Study of the phenomena related to the design of orodispersible mini tablets by direct compression

La possibilité d’administrer des formes sèches orales est encore de nos jours un enjeu dans certaines spécialités médicales telles que la pédiatrie, la neurologie ou la gériatrie. Les mini-comprimés orodispersibles présentent un intérêt majeur pour répondre à cette problématique.L’objectif de ce travail est d’étudier les différents phénomènes qui régissent la conception de cette forme pharmaceutique par compression directe.Trois axes de recherche ont été fixés pour la réalisation de ce travail : - Premièrement, étudier les paramètres de formulation et de fabrication des mini-comprimés orodispersibles.- Deuxièmement, améliorer notre compréhension des phénomènes qui régissent la désintégration de ces comprimés au travers de l’étude du comportement de l’excipient clé de la désintégration : le super-désintégrant.- Enfin, développer un matériau à base d’acide alginique et d’alginate de calcium ayant pour fonction d’accélérer la désintégration des mini-comprimés orodispersibles.Les résultats obtenus permettent d’orienter les choix des différents excipients et les paramètres techniques pour la fabrication de cette forme. D’autre part, ils mettent en évidence le besoin de définir des spécifications et des techniques de caractérisation qui lui sont dédiées. Les résultats obtenus lors de l’étude du comportement des super-désintégrants au moment de leur hydratation, soulignent l’importance de la capacité de conduction de l’eau des super-désintégrants dans le mécanisme de désintégration des mini-comprimés orodispersibles. Enfin, les résultats des travaux réalisés pour l’obtention de matériaux super-désintégrants à base d’acide alginique permettent d’établir de premières orientations à suivre dans leurs modes de production.Les différentes conclusions issues des travaux menés lors de cette thèse permettront de valoriser cette forme pharmaceutique innovante et d’en favoriser de nouveaux développements.Patient acceptability of a medical product is a key aspect in the development of medicines. Oral administration of dry forms presents still several limitations in some medical specialties such as pediatrics, neurology or geriatrics. Orodispersible Mini Tablets (ODMTs) have been described as a potential solution to these drawbacks.In this thesis, the different parameters governing the design of these pharmaceutical forms by direct compression have been studied.Three main lines of research have been followed to carry out this work:- Firstly, the different parameters of formulation and manufacture of orodispersible mini tablets were evaluated.- Secondly, the behavior of different commercial super disintegrants, key excipents in the disintegrating action, was studied in order to improve our understanding of the phenomena governing the disintegration mechanisms of the ODMTs.- Finally, various alginate-based materials were developed and its function as super disintegrants in orodispersible mini tablets was tested.The obtained results can be used as indicatives in the choice of excipient and the technical parameters for an effective manufacture of OMDTs. Moreover, they have highlighted the need to continue defining specifications and characterization techniques dedicated to further development of OMDTs. The results obtained during the hydration studies (swelling ratio, swelling force and water uptake) of the super disintegrants underline the importance of wicking in the disintegration mechanism of the ODMT.Finally, the prepared alginate-based materials have shown to present interesting mechanical properties for the development of effective and available super disintegrants for direct compression.The choice of suitable super disintegrants for ODMTs formulation requires extensive knowledge of their properties for promoting the breakout of the tablet and of their interaction with both, water and the various materials constituting the tablet. Thus, the knowledge gained in this thesis on super disintegrant functionality will promote the appropriate development of this innovative pharmaceutical form

Sodium alginate and alginic acid as pharmaceutical excipients for tablet formulation: Structure-function relationship

International audienceAlginic acid and its sodium salt are well-accepted pharmaceutical excipients fulfilling several roles in the development of solid oral dosage forms. Although they have attractive advantages as safety, abundance, relatively low cost and biodegradability, these natural polysaccharides possess a high variability that may limit their use as excipients for tablet formulation. Thus, to obtain robust formulations and high-quality drug products with consistent performance a complete understanding of the structure-property relationship becomes necessary as the structure of alginates affects both, technological and biopharmaceutical properties. This review compiles the compaction studies carried out that relate the structure of alginates to their mechanical and dissolution performances. The different analytical methods used to determine the chemical composition, primary structure and molecular weight distribution, major factors affecting the behavior of alginates in direct compression, are also exposed. Finally, different strategies reported to improve the properties of alginic acid as direct compression excipient are discussed

Flexible heteroionic calcium-magnesium alginate beads for controlled drug release

International audienceIn the present work heteroionic calcium-magnesium alginate beads have been prepared by ionotropic gelation using different Ca:Mg ratios. This simple and straightforward approach allowed the obtention of CaMg-alginate beads presenting different mechanical performance depending on the Mg:Ca ratio. The dynamic swelling behavior of the beads was investigated. Increase in the quantity of Mg2+ incorporated in the beads increased the rate of swelling at pH 1.2 and pH 7.2. Finally, the release of ibuprofen was investigated. It was found that increasing the Mg2+ present in the beads raised the drug release rate

Spray-dried solid dispersions of nifedipine and vinylcaprolactam/vinylacetate/PEG6000 for compacted oral formulations

International audienceThe aim of this work was to investigate an alternative processing technology for a new polymeric solubilizer used mainly in hot melt extrusion. Poorly soluble nifedipine was co-processed through spray-drying with poly(vinyl caprolactam-co-vinyl acetate-co-ethylene glycol) (PVCVAEG) in different ratios. The resulting spray-dried powders were formulated and compacted into tablets forms. Spray drying produced reduced smooth spherical particles with PVCVAEG and more rough surfaces without PVCVAEG. Crystallinity of the co-processed nifedipine with the polymeric solubilizer was reduced. Plasticization of the polymeric solubilizer was observed with increasing drug content. Diffraction patterns in the small angle region as well as transmission electron microscopy showed results supporting phase separation throughout the spray dried particles of high drug content. Compaction with PVCVAEG improved cohesiveness of spray-dried compacts. Heckel modeling showed that deformation of PVCVAEG containing powders was more plastic compared than brittle nifedipine powders. Dissolution kinetics of all spray-dried samples was improved compared to original nifedipine crystals. Co-processed nifedipine with PVCVAEG did not show improved dissolution rate when compared to spray drying nifedipine alone. All though PVCVAEG is more commonly co-processed with drugs by hot melt extrusion to produce solid dispersions, the results show that it also can be processed by spray drying to produce solid dispersions. PVCVAEG improved compactibility of formulated spray dried powders

Validation of an HPLC Assay Method for Routine QC Testing and Stability Study of Compounded Low-Dose Capsules of Acetylsalicylic Acid

The intolerance to Acetylsalicylic Acid (ASA) can be detected by conducting oral provocation testing (OPT), which is to gradually introduce low doses of ASA. To perform this test, hospital pharmacies compound small batches of different low-dosage ASA capsules. This work aims to validate a method for fast HPLC-UV assay that allows routine quality control and physicochemical stability studies of capsules

Fused Deposition Modelling 3D printing and solubility improvement of BCS II and IV active ingredients – A narrative review

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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

Structure-Properties Relationship in the Evaluation of Alginic Acid Functionality for Tableting

International audienceThe aim of this study is to investigate the relationship between the structural, molecular, and particulate properties of alginic acid and its functional characteristics in direct compression (tabletability, compressibility, elasticity, deformation mechanism, and disintegration ability). Therefore, accurate characterization of two different batches of alginic acid was executed (X-ray powder diffraction, Fourier-transform infrared spectroscopy, thermogravimetric analysis, scanning electronic microscopy, 1H nuclear magnetic resonance, size exclusion chromatographymulti angle light scattering, viscosimetry, carboxylic acid titration, powder flowability, true density, laser granulometry). Results showed that molecular weight seems to affect tablet properties and that the alginic acid with the lowest molecular weight provides the hardest tablets with the lowest elastic recovery. Furthermore, these results show the potential interest of exploiting alginic acid as filler excipient in tablet formulation. Finally, disintegration properties of tested materials were found to be close to that of commercial superdisintegrants (Glycolys® and Kollidon Cl®) but not correlated to their swelling force. It can be concluded, for the first time, that the determination of alginic acid molecular weight seems key for applications in direct compression and in particular for obtaining tablets with reproducible strength

Evaluation of the super disintegrant functionnalities of alginic acid and calcium alginate for the design of orodispersible mini tablets

International audienceThis study explores the influence of different synthesis methods and drying conditions in the preparation of sodium alginate-derivate xerogels presenting interesting disintegrant functionalities. Xerogels containing alginic acid (AA) or calcium alginate (CaA) and a mixture of both, AA/CaA, were isolated using two different drying methods oven and rotary evaporation. AA showed the best wettability behavior, in contrast to the rigid crosslinked CaA structure which showed a limited rate of water penetration. Interestingly, xerogel containing AA dried in the oven showed an enhanced maximum water uptake. Oven drying seems to favor the isolation of materials presenting good tabletability. Compression parameters of the formulations (tensile strength, elastic energy and porosity) were not affected by their presence (5%) in the design of OroDispersible Mini Tablets. In vitro disintegration results highlighted the water wicking as the key factor leading the disintegration mechanism of these materials. These results show promise of potential properties for the development of super disintegrant excipients

Chitin’s Functionality as a Novel Disintegrant: Benchmarking Against Commonly Used Disintegrants in Different Physicochemical Environments

International audienceDisintegrants are used as excipients to ensure rapid disintegration of pharmaceutical tablets and further ensure proper dissolution of the active pharmaceutical ingredient. This study investigates disintegration mechanisms of chitin and common disintegrants. Swelling assessment (swelling force and swelling ratio) in different media, and compaction behavior (pure or mixed with other excipients) tabletability, deformation (Heckel modeling), and compact disintegration times were investigated on the tested disintegrants (alginic acid calcium salt, crospovidone, sodium starch glycolate, croscarmellose sodium, and chitin). Results show that the physicochemical properties of the disintegration medium such as pH and ionic strength, as well as other formulation ingredients, affect the disintegrant functionalities. Heckel analysis using the mean yield pressure "Py" shows that alginic acid calcium salt is the most brittle among the studied disintegrants, while crospovidone has the most plastic deformation mechanism, followed by chitin. Chitin showed good tabletability and disintegration properties that were not influenced by the physicochemical formulation environment. Chitin is largely available and easily modifiable and thus a promising material that could be used as a multifunctional excipient in tablet formulation