Probing the mechanisms of drug release from amorphous solid dispersions in medium-soluble and medium-insoluble carriers

Sun, Dajun; Lee, Ping I.

doi:10.1016/j.jconrel.2015.06.004

Cited by 132 publications

(114 citation statements)

References 26 publications

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“…Therefore, the increasing dissolution rate is a function of copolymer composition as an increase in VP content will increase the overall hydrophilicity of the copolymer and thus the dissolution rate of the copolymer itself. These observations were all in accordance with a study by Sun and Lee, who suggested that for soluble (hydrophilic) polymers, the drug release mechanism is controlled by the dissolution of the drug, and for insoluble (hydrophobic) polymers, the drug release mechanism is controlled by the drug diffusion through the polymer matrix (15). However, the fastest dissolving system will not necessarily show the best in vivo performance as rapid generation of a supersaturated solution could generate a driving force for crystallization.…”

Section: Effect Of Copolymer Composition On Drug Dissolution At Non-ssupporting

confidence: 92%

“…Even though the underlying processes that govern the dissolution of amorphous solid dispersions are still not fully understood, the stabilization against crystallization is thought to be attributed to specific intermolecular interactions between the drug and polymer (13,14). Under non-sink dissolution conditions, both the dissolution rates and supersaturation levels obtained from amorphous solid dispersions have been reported to be higher with water-soluble (hydrophilic) carriers compared to systems with waterinsoluble (hydrophobic) carriers (15). This interlinks well with the fact that the two most commonly used carriers for marketed amorphous solid dispersion are the hydrophilic polymers hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) (10,16).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, studies have suggested that hydrophobicity is an important polymer property with respect to crystallization inhibition (15,18). This means that the fastest dissolving system may not necessarily show the best in vivo performance, and, hence, that the choice of polymer(s) will have a great effect on the dissolution profile and bioavailability of the amorphous solid dispersion (8,17).…”

Section: Introductionmentioning

confidence: 99%

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Influence of Copolymer Composition on In Vitro and In Vivo Performance of Celecoxib-PVP/VA Amorphous Solid Dispersions

Knopp

Nguyen

et al. 2016

AAPS J

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Abstract. Previous studies suggested that an amorphous solid dispersion with a copolymer consisting of both hydrophobic and hydrophilic monomers could improve the dissolution profile of a poorly watersoluble drug compared to the crystalline form. Therefore, this study investigated the influence of the copolymer composition of polyvinylpyrrolidone/vinyl acetate (PVP/VA) on the non-sink in vitro dissolution behavior and in vivo performance of celecoxib (CCX) amorphous solid dispersions. The study showed that the hydrophilic monomer vinylpyrrolidone (VP) was responsible for the generation of CCX supersaturation whereas the hydrophobic monomer vinyl acetate (VA) was responsible for the stabilization of the supersaturated solution. For CCX, there was an optimal copolymer composition around 50-60% VP content where further replacement of VP monomers with VA monomers did not have any biopharmaceutical advantages. A linear relationship was found between the in vitro AUC 0-4h and in vivo AUC 0-24h for the CCX:PVP/VA systems, indicating that the non-sink in vitro dissolution method applied in this study was useful in predicting the in vivo performance. These results indicated that when formulating a poorly water-soluble drug as an amorphous solid dispersion using a copolymer, the copolymer composition has a significant influence on the dissolution profile and in vivo performance. Thus, the dissolution profile of a drug can theoretically be tailored by changing the monomer ratio of a copolymer with respect to the required in vivo plasma-concentration profile. As this ratio is likely to be drug dependent, determining the optimal ratio between the hydrophilic (dissolution enhancing) and hydrophobic (crystallization inhibiting) monomers for a given drug is imperative.

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Section: Effect Of Copolymer Composition On Drug Dissolution At Non-ssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influence of Copolymer Composition on In Vitro and In Vivo Performance of Celecoxib-PVP/VA Amorphous Solid Dispersions

Knopp

Nguyen

et al. 2016

AAPS J

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“…The effect on water surface tension indicates that lower molecular weight grades effectively functions as a polymeric surfactant more than higher molecular weights. Polymeric surfactants have been shown to create micelle or other geometries in solution to stabilize drug concentrations (30) and also have been demonstrated to stabilize water-insoluble drugs in solution (31,32). This would support the results for the precipitation inhibition analysis where the lower molecular weights were more effective in reducing the rate of drug precipitation.…”

Section: Evaluation Of Pval Molecular Weightsupporting

confidence: 58%

Use of Polyvinyl Alcohol as a Solubility Enhancing Polymer for Poorly Water-Soluble Drug Delivery (Part 2)

Brough

Miller²,

Ellenberger

et al. 2016

AAPS PharmSciTech

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Abstract. The KinetiSol® Dispersing (KSD) technology has enabled the investigation into the use of polyvinyl alcohol (PVAL) as a concentration enhancing polymer for amorphous solid dispersions. Our previous study revealed that the 88% hydrolyzed grade of PVAL was optimal for itraconazole (ITZ) amorphous compositions with regard to solid-state properties, non-sink dissolution performance, and bioavailability enhancement. The current study investigates the influence of molecular weight for the 88% hydrolyzed grades of PVAL on the properties of KSD processed ITZ:PVAL amorphous dispersions. Specifically, molecular weights in the processable range of 4 to 18 mPa · s were evaluated and the 4-88 grade provided the highest AUC dissolution profile. Amorphous dispersions at 10, 20, 30, 40, and 50% ITZ drug loads in PVAL 4-88 were also compared by dissolution performance. Analytical tools of diffusion-ordered spectroscopy and Fourier transform infrared spectroscopy were employed to understand the interaction between drug and polymer. Finally, results from a 30-month stability test of a 30% drug loaded ITZ:PVAL 4-88 composition shows that stable amorphous dispersions can be achieved. Thus, this newly enabled polymer carrier can be considered a viable option for pharmaceutical formulation development for solubility enhancement.

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“…1 at a 32.9 wt% drug loading, the initial drug solubility improvement appears to be higher for ASDs based on watersoluble carriers (e.g., PVP and HPMCAS) but the extent of solubility improvement of indomethacin ASD in insoluble crosslinked PHEMA outperforms those in water-soluble carriers after 8 h. In this case, the dissolution medium for the indomethacin-PHEMA ASD system remains supersaturated even after 24 h in the absence of any dissolved polymer acting as a crystallization inhibitor in the dissolution medium. In fact, other properly designed supersaturating formulations regulated by matrix diffusion (i.e., based on other waterinsoluble carriers) have recently been shown to exhibit similar advantageous kinetic solubility profiles where drug supersaturation is sustained in the absence of any crystallization inhibitor (15). Additional observations showing a more sustained supersaturation resulting from a more gradual drug release have also been reported for the dissolution of griseofulvin from synthetic hectorite (i.e., an insoluble swelling clay) (16) and nilvadipine from crosslinked PVP (17).…”

Section: In Vitro In Vivo Relationship Of Supersaturation Generation mentioning

confidence: 99%

Haste Makes Waste: The Interplay Between Dissolution and Precipitation of Supersaturating Formulations

Sun

Lee

2015

AAPS J

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ABSTRACT. Contrary to the early philosophy of supersaturating formulation design for oral solid dosage forms, current evidence shows that an exceedingly high rate of supersaturation generation could result in a suboptimal in vitro dissolution profile and subsequently could reduce the in vivo oral bioavailability of amorphous solid dispersions. In this commentary, we outline recent research efforts on the specific effects of the rate and extent of supersaturation generation on the overall kinetic solubility profiles of supersaturating formulations. Additional insights into an appropriate definition of sink versus nonsink dissolution conditions and the solubility advantage of amorphous pharmaceuticals are also highlighted. The interplay between dissolution and precipitation kinetics should be carefully considered in designing a suitable supersaturating formulation to best improve the dissolution behavior and oral bioavailability of poorly water-soluble drugs.

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Probing the mechanisms of drug release from amorphous solid dispersions in medium-soluble and medium-insoluble carriers

Cited by 132 publications

References 26 publications

Influence of Copolymer Composition on In Vitro and In Vivo Performance of Celecoxib-PVP/VA Amorphous Solid Dispersions

Influence of Copolymer Composition on In Vitro and In Vivo Performance of Celecoxib-PVP/VA Amorphous Solid Dispersions

Use of Polyvinyl Alcohol as a Solubility Enhancing Polymer for Poorly Water-Soluble Drug Delivery (Part 2)

Haste Makes Waste: The Interplay Between Dissolution and Precipitation of Supersaturating Formulations

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