Original Research Paper
Utilizing spray drying technique to improve oral bioavailability of apigenin

https://doi.org/10.1016/j.apt.2018.04.002Get rights and content

Highlights

  • Apigenin suffer from low aqueous solubility and low overall bioavailability.

  • Solid dispersion techniques are strong tools to solve the solubility issues.

  • Spray drying technique was employed to improve the bioavailability of apigenin.

  • Spray dried apigenin showed significant improvement of around 5 folds for Cmax compared to pure apigenin.

Abstract

The aim of this study was to prepare, characterize, and evaluate apigenin in a solid dispersion system to improve the dissolution rate and bioavailability of such poorly soluble drug. Apigenin was dissolved in organic solvent with micelle forming polymer Pluronic F-127 (PL-F127). Solid dispersion of apigenin-PL F-127 was developed using spray drying technique. Physicochemical and in vitro characterization of the produced solid dispersion particles were conducted using scanning electron microscopy, differential scanning calorimetry, Fourier transform infrared spectroscopy, powder X-ray diffractometry and dissolution study. In addition, in vivo study was performed for the spray dried versus pure and marketed apigenin. Cmax was found to be around 5 folds higher for spray dried product compared to non spray dried materials. The prepared drug:polymer formulation showed elongated particles and complete lack of crystallinity at 1:4 ratio. The change in the vibrational wave numbers strongly suggested the formation of hydrogen bonding between apigenin and PL F-127. Significant increase in the dissolution rate and bioavailability of the spray dried apigenin showed the potential of solid dispersion system to overcome problem related to BCS II drugs.

Introduction

Apigenin is a bioflavonoid that is found in most fruits and vegetables (Fig. 1a) [1]. It is available, in nature, as a dimer that is mainly isolated form the flower of Hypericum perforalum [2]. Apigenin available commercially as light yellow crystals and has shown anti-inflammatory, anti-carcinogenic, antibiotic, anti-viral, antidiabetic, and anti-oxidant properties [3], [4], [5], [6]. There was much interest in carcinogenesis, which is the early development of cancer, and dietary management to interfere with such process, which is considered a cancer chemoprevention therapy [7], [8].

The clinical benefits of apigenin have drawn the attention of the pharmaceutical industry. However, apigenin belongs to biopharmaceutical classification system (BCS) class II, which features low solubility and high permeability. It is a weak acid with solubility of 1.43, 1.56, and 2.16 μg/mL in pH 1.0, 6.8, and 7.5, respectively [9]. Apigenin has major ionization step with pKa at C7-OH of 7.86 and reported aqueous solubility of <2 μg/mL [10], [11], [12]. Several factors affect apigenin solubility including; particle size, selected solvent, pH, and temperature [13]. Furthermore, low oral bioavailability in animal model was reported [14]. Thus, one needs to overcome different barriers for successful apigenin delivery.

Pluronic F-127 (PL F-127), which is known as poloxamer 407, is a synthetic amphiphilic copolymer of ethylene oxide and propylene oxide at ratio of (PEO101-PPO56-PEO101). Polypropylene oxide form the hydrophobic core, whereas, polyethylene oxide represent the hydrophilic component. Hydrogen bonding between the ether group of the polymer and water molecules is mainly responsible for the polymer aqueous solubility. PL F-127 form micelles when the critical micelle concentration is reached. At high poloxamer concentrations, micelles are closely packed leading to gel-like behavior [15], [16]. In previous studies, PL F-127 was used extensively to improve the wettability, overall solubility, and bioavailability of different active pharmaceutical ingredients (APIs) [17], [18], [19].

Different techniques are used to provide solid dispersion system. Selecting a suitable polymeric carrier is critical to resist the crystallization of already amorphous API. The thermodynamic solubility of any API in the selected polymer should not be exceed [20]. Dissolving both API and carrier in mutual organic solvent makes it possible to spray dry the formulation. Spray drying of poorly soluble drugs is common in the pharmaceutical arena. However, the stability of high energy amorphous state of any API still the outmost challenge [21]. Other factors should be carefully considered during spray drying such as; viscosity of the solution, volatility of the selected solvent, feeding rate, thermal stability, and toxicity of the residual solvent amount.

Apigenin was formulated as nanocrystal using supercritical fluid, self-microemulsifying drug delivery system, complexation with β-cyclodextrin, and apigenin-phospholipid phytosome to improve the in vitro/ in vivo characteristics [11], [22], [23], [24]. However, for the authors spray drying technique was not utilized for apigenin in the literature. Therefore, in this study, an apigenin-PL F1-27 solid dispersion prepared using spray drying technique was investigated for the morphology, chemical interactions, thermal stability, crystallinity state, in vitro release profile, and the bioavailability in animal model.

Section snippets

Materials

Apigenin (Fig. 1a) was obtained from Beijing Mesochem Technology Co., Ltd (Beijing, China). Poloxamer (F-127, PL F-127) (Fig. 1b) was obtained from BASF (Ludwigshafen, Germany). HPLC grade methyl alcohol (methanol) and ethyl alcohol (ethanol) were obtained from Sigma Aldrich (St. Louis, MO, USA).

Solid dispersion formation using spray drying

Apigenin with PL F-127 were prepared in drug:polymer mass ratios of 1:1, 1:2, and 1:4. Each drug with the polymer, at the selected mass ratio, was dissolved in 500 ml of ethanol. Continuous stirring was

Solid dispersion formation and apigenin content

We have investigated the solubility of apigenin in different solvents including water. The solubility for apigenin at 25 °C was found to be 0.02, 1.2, and 1.6 mg/g for water, methanol, and ethanol, respectively [12]. Water is an excellent solvent when used for spray drying due to its high surface tension. In addition, organic solvents, alone or as cosolvents, are commonly used due to the lack of sufficient solubility in the aqueous media for most of the drugs. When the solution is sprayed

Conclusion

This work reveals the importance of solid dispersion techniques to improve BCS II drugs. Apigenin lacks sufficient aqueous solubility and proves that dissolution is the rate-limiting step. Spray drying technique was employed successfully to render a complete amorphous form. The selection of appropriate drug:polymer ratio is crucial for successful amorphous formation. Formulated apigenin showed much faster dissolution rate compared to the pure apigenin. PL F-127 significantly improved the

Acknowledgements

The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for funding the research through research group project number RGP-1438-013.

References (47)

  • Z. Chen et al.

    Pharmacokinetic study of luteolin, apigenin, chrysoeriol and diosmetin after oral administration of Flos Chrysanthemi extract in rats

    Fitoterapia

    (2012)
  • S. Liu et al.

    Role of PPO–PEO–PPO triblock copolymers in phase transitions of a PEO–PPO–PEO triblock copolymer in aqueous solution

    Eur. Polym. J.

    (2015)
  • S. Wong et al.

    Enhancement of the dissolution rate and oral absorption of a poorly water soluble drug by formation of surfactant-containing microparticles

    Int. J. Pharmaceut.

    (2006)
  • A. Paudel et al.

    Manufacturing of solid dispersions of poorly water soluble drugs by spray drying: formulation and process considerations

    Int. J. Pharmaceut.

    (2013)
  • J. Zhang et al.

    Preparation of apigenin nanocrystals using supercritical antisolvent process for dissolution and bioavailability enhancement

    Eur. J. Pharm. Sci.

    (2013)
  • A.S. Zidan et al.

    Crystallinity evaluation of tacrolimus solid dispersions by chemometric analysis

    Int. J. Pharm.

    (2012)
  • S.K. Sathigari et al.

    Amorphous-state characterization of efavirenz–polymer hot-melt extrusion systems for dissolution enhancement

    J. Pharm. Sci.

    (2012)
  • A. Mackellar et al.

    The controlled crystallisation of a model powder: 1. The effects of altering the stirring rate and the supersaturation profile, and the incorporation of a surfactant (poloxamer 188)

    Int. J. Pharm.

    (1994)
  • D. Mahlin et al.

    Early drug development predictions of glass-forming ability and physical stability of drugs

    Eur. J. Pharm. Sci.

    (2013)
  • J.O. Eloy et al.

    Solid dispersions containing ursolic acid in Poloxamer 407 and PEG 6000: A comparative study of fusion and solvent methods

    Powder Technol.

    (2014)
  • L.-P. Ruan et al.

    Improving the solubility of ampelopsin by solid dispersions and inclusion complexes

    J. Pharm. Biomed. Anal.

    (2005)
  • H. Bley et al.

    Characterization and stability of solid dispersions based on PEG/polymer blends

    Int. J. Pharm.

    (2010)
  • W. Ali et al.

    Stochiometrically governed molecular interactions in drug: poloxamer solid dispersions

    Int. J. Pharm.

    (2010)
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