Dissolution mechanism of poorly water-soluble drug from extended release solid dispersion system with ethylcellulose and hydroxypropylmethylcellulose. Int J Pharm

Toho University, Edo, Tōkyō, Japan
International Journal of Pharmaceutics (Impact Factor: 3.65). 10/2005; 302(1-2):95-102. DOI: 10.1016/j.ijpharm.2005.06.019
Source: PubMed


The purpose of this study is to investigate the release mechanism of poorly water-soluble drug from the extended release solid dispersion systems with water-insoluble ethylcellulose (EC) and water-soluble hydroxypropylmethylcellulose (HPMC) (1:1). Indomethacin (IND) was used as a model of poorly water-soluble drug. Two kinds of solid dispersions were prepared by the solvent evaporation methods, which consist of the same formulation but exhibit different physical performance. It appeared that the dissolution behavior of IND depended on the structures of EC-HPMC matrices, which were governed by the preparation method. In addition, the dissolution behavior showed pH dependency that the dissolution rate of IND was slower in acidic medium than that in neutral medium. The experimental results revealed that the hydrophobic interaction between IND and EC occurred under lower pH and strongly delayed the dissolution rate of IND. The relationship between this hydrophobic interaction and the dissolution rate of IND was also proposed.

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    • "The XRD and DSC results confirm that most of the loaded drug remains amorphous in these polymeric matrices at 20 wt.% drug loading level. These results are consistent with previously reported thresholds of drug loading level in IND-polymer ASD systems above which amorphous-to-crystalline transition tends to occur: ~ 34 wt.% in PHEMA [8], 30–40 wt.% in PVP [18], N30 wt.% in Soluplus [19], N33.3 wt.% in ethylcellulose/HPMC (1:1) [20], and 25–50 wt.% in Eudragit E100 [21] [22]. "
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    ABSTRACT: The objective of the current study is to mechanistically differentiate the dissolution and supersaturation behaviors of amorphous drugs from amorphous solid dispersions (ASDs) based on medium-soluble versus medium-insoluble carriers under nonsink dissolution conditions through a direct head-to-head comparison. ASDs of indomethacin (IND) were prepared in several polymers which exhibit different solubility behaviors in acidic (pH1.2) and basic (pH7.4) dissolution media. The selected polymers range from water-soluble (e.g., PVP and Soluplus) and water-insoluble (e.g., ethylcellulose and Eudragit RL PO) to those only soluble in an acidic or basic dissolution medium (e.g., Eudragit E100, Eudragit L100, and HPMCAS). At 20wt.% drug loading, DSC and powder XRD analysis confirmed that the majority of incorporated IND was present in an amorphous state. Our nonsink dissolution results confirm that whether the carrier matrix is medium soluble determines the release mechanism of amorphous drugs from ASD systems which has a direct impact on the rate of supersaturation generation, thus in turn affecting the evolution of supersaturation in amorphous systems. For example, under nonsink dissolution conditions, the release of amorphous IND from medium-soluble carriers is governed by a dissolution-controlled mechanism leading to an initial surge of supersaturation followed by a sharp decline in drug concentration due to rapid nucleation and crystallization. In contrast, the dissolution of IND ASD from medium-insoluble carriers is more gradual as drug release is regulated by a diffusion-controlled mechanism by which drug supersaturation is built up gradually and sustained over an extended period of time without any apparent decline. Since several tested carrier polymers can be switched from soluble to insoluble by simply changing the pH of the dissolution medium, the results obtained here provide unequivocal evidence of the proposed transition of kinetic solubility profiles from the same ASD system induced by changes in the drug release mechanism in dissolution medium of a different pH. Copyright © 2015. Published by Elsevier B.V.
    Journal of Controlled Release 08/2015; 211:85-93. DOI:10.1016/j.jconrel.2015.06.004 · 7.71 Impact Factor
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    • "One is fully synthetic polymers, which includes povidone (PVP) (Simonelli and Mehta et al., 1969; Lloyd and Craig et al., 1999; Hasegawa and Hamaura et al., 2005; Karavas and Georgarakis et al., 2006; Pokharkar and Mandpe et al., 2006; van Drooge and Braeckmans et al., 2006; van Drooge and Hinrichs et al., 2006; Yoshihashi and Iijima et al., 2006), polyethyleneglycols (PEG) (Chiou and Riegelma.S, 1970; Guyot and Fawaz et al., 1995; Prabhu and Ortega et al., 2005; Yao and Bai et al., 2005; Urbanetz, 2006) and polymethacrylates (Ceballos and Cirri et al., 2005; Huang and Wigent et al., 2006). The other is natural product based polymers, which is composed of cellulose derivatives like hydroxypropylmethylcellulose (HPMC) (Ohara and Kitamura et al., 2005; Won and Kim et al., 2005; Konno and Taylor, 2006), ethylcellulose (Ohara and Kitamura et al., 2005; Desai and Alexander et al., 2006; Verreck and Decorte et al., 2006) or hydroxypropylcellulose (Tanaka and Imai et al., 2005; Tanaka and Imai et al., 2006) or starch derivates, like cyclodextrins (Rodier and Lochard et al., 2005; Garcia-Zubiri and Gonzalez-Gaitano et al., 2006). Amorphous solid dispersions can be classified into solid solutions, solid suspensions or a mixture of both (van Drooge and Braeckmans et al., 2006; van Drooge and Hinrichs et al., 2006). "
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    ABSTRACT: Solid dispersion, defined as the dispersion of one or more active ingredient in a carrier or matrix at solid state, is an efficient strategy for improving dissolution of poorly water-soluble drugs for enhancement of their bioavailability. Compared to other conventional formulations such as tablets or capsules, solid dispersion which can be prepared by various methods has many advantages. However, despite numerous studies which have been carried out, limitations for com-mercializing these products remain to be solved. For example, during the manufacturing process or storage, amorphous form of solid dispersion can be converted into crystalline form. That is, the dissolution rate of solid dispersion would continuously decrease during storage, resulting in a product of no value. To resolve these problems, studies have been conducted on the effects of excipients. In fact, modification of the solid dispersions to overcome these disadvantages has progressed from the first generation to the recent third generation products. In this review, an overview on solid dispersions in general will be given with emphasis on the various manufacturing processes which include the use of polymers and on the stabilization strategies which include methods to prevent crystallization.
    Journal of Pharmaceutical Investigation 06/2011; 41(3). DOI:10.4333/KPS.2011.41.3.125
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    • "This approach frequently improves bioavailability as well as therapeutic effects [13] [23] [24] that are limited or rate controlled by dissolution. Different polymers and sugars have frequently been used as a carrier in solid dispersion formulations [25] [26] [27] [28] [29] [30]. Mechanisms suggested as being responsible for the improved aqueous solubility/ dissolution properties of solid dispersions include reduction of the particle size of the incorporated drug, partial transformation of the crystalline drug to the amorphous state, formation of solid solutions, formation of complexes, reduction of aggregation and agglomeration, improved wetting of the drug and solubilisation of the drug by the carrier at the diffusion layer ([21,31–33]. "
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    ABSTRACT: Gliclazide is practically insoluble in water. In order to improve the drug dissolution rate, cogrinding method was used as an approach to prepare gliclazide coground/solid dispersions (SDs) in the carriers such as povidone (PVP-K30), crospovidone and microcrystalline cellulose (Avicel PH 101) with different drug to carrier ratios. The dissolution rate of gliclazide from the SDs was measured at two physiological pH values of 1.2 and 7.2 simulating gastric and intestinal fluids using USP dissolution apparatus II. The concentration of the dissolved drug in the medium was determined by direct or first-derivative UV spectroscopy. The dissolution rates of the formulations were dependent on the nature and ratio of drug to carriers in SDs and the corresponding physical mixtures as well as the pH of the medium. At a higher pH the drug has a faster dissolution than at a lower pH. The fastest dissolution rates were observed from coground formulations with the drug to carrier ratio of 1:5. The amount of drug dissolved in 15 min from these SDs was varied from 96% in the case of Avicel SD to 100% for SD of PVP. Whereas the amount of drug released in the same time from unground drug powder (UD), ground drug powder (GD) and all physical mixtures was between 60 and 80%. These results indicate that the dissolution rate is highly enhanced from the SDs. DSC as well as X-ray diffraction showed reduced drug crystallinity in SDs. Scanning electron microscopy and particle size analysis revealed significant decreased particle size of the drug in SDs. FT-IR spectroscopy demonstrated no detectable interactions between the drug and carriers. In addition to latter evidence, increased wettability and hydrophilicity of drug particles and deaggregation brought about by the carriers are the reasons for enhanced drug dissolution from the SDs. One of the possible advantages of formulating an insoluble drug such as gliclazide is that if it is used in preparation of capsules or tablets of the drug, its dose might be reduced which is economically beneficial.
    Powder Technology 01/2010; Volume 197:Pages 150-158. DOI:10.1016/j.powtec.2009.09.008 · 2.35 Impact Factor
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