Hydrophilic-hydrophobic polymer blend for modulation of crystalline changes and molecular interactions in solid dispersion

Abstract

This research study aimed to develop a new strategy for using a polymer blend in solid dispersion (SD) for dissolution enhancement of poorly water-soluble drugs. SDs with different blends of hydrophilic-hydrophobic polymers (zein/hydroxypropyl methylcellulose – zein/HPMC) were prepared using spray drying to modulate the drug crystal and polymer-drug interactions in SDs. Physicochemical characterizations, including power X-ray diffraction and Fourier transform infrared spectroscopy, were performed to elucidate the roles of the blends in SDs. Although hydrophobic polymers played a key role in changing the model drug from a crystal to an amorphous state, the dissolution rate was limited due to the wetting property. Fortunately, the hydrophilic-hydrophobic blend not only reduced the drug crystallinity but also resulted in a hydrogen bonding interaction between the drugs and the polymer for a dissolution rate improvement. This work may contribute to a new generation of solid dispersion using a blend of hydrophilic-hydrophobic polymers for an effective dissolution enhancement of poorly water-soluble drugs.

Introduction

Oral administration has been as an effective route in drug delivery systems due to its convenience and flexibility in dosage form design and patient compliance (Ummadi et al., 2013). Oral drug delivery still has some major limitations, including poor bioavailability, which subsequently affect the therapeutic efficacy and safety of the dosage form (Pridgen et al., 2015). Solubility is one of the key factors influencing the bioavailability of drugs (Leuner and Dressman, 2000, Tran et al., 2013) and is associated with an overwhelming number of challenges in drug development. Most of the new drug development have resulted from poor water solubility (Bosselmann and Williams III, 2012; Kalepu and Nekkanti, 2015). Currently, it is estimated that approximately 40% of new drugs from new chemical substances show limited solubility in water (Ha et al., 2011, Kumar and Singh, 2013). Therefore, improving the solubilization of poorly water-soluble drug has been considered a crucial challenge in modern pharmaceutical science. Solid dispersion (SD) is a promising method that provides various advantages over other strategies in solubility enhancement of low aqueous soluble drugs (Dalvi et al., 2015, Tran et al., 2011). Vasconcelos et al. defined SD as dispersing poorly water-soluble drugs into a hydrophilic matrix (Vasconcelos et al., 2007). Moreover, SD is widely used as a powerful technique to markedly enhance solubility and increase the dissolution rate of poorly water-soluble drugs due to drug particle size reduction, wettability improvement, higher porosity and amorphous formations of the drug (Vasconcelos et al., 2007). In preparation of SDs, hydrophilic polymers obviously play an important role in establishing a delayed barrier to avoid recrystallization of drugs (Yonemochi et al., 2013). Despite a wide range of applications of hydrophilic polymers in SD, hydrophilic polymers could not always change drug crystals to amorphous forms and therefore, they need a modification process for improving the dissolution rate of poorly water-soluble drugs (Nguyen et al., 2015, Nguyen et al., 2016). There have been studies of ternary solid dispersion using hydrophilic polymer blends to improve drug solubility (Al-Obaidi et al., 2011, Goddeeris et al., 2008, Janssens et al., 2008). Furthermore, although hydrophilic-hydrophobic polymer blends addressing crystal growth inhibition by the presence of hydrophobic polymer in hydrophilic synthetic polymer have been also investigated (Ilevbare et al., 2012, Liu et al., 2014, Marks et al., 2014), the studies focused on changes in drug structural behaviors rather than drug dissolution profiles (Li et al., 2013). Unlike those studies, in which the drug release occurred at a slow rate, we developed the SD system using a zein/HPMC blend for the current study and attempted to indicate that the presence of a suitable hydrophobic polymer in the SD could maximize the dissolution rate of a SD containing a poorly water-soluble drug.

Hydroxypropyl methylcellulose (HPMC) is firmly recognized as a safe agent with non-toxic, non-irritation properties and has been applied in a variety of dosage forms (Huichao et al., 2014). HPMC is widely employed as a hydrophilic matrix material with different levels of viscosity depending on the composition of methoxyl and hydroxypropyl in the structure. On the other hand, zein (a natural biopolymer that is poorly soluble at pH < 11) was selected as a hydrophobic polymer (Paliwal and Palakurthi, 2014). Isradipine (IDP) was used as the model drug in this study. IDP belongs to Biopharmaceutical Classification System (BCS) II that possesses low oral bioavailability (17–28%) and poor solubility (<10 mg/l) (Christensen et al., 2000).