Pharmaceutical nanotechnology
Development of a modified – solid dispersion in an uncommon approach of melting method facilitating properties of a swellable polymer to enhance drug dissolution

https://doi.org/10.1016/j.ijpharm.2015.02.064Get rights and content

Abstract

The study aimed to develop a modified-solid dispersion method using a swellable hydrophilic polymers accompanied by a conventional carrier to enhance the dissolution of a drug that possesses poor water solubility. Two swellable polymers (hydroxypropyl methylcellulose and polyethylene oxide) were swelled in melted polyethylene glycol 6000 (PEG 6000) in different ratios and under different conditions. The type, amount, and, especially, incorporation method of the swellable polymers were crucial factors affecting the dissolution rate, crystallinity, and molecular interaction of the drug. Interestingly, the method in which the swellable polymer was thoroughly mixed with the melted PEG 6000 as the first step was more effective in increasing drug dissolution than the method in which the drug was introduced to the melted PEG 6000 followed by the addition of the swellable polymer. This system has potential for controlling drug release due to high swelling capabilities of these polymers. Therefore, the current study can be considered to be a promising model for formulations of controlled release systems containing solid dispersions.

Introduction

Solid dispersion (SD) is a potential approach in enhancing dissolution and bioavailability of poorly water-soluble drugs. Advantages of the technique such as simplicity, economization, and others have been widely reported (Vasconcelos et al., 2007). There are two basic different preparation methods of SD including melting method and solvent evaporation method (Tran et al., 2009, Tran et al., 2010). Melting method was first demonstrated by Sekiguchi and Obi (1961). The product was prepared by melting drug with carrier, then cooling and pulverization. In the melting process, high mobility of carrier would change the combination of drug (van Drooge et al., 2006). In solvent evaporation method, drug and carrier were completely dissolved in a volatile solvent such as ethanol, chloroform, or a mixture of ethanol and dichloromethane (Hasegawa et al., 2005, Lloyd et al., 1999, Rodier et al., 2005) at a low temperature to avoid thermal degradation of drug and carrier (Won et al., 2005). The later method has some disadvantages such as high preparation cost, incomplete solvent removal, alteration in product performance with the change of condition applied (Vasconcelos et al., 2007).

The swellable hydrophilic polymers hydroxypropyl methylcellulose (HPMC) and polyethylene oxide (PEO) were introduced in this study to modulate drug release from a SD (Tran et al., 2011, Tran and Tran, 2013). As they are hydrophilic, these polymers may improve the solubility of poorly water-soluble drugs, and their swellable properties may be exploited to promote controlled drug release. The utilization of these two polymer properties in one system might facilitate the development of specialized drug delivery systems by both enhancing drug solubility and controlling the release of poorly water-soluble drugs. This hypothesis was tested herein through the preparation of SDs. However, these polymers are difficult to melt at high temperatures for SD preparation. On the other hand, disadvantages are usually met in the solvent method as mentioned above. Moreover, drugs may be precipitated during solvent removal, leading to the failure of the method intended to enhance drug solubility. Slow drug dissolution rates result when the drugs are not well distributed in the polymer. Therefore, the SD method is not always a successful approach to improve drug solubility. Thus, in this paper, an SD system using the melting method was developed as a new feasible technique using swellable hydrophilic polymers. The system was fabricated not only to increase the dissolution rates of poorly water-soluble drugs, but also to potentially control the release of those drugs. Curcumin (CUR), a poorly water-soluble drug with many potential applications, was used as the model drug in this study. The crystalline behaviors and molecular interactions in the system were investigated to elucidate the potential of this system.

Section snippets

Materials

Curcumin and sodium hydroxide (NaOH) were purchased from Guanghua Sci-Tech Company (China). Hydroxypropyl methyl cellulose (HPMC 4000, HPMC 6) and polyethylene oxide N-60K (PEO) was provided by from Dow Chemical Company (USA). Polyethylene glycol (PEG 6000) was purchased from Sino-Japan Chemical (Taiwan). Methanol (MeOH) was purchased from Fisher Scientific International, Inc. (US). Hydrochloric acid (HCl) and sodium chloride (NaCl) were purchased from Xilong Chemical Industry Incorporated

Dissolution and solubility studies

Our preliminary study showed that CUR was poorly soluble and had lower solubility in acidic medium than basic medium. Specifically, solubility of CUR at pH 1.2 and pH 6.8 were 7.230 ± 0.35 and 12.6 23 ± 3.54, respectively. For this reason, most dissolution release rate of CUR from SDs in the current studies in intestinal fluid (pH 6.8) was faster than that in gastric fluid (pH 1.2) and the percentage of pure CUR released in these media was under 5% in previous studies (Tran et al., 2015).

Conclusion

HPMC 4000 was demonstrated to be an effective swellable polymer in combination with PEG 6000 for enhancing drug dissolution in modified SDs. Method II, in which PEG 6000 and HPMC 4000 were mixed before the drug was dispersed in the polymer mixture, was found to be the best combination method to achieve the aim of the study. This combination method facilitated the swelling of HPMC 4000, resulting in good drug dispersion to change and maintain drug structure to amorphous form but also for

Acknowledgement

We would like to thank International University, Vietnam National University, Ho Chi Minh City (SV2013-01-BME) for partially supporting research grant.

References (25)

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