Impact of phase separation morphology on release mechanism of amorphous solid dispersions

Han, Yi Rang; Ma, Yingshan; Lee, Ping I.

doi:10.1016/j.ejps.2019.104955

Cited by 24 publications

(28 citation statements)

References 53 publications

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“…While pure HPMCAS solely tended to dissolve instead of swell, the situation profoundly changed for the ASDs containing CXB, which exhibited a high degree of swelling and a low degree of erosion. As reported by Han et al and Saboo et al this could be a result of incongruent release of polymer and drug from the ASD caused by water-induced phase separation [39,40]. The FT-IR spectra after buffer treatment indicated an AAPS of CXB and HPMCAS or at least revealed a weakening of the interactions between drug and polymer.…”

Section: Discussionmentioning

confidence: 56%

Impact of HPMCAS on the Dissolution Performance of Polyvinyl Alcohol Celecoxib Amorphous Solid Dispersions

Monschke

Wagner

2020

Pharmaceutics

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Amorphous solid dispersions (ASDs) have been proven to increase the bioavailability of poorly soluble drugs. It is desirable that the ASD provide a rapid dissolution rate and a sufficient stabilization of the generated supersaturation. In many cases, one polymer alone is not able to provide both features, which raises a need for reasonable polymer combinations. In this study we aimed to generate a rapidly dissolving ASD using the hydrophilic polymer polyvinyl alcohol (PVA) combined with a suitable precipitation inhibitor. Initially, PVA and hydroxypropylmethylcellulose acetate succinate (HPMCAS) were screened for their precipitation inhibitory potential for celecoxib in solution. The generated supersaturation in presence of PVA or HPMCAS was further characterized using dynamic light scattering. Binary ASDs of either PVA or HPMCAS (at 10% and 20% drug load) were prepared by hot-melt extrusion and solid-state analytics were conducted using differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and fourier-transformed infrared spectroscopy (FT-IR). The non-sink dissolution studies of the binary ASDs revealed a high dissolution rate for the PVA ASDs with subsequent precipitation and for the HPMCAS ASDs a suppressed dissolution. In order to utilize the unexploited potential of the binary ASDs, the PVA ASDs were combined with HPMCAS either predissolved or added as powder and also formulated as ternary ASD. We successfully generated a solid formulation consisting of the powdered PVA ASD and HPMCAS powder, which was superior in monophasic non-sink dissolution and biorelevant biphasic dissolution studies compared to the binary and ternary ASDs.

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Section: Discussionmentioning

confidence: 56%

Impact of HPMCAS on the Dissolution Performance of Polyvinyl Alcohol Celecoxib Amorphous Solid Dispersions

Monschke

Wagner

2020

Pharmaceutics

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“…The limit of congruency (LoC), which is the drug loading boundary above which the dissolution mechanism switches from being congruent to incongruent, varies from one drug-PVPVA system to another; however, it typically occurs at <25% drug loading and often acts as a limiting factor in achieving reasonable dosage sizes, especially for high dose drugs. In order to develop strategies to overcome this limitation, researchers have pursued understanding of this sudden change in dissolution mechanism at the LoC, whereby changes in the ASD microstructure and homogeneity during hydration appear to be important to the generation of a drug-rich layer at the surface of the ASD, which in turn results in slow drug release [ 4 , 7 , 14 , 17 , 35 , 36 , 37 ]. Once the water enters the ASD, it acts as an anti-solvent for the drug, generating a thermodynamic driving force for phase separation.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, when the hydrated ASDs showed semi-continuous or continuous drug-rich phases, the drug release mechanism was rendered incongruent with faster polymer release and a much slower drug release rate. For example, in a study by Han et al [ 36 ], for ritonavir–polyvinylpyrrolidone ASDs, the drug loading level at which the dissolution mechanism changed from being congruent to incongruent coincided with a change in phase separation morphology, whereby hydrophobic drug-rich domains were discrete in the former case, while a drug-rich continuous phase was found in the latter case. Similar, in the lopinavir–hydroxypropylmethylcellulose (HPMC) ASD film “immersion” study by Li and Taylor [ 35 ], only the lowest drug loading studied, 15% DL, showed discrete domains followed by complete dissolution, whereas apparent contiguous drug-rich material was left behind on the substrate for higher drug loadings as a result of incomplete dissolution.…”

Section: Discussionmentioning

confidence: 99%

Exploring the Role of Surfactants in Enhancing Drug Release from Amorphous Solid Dispersions at Higher Drug Loadings

et al. 2021

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To reduce the dosage size of amorphous solid dispersion (ASD)-based formulations, it is of interest to devise formulation strategies that allow increased drug loading (DL) without compromising dissolution performance. The aim of this study was to explore how surfactant addition impacts drug release as a function of drug loading from a ternary ASD, using felodipine as a model poorly soluble compound. The addition of 5% TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate, a surfactant) to felodipine-polyvinylpyrrolidone/vinyl acetate ASDs was found to facilitate rapid and congruent (i.e., simultaneous) release of drug and polymer at higher DLs relative to binary ASDs (drug and polymer only). For binary ASDs, good release was observed for DLs up to <20% DL; this increased to 35% DL with surfactant. Microstructure evolution in ASD films following exposure to 100% relative humidity was studied using atomic force microscopy coupled with nanoscale infrared imaging. The formation of discrete, spherical drug-rich domains in the presence of surfactant appeared to be linked to systems showing congruent and rapid release of drug and polymer. In contrast, a contiguous drug-rich phase was formed for systems without surfactant at higher DLs. This study supports the addition of surfactant to ASD formulations as a strategy to increase DL without compromising release. Furthermore, insights into the potential role of surfactant in altering ASD release mechanisms are provided.

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“…The phenomenon of AAPS has been shown to be facilitated in presence of moisture as a consequence of an increased molecular mobility of the drug within the polymeric matrix (48,49). The formation of a drug-rich phase and a polymer-rich phase has been shown to negatively influence the dissolution behavior as upon AAPS, a congruent release of drug and polymer could turn into an undesirable incongruent release of drug and polymer (50,51).…”

Section: Phase Separation Upon Immersion In Hydrochloric Acidmentioning

confidence: 99%

“…The formation of a drug-rich phase and a polymer-rich phase has been shown to negatively influence the dissolution behavior as upon AAPS, a congruent release of drug and polymer could turn into an undesirable incongruent release of drug and polymer (50,51). An incongruent release could lead to the fact that the dissolution is drugcontrolled which was shown to profoundly decrease the dissolution rate of an ASD (48,52). These findings are in line with the observations within our study and explain the decreased dissolution rate after exposure to acidic medium.…”

Section: Phase Separation Upon Immersion In Hydrochloric Acidmentioning

confidence: 99%

Influence of Particle Size and Drug Load on Amorphous Solid Dispersions Containing pH-Dependent Soluble Polymers and the Weak Base Ketoconazole

2021

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Among 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 phase separation morphology on release mechanism of amorphous solid dispersions

Cited by 24 publications

References 53 publications

Impact of HPMCAS on the Dissolution Performance of Polyvinyl Alcohol Celecoxib Amorphous Solid Dispersions

Impact of HPMCAS on the Dissolution Performance of Polyvinyl Alcohol Celecoxib Amorphous Solid Dispersions

Exploring the Role of Surfactants in Enhancing Drug Release from Amorphous Solid Dispersions at Higher Drug Loadings

Influence of Particle Size and Drug Load on Amorphous Solid Dispersions Containing pH-Dependent Soluble Polymers and the Weak Base Ketoconazole

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