The impact of applying an additional polymer coating on high drug-loaded amorphous solid dispersions layered onto pellets.

Inhibiting surface crystallization is an interesting strategy to enhance the physical stability of amorphous solid dispersions (ASDs), still preserving high drug loads. The aim of this study was to investigate the potential surface crystallization inhibitory effect of an additional polymer coating onto ASDs, comprising high drug loads of a fast crystallizing drug, layered onto pellets. For this purpose, bilayer coated pellets were generated with fluid-bed coating, of which the first layer constitutes a solid dispersion of naproxen (NAP) in poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) in a 40:60 or 35:65 (w/w) ratio, and ethyl cellulose (EC) composes the second layer. The physical stability of these double-layered pellets, in comparison to pellets with an ASD layer only, was assessed under accelerated conditions by monitoring with X-ray powder diffraction (XRPD) at regular time intervals. Bilayer coated pellets were however found to be physically less stable than pellets with an ASD layer only. Applying the supplementary EC coating layer induced crystallization and heterogeneity in the 40:60 and 35:65 (w/w) NAP-PVP-VA ASDs, respectively, attributed to the initial contact with the solvent. Caution is thus required when applying an additional coating layer on top of an ASD layer with fluid-bed coating, for instance for controlled release purposes, especially if the ASD consists of high loads of a fast crystallizing drug.

The Value of Bead Coating in the Manufacturing of Amorphous Solid Dispersions: A Comparative Evaluation with Spray Drying.

Despite the fact that an amorphous solid dispersion (ASD)-coated pellet formulation offers potential advantages regarding the minimization of physical stability issues, there is still a lack of in-depth understanding of the bead coating process and its value in relation to spray drying. Therefore, bead coating and spray drying were both evaluated for their ability to manufacture high drug-loaded ASDs and for their ability to generate physically stable formulations. For this purpose, naproxen (NAP)-poly(vinyl-pyrrolidone-co-vinyl acetate) (PVP-VA) was selected as an interacting drug-polymer model system, whilst naproxen methyl ester (NAPME)-PVP-VA served as a non-interacting model system. The solvent employed in this study was methanol (MeOH). First, a crystallization tendency study revealed the rapid crystallization behavior of both model drugs. In the next step, ASDs were manufactured with bead coating as well as with spray drying and for each technique the highest possible drug load that still results in an amorphous system was defined via a drug loading screening approach. Bead coating showed greater ability to manufacture high drug-loaded ASDs as compared to spray drying, with a rather small difference for the interacting drug-polymer model system studied but with a remarkable difference for the non-interacting system. In addition, the importance of drug-polymer interactions in achieving high drug loadings is demonstrated. Finally, ASDs coated onto pellets were found to be more physically stable in comparison to the spray dried formulations, strengthening the value of bead coating for ASD manufacturing purposes.

The underestimated contribution of the solvent to the phase behavior of highly drug loaded amorphous solid dispersions.

In spite of the fact that spray drying is widely applied for the formulation of amorphous solid dispersions (ASDs), the influence of the solvent on the physical properties of the ASDs is still not completely understood. Therefore, the impact of organic solvents on the kinetic stabilization of drug components in a polymer matrix prepared by either film casting or spray drying was investigated. One polymer, PVPVA 64, together with one of four poorly water soluble drugs, naproxen, indomethacin, fenofibrate or diazepam, were film casted and spray dried using either methanol, ethanol, isopropanol, acetonitrile, acetone, dichloromethane or ethyl acetate. For every combination, the highest drug loading that could be formulated as a single amorphous phase was established. The solvent determined the maximum amount of drug that could be kinetically trapped in the polymer matrix and thereby the extent of kinetic stabilization. These maximum drug loadings were compared to the thermodynamic solubilities of the drugs in the seven solvents. Generally, there was no relation between the thermodynamic solubility of a drug and its highest drug loading attained using the same solvent. Hence, the contribution of the solvent to the generation of a supersaturated state should not be underestimated.

Solvent influence on manufacturability, phase behavior and morphology of amorphous solid dispersions prepared via bead coating.

Bead coating or fluid-bed coating serves as an auspicious solvent-based amorphous solid dispersion (ASD) manufacturing technique in respect of minimization of potential physical stability issues. However, the impact of solvent selection on the bead coating process and its resulting pellet formulation is, to the best of our knowledge, never investigated before. This study therefore aims to investigate the influence of the solvent on the bead coating process itself (i.e. manufacturability) and on solid-state characteristics of the resulting ASDs coated onto beads. For this purpose, the drug-polymer system felodipine (FEL)-poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) was coated onto microcrystalline cellulose (MCC) beads from acetonitrile (ACN), methanol (MeOH), ethanol (EtOH), acetone (Ac), 2-propanol (PrOH), dichloromethane (DCM) and ethyl acetate (EthAc). A drug loading screening approach with bead coating revealed analogous ability to manufacture high drug-loaded ASDs from the different organic solvents. The results show no correlation with crystallization tendency or with equilibrium solubility of the drug in the different solvents, nor with the solvent-dependent drug-polymer miscibility obtained from film casting experiments. Distinct coating morphologies were however observed for PVP-VA and FEL-PVP-VA ASDs deposited onto beads from the various solvents, which is attributed to differences in solvent evaporation kinetics.

Development of a Surface Coating Technique with Predictive Value for Bead Coating in the Manufacturing of Amorphous Solid Dispersions.

The aim of this paper was to investigate whether a surface coating technique could be developed that can predict the phase behavior of amorphous solid dispersions (ASDs) coated on beads. ASDs of miconazole (MIC) and poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) in methanol (MeOH) were studied as a model system. First, the low crystallization tendency of the model drug in MeOH was evaluated and confirmed. In a next step, a drug loading screening was performed on casted films and coated beads in order to define the highest possible MIC loading that still results in a one-phase amorphous system. These results indicate that film casting is not suitable for phase behavior predictions of ASDs coated on beads. Therefore, a setup for coating a solid surface was established inside the drying chamber of a spray dryer and it was found that this surface coating technique could predict the phase behavior of MIC-PVP-VA systems coated on beads, in case an intermittent spraying procedure is applied. Finally, spray drying was also evaluated for its ability to manufacture high drug-loaded ASDs. The highest possible drug loadings that still result in a one-phase amorphous system were obtained for bead coating and its predictive intermittent surface coating technique, followed by spray drying and finally by film casting and the continuous surface coating technique, thereby underlining the importance for further research into the underexplored bead coating process.

Unraveling Particle Formation: From Single Droplet Drying to Spray Drying and Electrospraying.

Spray drying and electrospraying are well-established drying processes that already have proven their value in the pharmaceutical field. However, there is currently still a lack of knowledge on the fundamentals of the particle formation process, thereby hampering fast and cost-effective particle engineering. To get a better understanding of how functional particles are formed with respect to process and formulation parameters, it is indispensable to offer a comprehensive overview of critical aspects of the droplet drying and particle formation process. This review therefore closely relates single droplet drying to pharmaceutical applications. Although excellent reviews exist of the different aspects, there is, to the best of our knowledge, no single review that describes all steps that one should consider when trying to engineer a certain type of particle morphology. The findings presented in this article have strengthened the predictive value of single droplet drying for pharmaceutical drying applications like spray drying and electrospraying. Continuous follow-up of the particle formation process in single droplet drying experiments hence allows optimization of manufacturing processes and particle engineering approaches and acceleration of process development.

Comparative study of the potential of poly(2-ethyl-2-oxazoline) as carrier in the formulation of amorphous solid dispersions of poorly soluble drugs.

Despite the fact that solid dispersions are gaining momentum, the number of polymers that have been used as a carrier during the past 50 years is rather limited. Recently, the poly(2-alkyl-2-oxazoline) (PAOx) polymer class profiled itself as a versatile platform for a wide variety of applications in drug delivery, including their use as amorphous solid dispersion (ASD) carrier. The aim of this study was to investigate the potential of poly(2-ethyl-2-oxazoline) (PEtOx) by applying a benchmark approach with well-known, commercially available carriers (i.e. polyvinylpyrrolidone (PVP) K30, poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) 64 and hydroxypropylmethylcellulose (HPMC)). For this purpose, itraconazole (ITC) and fenofibrate (FFB) were selected as poorly water-soluble model drugs. The four polymers were compared by establishing their supersaturation maintaining potential and by investigating their capability as carrier for ASDs with high drug loadings. Spray drying, as well as hot melt extrusion and cryo-milling were implemented as ASD manufacturing technologies for comparative evaluation. For each manufacturing technique, the formulations with the highest possible drug loadings were tested with respect to in vitro drug release kinetics. This study indicates that PEtOx is able to maintain supersaturation of the drugs to a similar extent as the commercially available polymers and that ASDs with comparable drug loadings can be manufactured. The results of the in vitro dissolution tests reveal that high drug release can be obtained for PEtOx formulations. Overall, proof-of-concept is provided for the potential of PEtOx for drug formulation purposes.