Molecular Indicators of Surface and Bulk Instability of Hot Melt Extruded Amorphous Solid Dispersions

In this study molecular modelling is introduced as a novel approach for the development of pharmaceutical solid dispersions. A computational model based on quantum mechanical (QM) calculations was used to predict the miscibility of various drugs in various polymers by predicting the binding strength between the drug and dimeric form of the polymer. The drug/polymer miscibility was also estimated by using traditional approaches such as Van Krevelen/Hoftyzer and Bagley solubility parameters or Flory Huggins interaction parameter in comparison to the molecular modelling approach.The molecular modelling studies predicted successfully the drug-polymer binding energies and the preferable site of interaction between the functional groups. The drug-polymer miscibility and the physical state of bulk materials, physical mixtures and solid dispersions were determined by thermal analysis (DSC/MTDSC) and X-ray diffraction. The produced solid dispersions were analysed by X-ray photoelectron spectroscopy (XPS), which confirmed not only the exact type of the intermolecular interactions between the drugpolymer functional groups but also the binding strength by estimating the N-coefficientvalues. The findings demonstrate that QM-based molecular modelling is a powerful tool to predict the strength and type of intermolecular interactions in a range of drug/polymeric systems for the development of solid dispersions.

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“…Thermal analysis has been used as a valuable tool to predict drug-polymer miscibility 19,[32][33][34] .…”

Section: Flory Huggins (F-h) Theory For the Prediction Of Drug/polymementioning

confidence: 99%

Molecular Modeling as a Predictive Tool for the Development of Solid Dispersions

et al. 2015

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“…Having a high number of coated pellets also reduces the risk for dose-dumping 3,4 . Furthermore, the surface of amorphous solid dispersion formulations has also been shown to be more vulnerable to crystallization of the amorphous drug phase 5 , hence an additional coating layer could potentially stabilize these formulations.…”

Section: Introductionmentioning

confidence: 99%

“…Controlling the release of glass solutions also allows for a decreased dosing scheme, a better patient compliance and a reduced risk of side effects 6 . It could, however, be 5 argued that poorly soluble drugs already inherently possess a slow release dissolution profile, but this is compound specific, and non-adjustable.…”

Section: Introductionmentioning

confidence: 99%

Controlling the Release of Indomethacin from Glass Solutions Layered with a Rate Controlling Membrane Using Fluid-Bed Processing. Part 1: Surface and Cross-Sectional Chemical Analysis

et al. 2017

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den Mooter, Guy (2017) Controlling the release of indomethacin from glass solutions layered with a rate controlling membrane using fluid-bed processing. A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. AbstractFluid bed coating has been shown to be an adequate manufacturing technique to formulate poorly soluble drugs in glass solutions. Layering inert carriers with a drug-polymer mixture enables these beads to be immediately filled into capsules, thus avoiding additional, potentially destabilizing, downstream processing. In this study fluid bed coating is proposed for the production of controlled release dosage forms of glass solutions by applying a second, rate controlling membrane on top of the glass solution. Adding a second coating layer adds to the physical and chemical complexity of the drug delivery system so a thorough understanding of the physical structure and phase behavior of the different coating layers is needed. This study aimed to investigate the surface and cross-sectional characteristics (employing SEM and ToF-SIMS) of an indomethacin-polyvinylpyrrolidone (PVP) glass solution, top-coated with a release rate controlling membrane consisting of either ethyl cellulose or Eudragit RL. The implications on the addition of a pore former (PVP) and the coating medium (ethanol or water) were also considered. In addition, polymer miscibility and the phase analysis of the underlying glass solution were investigated.Significant differences in surface and cross sectional topography of the different rate controlling membranes or the way they are applied (solution vs. dispersion) were observed. These observations can be linked to the polymer miscibility differences. The presence of PVP was observed in all rate controlling membranes, even if it is not part of the coating solution. This could be attributed to residual powder presence in the coating chamber. The distribution of PVP among the sample surfaces depends on the concentration and the rate controlling polymer used.Differences can again be linked to polymer miscibility. Finally, it was shown that the underlying glass solution layer remains amorphous after coating of the rate controlling membrane, whether formed from an ethanol solution or an aqueous dispersion.4

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“…O primeiro está relacionado à temperatura do processo, que deve ser monitorado para que não ocorra a degradação do fármaco, enquanto que o outro, relaciona-se com quantidade de ativo carreada pelo polímero, que se for muito elevada pode comprometer a estabilidade da formulação, mais precisamente, a sua dissolução (ALMEIDA et al, 2012;GRYCZE, 2012;YANG et al, 2015).…”

Section: Resultsunclassified

“…No caso das formulações com 30% de carga, o pico do SCM se manteve, porém, de modo menos pronunciado, levando à suposição de que parte do material, ainda no estado cristalino se encontra disperso no polímero (ALMEIDA et al, 2012;GRYCZE, 2012;YANG et al, 2015). De acordo com estes resultados, optou-se por utilizar as mesmas condições no DOE, de modo a avaliar a influência da carga de fármaco, temperatura e tamanho do grânulo na dissolução do SCM.…”

Section: Resultsunclassified

Desenvolvimento de sistemas multiparticulados de liberação imediata e modificada para associação de fármacos anti-hipertensivos

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Molecular Indicators of Surface and Bulk Instability of Hot Melt Extruded Amorphous Solid Dispersions

Cited by 14 publications

References 35 publications

Molecular Modeling as a Predictive Tool for the Development of Solid Dispersions

Molecular Modeling as a Predictive Tool for the Development of Solid Dispersions

Controlling the Release of Indomethacin from Glass Solutions Layered with a Rate Controlling Membrane Using Fluid-Bed Processing. Part 1: Surface and Cross-Sectional Chemical Analysis

Desenvolvimento de sistemas multiparticulados de liberação imediata e modificada para associação de fármacos anti-hipertensivos

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