Nucleation and crystal growth in supersaturated solutions of a model drug

Lindfors, Lennart; Forssén, Sara; Westergren, Jan; Olsson, Ulf

doi:10.1016/j.jcis.2008.05.034

Cited by 215 publications

(193 citation statements)

References 35 publications

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“…Specifically, the amorphous character of the precipitated particles significantly increases solubility in the aqueous media relative to the crystalline state resulting in a supersaturated solution which is prone to nucleation and crystal growth (37). A number of excipients, especially hydrophilic polymers such as PVP and cellulose derivatives, i.e., hypromellose, have been reported in the literature to inhibit nucleation or crystal growth (38)(39)(40). Even though only a small amount of PVP adsorbed onto the particle surface compared with NaDC (Table IV), its stabilizing effect against recrystallization seems to be much more significant.…”

Section: Crystallinitymentioning

confidence: 99%

“…Even though only a small amount of PVP adsorbed onto the particle surface compared with NaDC (Table IV), its stabilizing effect against recrystallization seems to be much more significant. Lindfors et al have reported that PVP concentrations as low as 0.01% (w/w) significantly reduced the crystal growth rate of bicalutamide in aqueous supersaturated solutions (38). It was demonstrated that PVP adsorbs to already formed crystals thereby preventing further accumulation of the drug at the growing crystal surface.…”

Section: Crystallinitymentioning

confidence: 99%

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Influence of Formulation and Processing Variables on Properties of Itraconazole Nanoparticles Made by Advanced Evaporative Precipitation into Aqueous Solution

et al. 2012

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Abstract. Nanoparticles, of the poorly water-soluble drug, itraconazole (ITZ), were produced by the Advanced Evaporative Precipitation into Aqueous Solution process (Advanced EPAS). This process combines emulsion templating and EPAS processing to provide improved control over the size distribution of precipitated particles. Specifically, oil-in-water emulsions containing the drug and suitable stabilizers are sprayed into a heated aqueous solution to induce precipitation of the drug in form of nanoparticles. The influence of processing parameters (temperature and volume of the heated aqueous solution; type of nozzle) and formulation aspects (stabilizer concentrations; total solid concentrations) on the size of suspended ITZ particles, as determined by laser diffraction, was investigated. Furthermore, freeze-dried ITZ nanoparticles were evaluated regarding their morphology, crystallinity, redispersibility, and dissolution behavior. Results indicate that a robust precipitation process was developed such that size distribution of dispersed nanoparticles was shown to be largely independent across the different processing and formulation parameters. Freeze-drying of colloidal dispersions resulted in micron-sized agglomerates composed of spherical, sub-300-nm particles characterized by reduced crystallinity and high ITZ potencies of up to 94% (w/w). The use of sucrose prevented particle agglomeration and resulted in powders that were readily reconstituted and reached high and sustained supersaturation levels upon dissolution in aqueous media.

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Section: Crystallinitymentioning

confidence: 99%

Section: Crystallinitymentioning

confidence: 99%

Influence of Formulation and Processing Variables on Properties of Itraconazole Nanoparticles Made by Advanced Evaporative Precipitation into Aqueous Solution

et al. 2012

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“…As these are typically metastable systems, maintaining physical stability by preventing recrystallization is crucial. Polymers are extremely effective when used to prevent recrystallization (9)(10)(11)(12); however, the manufacturing process used may limit the range of polymers that can be utilized. In this study, it was hypothesized that the formulation design space could be increased by using KinetiSol® Dispersing (KSD) as opposed to hot-melt extrusion (HME) for the manufacture of amorphous solid dispersions (ASD), mainly with regard to polymers of increasing molecular weight.…”

Section: Introductionmentioning

confidence: 99%

Thermal Processing of PVP- and HPMC-Based Amorphous Solid Dispersions

et al. 2015

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Abstract. Thermal processing technologies continue to gain interest in pharmaceutical manufacturing. However, the types and grades of polymers that can be utilized in common thermal processing technologies, such as hot-melt extrusion (HME), are often limited by thermal or rheological factors. The objectives of the present study were to compare and contrast two thermal processing methods, HME and KinetiSol® Dispersing (KSD), and investigate the influence of polymer type, polymer molecular weight, and drug loading on the ability to produce amorphous solid dispersions (ASDs) containing the model compound griseofulvin (GRIS). Dispersions were analyzed by a variety of imaging, solid-state, thermal, and solution-state techniques. Dispersions were prepared by both HME and KSD using polyvinylpyrrolidone (PVP) K17 or hydroxypropyl methylcellulose (HPMC) E5. Dispersions were only prepared by KSD using higher molecular weight grades of HPMC and PVP, as these could not be extruded under the conditions selected. Powder X-ray diffraction (PXRD) analysis showed that dispersions prepared by HME were amorphous at 10% and 20% drug load; however, it showed significant crystallinity at 40% drug load. PXRD analysis of KSD samples showed all formulations and drug loads to be amorphous with the exception of trace crystallinity seen in PVP K17 and PVP K30 samples at 40% drug load. These results were further supported by other analytical techniques. KSD produced amorphous dispersions at higher drug loads than could be prepared by HME, as well as with higher molecular weight polymers that were not processable by HME, due to its higher rate of shear and torque output.

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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: 70%

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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Nucleation and crystal growth in supersaturated solutions of a model drug

Cited by 215 publications

References 35 publications

Influence of Formulation and Processing Variables on Properties of Itraconazole Nanoparticles Made by Advanced Evaporative Precipitation into Aqueous Solution

Influence of Formulation and Processing Variables on Properties of Itraconazole Nanoparticles Made by Advanced Evaporative Precipitation into Aqueous Solution

Thermal Processing of PVP- and HPMC-Based Amorphous Solid Dispersions

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

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