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

Fluid bed coating has been shown to be a suitable 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 scanning electron microscopy (SEM) and time of flight secondary ion mass spectrometry (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 of 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

Broadening the scope of amorphous solid dispersions: alternative manufacturing and formulation approaches

Because of the different challenges still faced in solid dispersion research today, an alternative manufacturing approach was investigated in the form of fluid bed coating, which enables efficient drying and the omission of additional processing steps which can destabilize solid dispersions. Also, alternative formulation approaches are exploited by incorporating controlled release polymers into solid dispersions, either as a rate controlling membrane or as (part of) the solid dispersion carrier. A first study describes the search for an mDSC sample preparation method for the analysis of INDO-PVP glass solutions coated onto inert sucrose beads using fluid bed coating. The spherical shape of these beads compromises the contact area with the bottom of a DSC sample pan. Grinding the coated beads and separating the resulting particles into different particle size ranges, resulted in a visible glass transition signal. This glass transition, however, shifted and broadened in particle samples with increasing size range. This phenomenon was confirmed in glass solutions prepared as isolated films by rotary evaporation, with different API’s and from different solvent systems. Resulting from TGA analysis, where a difference was made between sub-Tg and above-Tg residual solvent evaporation, it could be concluded that the observed Tg shift and broadening could be ascribed to the differences in residual solvent mass loss from the bulk of the particles and from the surface. Since particles with a smaller size range exhibit a higher surface to mass ratio, they possess more solvent poor surface, as compared to particles with a larger size range, which possess more solvent rich bulk. These findings were confirmed by a correlation between the deviation from the Gordon-Taylor derived Tg and solvent mass loss from the Tg on. In order to control the release of INDO from coated glass solutions, an additional rate controlling coating was applied on top of the glass solution. This can be done consecutively using fluid bed coating. The resulting multilayer coated beads require a combination of surface and bulk characterization to understand the phase behaviour. Different rate controlling membranes were applied on INDO-PVP glass solutions comprising two possible controlled release polymers, different amounts of pore former can be added and the rate controlling membrane can be applied from an ethanol solution or an aqueous dispersion. The investigation of these different formulations on the phase behaviour of the drug delivery system is described in a second investigation. Surface and cross-sectional topography was investigated by SEM. Chemical composition and distribution analysis of these surfaces and cross-sections was performed using ToF-SIMS. Polymer miscibility was assessed with mDSC and crystallinity with XRPD. Topography differences observed on the surface or in the cross-sections of the coated beads can be ascribed to polymer miscibility differences or coating from a solution or a dispersion. PVP presence at the surface of pure ERL or EC coatings is the result of a coating contamination. The distributional changes of PVP, when incorporated as a pore former can also be explained by polymer miscibility differences. Limited INDO and PVP migration into the rate controlling membrane can be evidenced from cross-sectional ToF-SIMS analysis. Lastly, XRPD analysis shows that INDO remains amorphous after application of a rate controlling membrane, even if it is coated from an aqueous dispersion. The influence of the above described formulation changes and rate controlling membrane thickness on the release of INDO was investigated. In addition to this, the role of a charge interaction between drug and controlled release polymer on the release of the former was investigated as well. Diffusion experiments showed a clear influence of the controlled release polymer used, pore former concentration and coating from a solution or suspension on the permeability of rate controlling membranes. These findings could be readily translated to their influence on drug release, pinpointing diffusion through the rate controlling membrane as the rate limiting step for drug release and showing the potential of these diffusion experiments for screening purposes of rate controlling membranes. A charge interaction between INDO and ERL was confirmed by ss-NMR but no clear influence of this interaction on the drug release was observed. The diffusion and release differences through ERL and EC coatings are mainly the result of the higher hydrophilicity of the former. Finally, the use of ERL as a solid dispersion carrier is investigated, either alone or in combination with the hydrophilic polymer PVP. The solid dispersions are produced by spray drying and analysed with respect to their phase behaviour and in vitro drug dissolution. After in vitro dissolution, precipitates are collected and analysed again with mDSC. ERL solid dispersions with INDO and NAP showed extended supersaturated drug concentrations, when compared to the hydrophilic polymer PVP. Combinations of PVP and ERL as a carrier combined this extended supersaturation with higher drug concentrations compared to ERL alone. Phase behaviour analysis showed that ERL can form glass solutions and, in the case of INDO, one phase systems are found after 24h dissolution as well. Low drug loadings in combination with ERL as a carrier resulted in slow diffusion out of the carrier making this approach unfavourable. Oversaturated INDO and NAP solutions formed stable nanocrystals in presence of ERL. This formation can be explained by a dynamic interplay of dissolution, sorption and desorption. High sorption levels are necessary for this nanocrystal formation, and a charge interaction between INDO/NAP and ERL provide the necessary driving force for sorption.status: publishe

The peculiar behavior of the glass transition temperatureof amorphous drug-polymer films coated on inert sugar spheres

Fluid bed coating has been proposed in the past as an alternative technology for manufacturing of drug-polymer amorphous solid dispersions, or so-called glass solutions. It has the advantage of being a one-step process, and thus omitting separate drying steps, addition of excipients, or manipulation of the dosage form. In search of an adequate sample preparation method for modulated differential scanning calorimetry analysis of beads coated with glass solutions, glass transition broadening and decrease of the glass transition temperature (Tg ) were observed with increasing particle size of crushed coated beads and crushed isolated films of indomethacin (INDO) and polyvinylpyrrolidone (PVP). Substituting INDO with naproxen gave comparable results. When ketoconazole was probed or the solvent in INDO-PVP films was switched to dichloromethane (DCM) or a methanol-DCM mixture, two distinct Tg regions were observed. Small particle sizes had a glass transition in the high Tg region, and large particle sizes had a glass transition in the low Tg region. This particle size-dependent glass transition was ascribed to different residual solvent amounts in the bulk and at the surface of the particles. A correlation was observed between the deviation of the Tg from that calculated from the Gordon-Taylor equation and the amount of residual solvent at the Tg of particles with different sizes.status: publishe

DEVELOPMENT OF A CONTROLLED RELEASE FORMULATION FROM GLASS SOLUTIONS BY FLUID-BED COATING

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Particle size dependent glass transition in pharmaceutical glass solution films and coatings

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Particle size dependent glass transition in pharmaceutical glass solution films and coatings

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Controlling the drug release of indomethacin glass solutions, prepared by fluid bed coating

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Controlling the drug release of indomethacin glass solutions, prepared by fluid bed coating

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Eudragit RL as a stabilizer for supersaturation and a substrate for nanocrystal formation

In order to optimize supersaturation levels and avoid early drug precipitation, Eudragit® RL was tested as a carrier in solid dispersions, either alone or in combination with a hydrophilic polymer (PVP K25). In vitro dissolution performance of the spray dried solid dispersions was tested. The phase behavior of the produced solid dispersions was analyzed as well as dissolution precipitates. In case of weak acid model compounds (indomethacin and naproxen), the incorporation of Eudragit® RL resulted in a prolongation of supersaturation. A combination of PVP and Eudragit® RL led to high and stable drug concentrations. Eudragit® RL was only suited as a carrier in combination with higher drug loadings. Phase behavior analysis of the produced solid dispersions showed that Eudragit® RL could form glass solutions, and precipitate analysis showed that these drug-polymer combinations remained amorphous after in vitro dissolution for 24h. Surprisingly, indomethacin and naproxen also formed nanocrystals in presence of Eudragit® RL. These nanocrystals were formed by a dynamic interplay of dissolution, sorption and desorption. A charge interaction between anionic drugs and a cationic polymer provided a high driving force for sorption, which was necessary for nanocrystal formation and supersaturation stabilization.publisher: Elsevier articletitle: Eudragit® RL as a stabilizer for supersaturation and a substrate for nanocrystal formation journaltitle: European Journal of Pharmaceutics and Biopharmaceutics articlelink: http://dx.doi.org/10.1016/j.ejpb.2017.02.002 content_type: article copyright: © 2017 Elsevier B.V. All rights reserved.status: publishe

Controlling the release of indomethacin from glass solutions layered with a rate controlling membrane using fluid bed processing. Part 2: The influence of formulation parameters on drug release

This study aimed to investigate the pharmaceutical performance of an indomethacin-polyvinylpyrrolidone (PVP) glass solution applied using fluid bed processing as a layer on inert sucrose spheres and subsequently top-coated with a release rate controlling membrane consisting of either ethyl cellulose or Eudragit RL. The implications of the addition of a pore former (PVP) and the coating medium (ethanol or water) on the diffusion and release behavior were also considered. In addition, the role of a charge interaction between drug and controlled release polymer on the release was investigated. Diffusion experiments pointed to the influence of pore former concentration, rate controlling polymer type, and coating solvent on the permeability of the controlled release membranes. This can be translated to drug release tests, which show the potential of diffusion tests as a preliminary screening test and that diffusion is the main factor influencing release. Drug release tests also showed the effect of coating layer thickness. A charge interaction between INDO and ERL was demonstrated, but this had no negative effect on drug release. The higher diffusion and release observed in ERL-based rate controlling membranes was explained by a higher hydrophilicity, compared to EC.status: publishe