of oxygenated groups (ketone, ether, carboxylic, ester) by free radical polymerization would be an efficient way to integrate electrostatic and steric repulsion effects between the treated beads and the syringe walls. Once the electrostatic and steric repulsion effects overcome the van der Waals attraction effect between the PS-DVB and the wall, the beads would repulse the inner wall and be kept in suspension. The inspection system would then be able to retrace their motion.;Polymerization by chemical vapor deposition (CVD) is a useful technique to treat surfaces in gas phase. This method has the advantages of simplifying downstream treatment and being transposable to higher scales. The substrate to be surface modified is brought into close contact with active chemical species or "precursors". These precursors are activated thanks to a thermal, plasma or luminous energy source. They further adsorb to the substrate and enable the free radical polymerization process. Photo-initiated CVD (PICVD) is the most simple and economical CVD form, as it only requires a low energy input, with UV light being the only polymerization activation source. Moreover, since the energy input is low and the operational conditions are smooth, this method favors a better retention of the grafted functional groups. The principal drawback of PICVD is to find a photo-active initiator that is efficient, versatile and able to absorb energy at reasonable wavelengths of UV light. Fortunately, PS-DVB provides its own free radicals to initiate free radical polymerization. It only needs to be exposed to the UV light of a germicidal lamp operating at 253.7 nm.;In the following work, PICVD is been used in order to graft oxygenated functional groups on PS-DVB beads of sizes ranged between 100 and 500 mum of diameter. Air, ozone and syngas were evaluated as precursors. For each of these, the optimal functionalization protocol was developed according to the results of an experimental plan varying the principal process parameters. Polystyrene films were characterized before and after treatment through goniometry, FTIR, XPS and AFM. Results confirmed the grafting of ketone, hydroxyl, carboxyl, ether and ester groups. Zeta potential calculations and dispersion tests finally indicated that PS-DVB beads were kept in suspension inside control syringes after treatment, contrary to untreated beads. The solution to the adhesion problem as presented in this thesis will allow the pharmaceutical industry to meet the high quality control standards while making a significant economy of both time and money. This solution is also transposable to any other industry facing particle adhesion issues. The principal recommendation for future work would be to extend the functionalization process to native contaminants commonly found in the industry. This will allow production of control syringe sets that would not only be of optimal quality, but which would also be more representative of reality.