Understanding the Behavior of Amorphous Pharmaceutical Systems during Dissolution

Alonzo, David E.; Zhang, Geoff G. Z.; Zhou, Deliang; Gao, Yi; Taylor, Lynne S.

doi:10.1007/s11095-009-0021-1

Cited by 412 publications

(312 citation statements)

References 35 publications

(34 reference statements)

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“…Furthermore, the polymer has an inherent binding site that allows hydrogen bonding and/or van der Waal's interactions with drug molecules, which can lead to the stabilization of the drug molecule in the matrix. 14) Considering this background, Soluplus ® has been applied to solid dispersion formulations prepared by freeze-drying, spraydrying, and melt-extrusion techniques to enhance the solubility and bioavailability of poorly water-soluble compounds. [15][16][17] However, the solubilizing mechanism of Soluplus ® ascribed to micellization has yet to be elucidated.…”

mentioning

confidence: 99%

Evaluation of the Micellization Mechanism of an Amphipathic Graft Copolymer with Enhanced Solubility of Ipriflavone

Tanida

Kurokawa

Sato

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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The main purpose of this study was to investigate the solubilization enhancement properties of an amphipathic graft copolymer, Soluplus ® , on test compounds. Micellization of Soluplus ® in solution was characterized by evaluating the changes in the surface activity, turbidity, and thermodynamic behavior. To assess the feasibility of Soluplus ® as a polymeric carrier of solid dispersions, freeze-dried samples of ipriflavone were prepared, and the physicochemical properties of the carrier plus ipriflavone were evaluated in terms of solubility, dissolution, and crystallinity. The surface tension of the solution decreased depending on the polymer concentration, and gradual turbidity increase was observed. Isothermal titration calorimetry was used to measure the thermal reaction accompanying the micellization of Soluplus ® and indicated that a colloidal micelle formation improved solubility. The prepared formulations, particularly at a ratio of ipriflavone : Soluplus ® 1 : 10 (w/w) exhibited a dramatically improved solubility of ipriflavone that was ca. 70-fold higher than that of untreated ipriflavone. The solubilization mechanism of Soluplus ® was partially elucidated and suggested that its strategic application could improve the solubility of hydrophobic compounds.Key words isothermal titration calorimetry; ipriflavone; amphipathic graft copolymer; solubility Among the available technologies, the solid dispersion technique is commonly used as one of the most promising strategies for the enhancement of the solubility, dissolution rate, and bioavailability of poorly water-soluble compounds. A solid dispersion system can be defined as a distribution of active pharmaceutical ingredients as molecular amorphous particles and/or in the microcrystalline state into a carrier matrix-like polymer.1) The physicochemical characteristics of polymeric carriers could dominate the pharmaceutical properties of a solid dispersion system. 2,3) Based on the characteristic properties of a polymeric carrier, a number of solid dispersion systems possessing various functional properties such as sustained release, pH-dependent release, self-emulsifying properties, and site-specific release have been developed. [4][5][6][7] In particular, amphiphilic polymers have been found to be beneficial for the enhancement of not only solubility but also of the oral bioavailability of poorly water-soluble compounds because they form micellar structures that contain the compound. 6,8) Soluplus ® , a graft copolymer consisting of polyvinyl caprolactam, polyvinyl acetate, and polyethyleneglycol, has been applied to the design of solid-dispersion formulations with poorly water-soluble substances to improve their solubility and bioavailability.9,10) The copolymer exhibits an amphipathic property attributed to its hydrophilic and hydrophobic residues, which could contribute to the formation of micelles in water. Unlike conventional polymers such as polyvinylpyrrolidone and hydroxypropyl methylcellulose, Soluplus ® is bifunctional and can act as both a polym...

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mentioning

confidence: 99%

Evaluation of the Micellization Mechanism of an Amphipathic Graft Copolymer with Enhanced Solubility of Ipriflavone

Tanida

Kurokawa

Sato

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…25 Another theory is that the polymers bind to the surface of crystallites or nuclei and hinder further crystal growth. 26,27 In this study, the complex of the polymer and the API in the polymeric fraction (peak 1) was rather stable, because there was still ABT-102 bound to the polymer after 12 minutes runtime and dilution with approximately 15 mL of buffer. The molecular mass distribution of the polymeric peak in the dispersion of the extrudate was in good accordance with the molecular mass distribution of the polymer solution.…”

Section: Discussionmentioning

confidence: 68%

The amorphous solid dispersion of the poorly soluble ABT-102 forms nano/microparticulate structures in aqueous medium: impact on solubility

Frank¹,

Westedt²,

Rosenblatt³

et al. 2012

IJN

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Amorphous solid dispersions (ASDs) are a promising formulation approach for poorly soluble active pharmaceutical ingredients (APIs), because they ideally enhance both dissolution rate and solubility. However, the mechanism behind this is not understood in detail. In the present study, we investigated the supramolecular and the nano/microparticulate structures that emerge spontaneously upon dispersion of an ASD in aqueous medium and elucidated their influence on solubility. The ASD, prepared by hot melt extrusion, contained the poorly soluble ABT-102 (solubility in buffer, 0.05 µg/mL), a hydrophilic polymer, and three surfactants. The apparent solubility of ABT-102 from the ASD-formulation was enhanced up to 200 times in comparison to crystalline ABT-102. At the same time, the molecular solubility, as assessed by inverse equilibrium dialysis, was enhanced two times. Asymmetrical flow field-flow fractionation in combination with a multiangle light-scattering detector, an ultraviolet detector, and a refractometer enabled us to separate and identify the various supramolecular assemblies that were present in the aqueous dispersions of the API-free ASD (placebo) and of binary/ternary blends of the ingredients. Thus, the supramolecular assemblies with a molar mass between 20,000 and 90,000 could be assigned to the polyvinylpyrrolidone/vinyl acetate 64, while two other kinds of assemblies were assigned to different surfactant assemblies (micelles). The amount of ABT-102 remaining associated with each of the assemblies upon fractionation was quantified offline with high-performance liquid chromatography-ultraviolet-visible. The polymeric and the micellar fraction contributed to the substantial increase in apparent solubility of ABT-102. Furthermore, a microparticulate fraction was isolated by centrifugation and analyzed by scanning electron microscopy, X-ray scattering, and infrared spectroscopy. The microparticles were found to be amorphous and to contain two of the surfactants besides ABT-102 as the main component. The amorphous microparticles are assumed to be the origin of the observed increase in molecular solubility ("true" supersaturation).

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“…Solution stability of supersaturated solutions prepared from the nifedipine amorphous solid dispersions was carried out as previously described with minor adaptations (13,14,17). Briefly, supersaturated solutions of nifedipine were obtained by dissolving an appropriate amount of the 10% (w/w) nifedipine ASD powder into 10 mM MES buffer pH6.5 to achieve supersaturated solutions of various times the equilibrium solubility of crystalline nifedipine (8 μg/mL).…”

Section: Determination Of Supersaturation Vs Timementioning

confidence: 99%

“…The amorphous state has long been recognized as a way to increase the free energy and the apparent aqueous solubility of poorly soluble pharmaceuticals (13)(14)(15)(16)(17)(18). Amorphous solid dispersion (ASD) technologies have emerged to allow stabilization of the amorphous state both in the dosage form and during supersaturation in the intestinal milieu, and delivery of some of the most important drugs of the twentyfirst century has been made possible through amorphous solid dispersion technologies.…”

Section: Introductionmentioning

confidence: 99%

The Twofold Advantage of the Amorphous Form as an Oral Drug Delivery Practice for Lipophilic Compounds: Increased Apparent Solubility and Drug Flux Through the Intestinal Membrane

Dahan

Beig

Ioffe-Dahan

et al. 2012

AAPS J

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Abstract. The purposes of this study were to assess the efficiency of different nifedipine amorphous solid dispersions (ASDs) in achieving and maintaining supersaturation and to investigate the solubilitypermeability interplay when increasing the apparent solubility via ASD formulations. Spray-dried ASDs of nifedipine in three different hydrophilic polymers, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), copovidone, and polyvinylpyrrolidone (PVP), were prepared and characterized by powder X-ray diffraction and differential scanning calorimetry. The ability of these formulations to achieve and maintain supersaturation over 24 h was assessed. Then, nifedipine's apparent intestinal permeability was investigated as a function of increasing supersaturation in the parallel artificial membrane permeability assay model and in the single-pass rat intestinal perfusion model. The efficiency of the different ASDs to achieve and maintain supersaturation of nifedipine was found to be highly polymer dependent; while a dispersion in HPMC-AS enabled supersaturation 20× that of the crystalline aqueous solubility, a dispersion in copovidone enabled 10×, and PVP allowed supersaturation of only 5× that of the crystalline solubility. Nifedipine flux across the intestine from supersaturated solutions was increased, and the apparent intestinal permeability was constant, irrespective of the degree of supersaturation or the polymer being used. In conclusion, while with other solubility-enabling approaches (e.g., surfactants, cyclodextrins, cosolvents), it is not enough to increase the apparent solubility, but to strike the optimal solubility-permeability balance, which limits the chances for successful drug delivery, the amorphous form emerges as a more advantageous strategy, in which higher apparent solubility (i.e., supersaturation) will be readily translated into higher drug flux and overall absorption.

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Understanding the Behavior of Amorphous Pharmaceutical Systems during Dissolution

Cited by 412 publications

References 35 publications

Evaluation of the Micellization Mechanism of an Amphipathic Graft Copolymer with Enhanced Solubility of Ipriflavone

Evaluation of the Micellization Mechanism of an Amphipathic Graft Copolymer with Enhanced Solubility of Ipriflavone

The amorphous solid dispersion of the poorly soluble ABT-102 forms nano/microparticulate structures in aqueous medium: impact on solubility

The Twofold Advantage of the Amorphous Form as an Oral Drug Delivery Practice for Lipophilic Compounds: Increased Apparent Solubility and Drug Flux Through the Intestinal Membrane

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