Hot-melt extrudability of amorphous solid dispersions of flubendazole-copovidone: An exploratory study of the effect of drug loading and the balance of adjuvants on extrudability and dissolution

AbstractAmong the great number of poorly soluble drugs in pharmaceutical development, most of them are weak bases. Typically, they readily dissolve in an acidic environment but are prone to precipitation at elevated pH. This was aimed to be counteracted by the preparation of amorphous solid dispersions (ASDs) using the pH-dependent soluble polymers methacrylic acid ethylacrylate copolymer (Eudragit L100–55) and hydroxypropylmethylcellulose acetate succinate (HPMCAS) via hot-melt extrusion. The hot-melt extruded ASDs were of amorphous nature and single phased with the presence of specific interactions between drug and polymer as revealed by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FT-IR). The ASDs were milled and classified into six particle size fractions. We investigated the influence of particle size, drug load, and polymer type on the dissolution performance. The best dissolution performance was achieved for the ASD made from Eudragit L100–55 at a drug load of 10%, whereby the dissolution rate was inversely proportional to the particle size. Within a pH-shift dissolution experiment (from pH 1 to pH 6.8), amorphous-amorphous phase separation occurred as a result of exposure to acidic medium which caused markedly reduced dissolution rates at subsequent higher pH values. Phase separation could be prevented by using enteric capsules (Vcaps Enteric®), which provided optimal dissolution profiles for the Eudragit L100–55 ASD at a drug load of 10%.

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Impact of Hot-Melt Extrusion Processing Conditions on Physicochemical Properties of Amorphous Solid Dispersions Containing Thermally Labile Acrylic Copolymer

Journal of Pharmaceutical Sciences ◽

10.1016/j.xphs.2019.10.005 ◽

2020 ◽

Vol 109 (2) ◽

pp. 1008-1019 ◽

Cited By ~ 3

Author(s):

Alex Mathers ◽

Fatima Hassouna ◽

Lenka Malinová ◽

Jan Merna ◽

Květoslav Růžička ◽

...

Keyword(s):

Physicochemical Properties ◽

Solid Dispersions ◽

Amorphous Solid ◽

Hot Melt Extrusion ◽

Processing Conditions ◽

Melt Extrusion ◽

Amorphous Solid Dispersions ◽

Acrylic Copolymer ◽

Extrusion Processing ◽

Hot Melt

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Influence of Carbamazepine Dihydrate on the Preparation of Amorphous Solid Dispersions by Hot Melt Extrusion

Pharmaceutics ◽

10.3390/pharmaceutics12040379 ◽

2020 ◽

Vol 12 (4) ◽

pp. 379 ◽

Cited By ~ 5

Author(s):

Xiangyu Ma ◽

Felix Müller ◽

Siyuan Huang ◽

Michael Lowinger ◽

Xu Liu ◽

...

Keyword(s):

Energy State ◽

Solid Dispersions ◽

Amorphous Solid ◽

Hot Melt Extrusion ◽

Water Soluble ◽

Melt Extrusion ◽

Amorphous Solid Dispersions ◽

Water Soluble Drugs ◽

The Impact ◽

Hot Melt

Amorphous solid dispersions (ASDs) are commonly used in the pharmaceutical industry to improve the dissolution and bioavailability of poorly water-soluble drugs. Hot melt extrusion (HME) has been employed to prepare ASD based products. However, due to the narrow processing window of HME, ASDs are normally obtained with high processing temperatures and mechanical stress. Interestingly, one-third of pharmaceutical compounds reportedly exist in hydrate forms. In this study, we selected carbamazepine (CBZ) dihydrate to investigate its solid-state changes during the dehydration process and the impact of the dehydration on the preparation of CBZ ASDs using a Leistritz micro-18 extruder. Various characterization techniques were used to study the dehydration kinetics of CBZ dihydrate under different conditions. We designed the extrusion runs and demonstrated that: 1) the dehydration of CBZ dihydrate resulted in a disordered state of the drug molecule; 2) the resulted higher energy state CBZ facilitated the drug solubilization and mixing with the polymer matrix during the HME process, which significantly decreased the required extrusion temperature from 140 to 60 °C for CBZ ASDs manufacturing compared to directly processing anhydrous crystalline CBZ. This work illustrated that the proper utilization of drug hydrates can significantly improve the processability of HME for preparing ASDs.

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

Pharmaceutics ◽

10.3390/pharmaceutics12090878 ◽

2020 ◽

Vol 12 (9) ◽

pp. 878

Author(s):

Eline Boel ◽

Piyush Panini ◽

Guy Van den Mooter

Keyword(s):

Phase Behavior ◽

Spray Drying ◽

Surface Coating ◽

Drug Loading ◽

Solid Dispersions ◽

Amorphous Solid ◽

Film Casting ◽

Amorphous Solid Dispersions ◽

Coating Technique ◽

Amorphous System

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.

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