Etude de l'impression 3D par frittage laser sélectif pour la conception et le développement de formes pharmaceutiques orales sèches

Selective laser sintering (SLS) is a 3D printing technique based on the consolidation of powder particles using laser energy. This process has shown great interest in personalized medicine.As such, this thesis project aims to explore the possibilities and limitations of the SLS technology in the design and development of pharmaceutical solid oral forms using copovidone as raw material.This work focused on four areas:-Demonstrate the feasibility of producing pharmaceutical forms using a CO2 laser SLS printer.-Determine the physicochemical properties of pharmaceutical materials crucial for their printability and the characteristics of solid oral forms.-Define the critical SLS parameters that can influence the printability of powders and the properties of printed solid oral forms.-Screen excipients allowing the optimization of the SLS process.The results obtained during this study show the ability of a CO2 laser SLS printer to manufacture solid oral forms without the use of an absorbance enhancer while guaranteeing the thermal stability of the active ingredients. Powder properties that affect printability include flowability and absorbance, but others, such as compactness, can also affect the properties of the printed forms (their porosity). For a given powder, it is possible to optimize the printing parameters (laser power, scan speed and layer thickness) to maximize the printing yield and personalize the properties of the printed forms (dose and dissolution rate) by applying a design of experiments in a Quality by Design dynamic. The heating temperature is an important parameter for printability and must be optimal in order to prevent curling. This optimal temperature depends on the thermal properties of the polymer and can be reduced following the introduction of active ingredients or excipients with plasticizing properties. In this study, this was demonstrated with dicarboxylic acids, and in particular with succinic acid. The understanding of these technical aspects is necessary to optimize the selective laser sintering process and accelerate its deployment in the pharmaceutical landscape.Le frittage laser sélectif (SLS) est une technique d’impression 3D basée sur la consolidation de particules de poudre grâce à l’énergie du laser. Ce procédé a montré un grand intérêt en médecine personnalisée.A ce titre, ce projet de thèse a pour objectif d’explorer les possibilités et les limites de la technologie SLS dans le cadre de la conception et du développement de formes pharmaceutiques orales sèches en utilisant la copovidone comme matière première.Ce travail s’est articulé autour de quatre axes :-Démontrer la possibilité de produire des imprimés pharmaceutiques à l’aide d’une imprimante SLS à laser CO2.-Déterminer les propriétés physicochimiques des matériaux pharmaceutiques déterminantes pour leur imprimabilité et les caractéristiques des formes orales sèches.-Définir les paramètres critiques de la SLS pouvant influencer l’imprimabilité des poudres et les propriétés des formes orales sèches imprimées.-Rechercher des excipients permettant d’optimiser le procédé SLS.Les différents résultats obtenus au cours de cette étude montrent l’aptitude d’une imprimante SLS à laser CO2 pour fabriquer des formes orales sèches sans recours à un amplificateur d’absorbance tout en garantissant la stabilité thermique des principes actifs. Les propriétés des poudres qui influent sur l’imprimabilité sont notamment l’écoulement et l’absorbance, mais d’autres, comme la compacité, peuvent également affecter les propriétés des imprimés (leur porosité). Pour une poudre donnée, il est possible d’optimiser les paramètres d’impression (puissance du laser, vitesse de balayage et épaisseur de couche) afin de maximiser le rendement d’impression et personnaliser les propriétés des imprimés (dose et vitesse de dissolution) en appliquant un plan d’expériences dans une dynamique de Quality by Design. La température de chauffage est un paramètre déterminant pour l’imprimabilité et doit être optimale afin de prévenir le phénomène de curling (courbure). Cette température optimale dépend des propriétés thermiques du polymère et peut être réduite suite à l’introduction de principes actifs ou d’excipients aux propriétés plastifiantes. Dans cette étude, cela a été démontré avec les acides dicarboxyliques, en particulier l’acide succinique. La maîtrise de ces aspects techniques est nécessaire afin d’optimiser le processus de frittage laser sélectif et accélérer son déploiement dans le paysage pharmaceutique

Study of 3D printing by selective laser sintering for the design and development of pharmaceutical solid oral forms

Le frittage laser sélectif (SLS) est une technique d’impression 3D basée sur la consolidation de particules de poudre grâce à l’énergie du laser. Ce procédé a montré un grand intérêt en médecine personnalisée.A ce titre, ce projet de thèse a pour objectif d’explorer les possibilités et les limites de la technologie SLS dans le cadre de la conception et du développement de formes pharmaceutiques orales sèches en utilisant la copovidone comme matière première.Ce travail s’est articulé autour de quatre axes :- Démontrer la possibilité de produire des imprimés pharmaceutiques à l’aide d’une imprimante SLS à laser CO2.- Déterminer les propriétés physicochimiques des matériaux pharmaceutiques déterminantes pour leur imprimabilité et les caractéristiques des formes orales sèches.- Définir les paramètres critiques de la SLS pouvant influencer l’imprimabilité des poudres et les propriétés des formes orales sèches imprimées.- Rechercher des excipients permettant d’optimiser le procédé SLS.Les différents résultats obtenus au cours de cette étude montrent l’aptitude d’une imprimante SLS à laser CO2 pour fabriquer des formes orales sèches sans recours à un amplificateur d’absorbance tout en garantissant la stabilité thermique des principes actifs. Les propriétés des poudres qui influent sur l’imprimabilité sont notamment l’écoulement et l’absorbance, mais d’autres, comme la compacité, peuvent également affecter les propriétés des imprimés (leur porosité). Pour une poudre donnée, il est possible d’optimiser les paramètres d’impression (puissance du laser, vitesse de balayage et épaisseur de couche) afin de maximiser le rendement d’impression et personnaliser les propriétés des imprimés (dose et vitesse de dissolution) en appliquant un plan d’expériences dans une dynamique de Quality by Design. La température de chauffage est un paramètre déterminant pour l’imprimabilité et doit être optimale afin de prévenir le phénomène de curling (courbure). Cette température optimale dépend des propriétés thermiques du polymère et peut être réduite suite à l’introduction de principes actifs ou d’excipients aux propriétés plastifiantes. Dans cette étude, cela a été démontré avec les acides dicarboxyliques, en particulier l’acide succinique. La maîtrise de ces aspects techniques est nécessaire afin d’optimiser le processus de frittage laser sélectif et accélérer son déploiement dans le paysage pharmaceutique.Selective laser sintering (SLS) is a 3D printing technique based on the consolidation of powder particles using laser energy. This process has shown great interest in personalized medicine.As such, this thesis project aims to explore the possibilities and limitations of the SLS technology in the design and development of pharmaceutical solid oral forms using copovidone as raw material.This work focused on four areas:- Demonstrate the feasibility of producing pharmaceutical forms using a CO2 laser SLS printer.- Determine the physicochemical properties of pharmaceutical materials crucial for their printability and the characteristics of solid oral forms.- Define the critical SLS parameters that can influence the printability of powders and the properties of printed solid oral forms.- Screen excipients allowing the optimization of the SLS process.The results obtained during this study show the ability of a CO2 laser SLS printer to manufacture solid oral forms without the use of an absorbance enhancer while guaranteeing the thermal stability of the active ingredients. Powder properties that affect printability include flowability and absorbance, but others, such as compactness, can also affect the properties of the printed forms (their porosity). For a given powder, it is possible to optimize the printing parameters (laser power, scan speed and layer thickness) to maximize the printing yield and personalize the properties of the printed forms (dose and dissolution rate) by applying a design of experiments in a Quality by Design dynamic. The heating temperature is an important parameter for printability and must be optimal in order to prevent curling. This optimal temperature depends on the thermal properties of the polymer and can be reduced following the introduction of active ingredients or excipients with plasticizing properties. In this study, this was demonstrated with dicarboxylic acids, and in particular with succinic acid. The understanding of these technical aspects is necessary to optimize the selective laser sintering process and accelerate its deployment in the pharmaceutical landscape

Selective Laser Sintering (SLS), a New Chapter in the Production of Solid Oral Forms (SOFs) by 3D Printing

International audience3D printing is a new emerging technology in the pharmaceutical manufacturing landscape. Its potential advantages for personalized medicine have been widely explored and commented on in the literature over recent years. More recently, the selective laser sintering (SLS) technique has been investigated for oral drug-delivery applications. Thus, this article reviews the work that has been conducted on SLS 3D printing for the preparation of solid oral forms (SOFs) from 2017 to 2020 and discusses the opportunities and challenges for this state-of-the-art technology in precision medicine. Overall, the 14 research articles reviewed report the use of SLS printers equipped with a blue diode laser (445–450 nm). The review highlights that the printability of pharmaceutical materials, although an important aspect for understanding the sintering process has only been properly explored in one article. The modulation of the porosity of printed materials appears to be the most interesting outcome of this technology for pharmaceutical applications. Generally, SLS shows great potential to improve compliance within fragile populations. The inclusion of “Quality by Design” tools in studies could facilitate the deployment of SLS in clinical practice, particularly where Good Manufacturing Practices (GMPs) for 3D-printing processes do not currently exist. Nevertheless, drug stability and powder recycling remain particularly challenging in SLS. These hurdles could be overcome by collaboration between pharmaceutical industries and compounding pharmacies

A QbD Approach for Evaluating the Effect of Selective Laser Sintering Parameters on Printability and Properties of Solid Oral Forms

International audienceThe aim of this work was to investigate the effect of process parameters on the printability of a formulation containing copovidone and paracetamol, and on the properties of solid oral forms 3D-printed through selective laser sintering. Firstly, the influence of the heating temperature was evaluated individually, and it was revealed that this parameter was critical for printability, as a sufficiently high temperature (100 °C) is necessary to avoid curling. Secondly, the effects of laser power, scan speed, and layer thickness were determined using a Box–Behnken design. The measured responses, printing yield, height, weight, hardness, disintegration time, and percentage of drug release at 10 min showed the following ranges of values: 55.6–100%, 2.92–3.96 mm, 98.2–187.2 mg, 9.2–83.4 N, 9.7–997.7 s, and 25.8–99.9%, respectively. Analysis of variance (ANOVA) proved that the generated quadratic models and the effect of the three–process parameters were significant (p < 0.05). Yield improved at high laser power, low scan speed, and increased layer thickness. Height was proportional to laser power, and inversely proportional to scan speed and layer thickness. Variations in the other responses were related to the porosity of the SOFs, which were dependent on the value of energy density. Low laser power, fast scan speed, and high layer thickness values favored a lower energy density, resulting in low weight and hardness, rapid disintegration, and a high percentage of drug release at 10 min. Finally, an optimization was performed, and an additional experiment validated the model. In conclusion, by applying a Quality by Design approach, this study demonstrates that process parameters are critical for printability, but also offer a way to personalize the properties of the SOFs

Selective Laser Sintering of Solid Oral Dosage Forms with Copovidone and Paracetamol Using a CO2 Laser

International audienceMaterial suitability needs to be considered for the 3D printing of solid oral dosage forms (SODFs). This work aims to assess the suitability of a CO2 laser (λ = 10.6 μm) for selective laser sintering of SODFs containing copovidone and paracetamol. First, physicochemical characterization of powders (two grades of copovidone, two grades of paracetamol and their mixtures at various proportions) was conducted: particle size distribution, morphology, infrared absorbance, flowability, and compactness. Then, printing was launched, and printability of the powders was linked to their physicochemical characteristics. The properties of the sintered SODFs were evaluated (solid state, general aspect, porosity, hardness, drug content and release). Hence, it was found that as copovidone absorbs at the laser’s wavelength, sintering was feasible without using an absorbance enhancer. Also, flowability, which mainly depends on the particle size, represents the first control line for “sinterability” as a fair flow is at least required. Low compactness of copovidone and mixtures reduces the mechanical properties of the SODFs but also increases porosity, which can modulate drug release. Moreover, the drug did not undergo degradation and demonstrated a plasticizer effect by lowering the heating temperature. In conclusion, this work proves the applicability of CO2 laser SLS printer to produce SODFs