Elsevier

Powder Technology

Volume 302, November 2016, Pages 396-405
Powder Technology

Design of experiment approach in development of febuxostat nanocrystal: Application of Soluplus® as stabilizer

https://doi.org/10.1016/j.powtec.2016.09.004Get rights and content

Highlights

  • Role of Soluplus® was explored as a stabilizer for nanocrystals

  • Systematic optimization of formulation using design of experiment

  • Significant improvement in solubility and bioavailability was achieved

  • Ball milling is an industrial applicable process and hence can be further scaled up

  • Smaller particle and size distribution compared to previously published literature

Abstract

The objective of present study was to explore the application of Soluplus® as a stabilizer for the preparation of febuxostat (FEB) nanocrystals using ball milling technique. Preliminary trials were performed for the selection of stabilizer from HPMC VLV, PVA, PVP K30, Poloxamer 188 and Soluplus®. Soluplus® stabilized FEB nanocrystals were found stable and had least particle size as compared to the batches prepared using other stabilizers. A systematic optimization of critical process parameters, stirring time and amount of bead, of ball milling process was performed with aid of central composite design. Particle size (D50 and D90) and the size distribution (SPAN) were taken as responses for the evaluation of design batches and were used as the criteria for selection of optimized batch. Optimized formulation was characterized using SEM, XRD and DSC, depicted conversion of crystalline FEB into amorphous form having 26.08 times (in pH 1.2) and 1.67 times (in pH 6.0) more saturation solubility. In vitro drug dissolution study showed 9 times faster drug release while in vivo pharmacokinetic study showed an increase in oral bioavailability, Cmax and AUC, of FEB nanocrystals as compared to FEB API. Thus, current study supports the suitability of Soluplus® as stabilizer for the preparation of FEB nanocrystals.

Introduction

The insurmountable advantages of oral drug delivery elucidate this route as lucrative and niche among the other routes of drug delivery. Instead of local/topical drug delivery (in ocular or skin diseases) where local drug action is required/to avoid systematic side effects of drugs, oral route still remains an entrenched route due to higher patient compliance [1], [2], [3]. However, there are some peculiar properties of the drug molecules, like-low solubility, first pass metabolism, unsuitability of drug in GIT environment etc., which intricate effective drug delivery through oral route. Among these properties, low solubility is the most common concern for newly developed drug molecules, due to higher molecular weight and lipophilicity, to improve efficacy which create hurdle in effective achievement of blood plasma concentration. This has provoked formulation scientists to develop an effective formulation for such drugs which help in improving their bioavailability [4], [5], [6].

The principle of size reduction in order to enhance solubility is a promising approach which can be expanded for poorly soluble drugs. Feasibility of size reduction for all types of drugs makes this process a universal process [7], [8], [9], [10]. The effect of particle size on solubility becomes more prominent below a critical size of 1–2 μm. Below this size range, saturation solubility of a drug increases with decrease in the particle size, thus resulting in an increased dissolution rate. This can be further explained by Noyes-Whitney equation-“rate of dissolution is directly proportional to the surface area of the drug particle while inversely proportional to the thickness of boundary layer near to the dissolution particle surface”. Thus, the particle size reduction results in increase in the surface area of the particle and decrease in thickness of the boundary layer, resulting in enhanced dissolution rate [4], [11].

With a view to overcome the problem of low solubility of drugs, nanocrystal concept was introduced way back in 1990 with the filing of first patent on this technology [12], [13]. In last two and half decades, there has been a paradigm shift in the technology for the production of drug nanocrystals. Newer technologies have shown successful production of nanocrystals with narrow particle size distribution and consistent quality. Ball milling is one of the most acceptable and cost effective technology, among the other technologies used for the production of drug nanocrystals. A number of nanocrystal based formulations are present in the market worldwide, which are developed using ball milling technique [7], [14].

Febuxostat (FEB) is a nonpurine selective inhibitor of xanthine oxidase which is used for the treatment of hyperuricemia in adults with gout. It is the first drug approved and marketed in United States after the approval of allopurinol in 1964 [15]. FEB is weakly acidic (pKa ~ 3.08) in nature and belongs to BCS class II. Due to its low aqueous solubility and vulnerability to enzymatic degradation, FEB shows low oral bioavailability. Also, the presence of food significantly decreases the Cmax (38–49%) and AUC (16–19%) of FEB as compared to unfed state [16]. Researchers have developed several formulations of FEB with improved solubility and dissolution, resulting in significant improvement of its oral bioavailability [17], [18], [19], [20], [21]. Nanocrystal based approach improves the solubility and dissolution of poorly soluble drugs and also eliminates the effect of presence of food on its bioavailability [22], [23], [24]. Thus, FEB was taken as model drug for this study.

Stabilizer is the key ingredient of nanosuspension which prevents aggregation of particles in the dispersion media. Stabilizers get adsorbed at the interface of the drug particle and dispersion media. Stabilizers can be classified as - polymeric (hydroxylpropyl methyl cellulose (HPMC), hydroxylpropyl cellulose (HPC), polyvinyl alcohol (PVA), polyvinyl pyrollidone/povidone (PVP)), ionic surfactants (sodium dodecyl sulfate (SDS)) and non-ionic surfactants (Poloxamers, Tween, Vitamin E polyethylene glycol succinate (TPGS) [25]. Stabilizers provide stability to the nanocrystals majorly via two mechanisms- steric hindrance (polymeric and non-ionic stabilizers) and electrostatic repulsion (ionic stabilizers) [26].

Soluplus® is a graft copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol with excellent solubilizing properties for poorly soluble drugs (BCS class II and IV). Application of Soluplus® in solubility and dissolution enhancement was mainly explored in the form of solid solution prepared using extrusion method and had shown favorable results [27], [28]. However, being a surfactant (amphiphilic) type of molecule, its application as stabilizer for nanocrystals was not explored much. Yang et al., investigated the stabilizing property of Soluplus® for the first time in the development of fenofibrate nanocrystals and found that the stabilizing property of Soluplus® was better as compared to HPMC [29].

In the present study, application of Soluplus® as stabilizer was explored for the development of FEB nanocrystals. Ball milling technique was used in the development of FEB nanocrystals. Formulation was systemically optimized using the concept of design of experiment (DOE). Optimized formulation was freeze dried and characterized for particle size analysis, saturation solubility study, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR) and in vitro dissolution study. In vivo bioavailability of the optimized formulation was also performed in animal model and was compared with the suspension of FEB API.

Section snippets

Materials

FEB was kindly donated by Zydus Cadila (Ahmedabad, India). Soluplus® and Poloxamer 188 were obtained as gratis sample from BASF (Mumbai, India). HPMC VLV (very low viscosity grade) and PVP K30 were gifted by Dow chemicals (Mumbai, India) and Ashland India Pvt. Ltd. (Mumbai, India) respectively. PVA was obtained as gift sample from Nippon Gohsei, Dusseldorf, Germany. Yttria coated zirconium oxide beads (0.5 mm) were obtained as gift sample from SYNCO Industries Limited, Jodhpur, Rajasthan, India.

Preliminary trials for selection of stabilizer

In all the batches of preliminary trials, various non-ionic polymeric stabilizers, HPMC VLV, PVA, PVP K30, Poloxamer 188 and Soluplus®, were used in the same concentration, while keeping all other parameters of ball milling process at constant value, to screen the best suited stabilizer for FEB nanocrystals. Results of particle size of various batches prepared using different stabilizers, shown in Fig. 1, were analyzed using a one-way ANOVA. Statistical difference in the particle sizes (D50 and

Conclusions

In this study, FEB nanocrystals were successfully prepared by ball milling technique using Soluplus® as stabilizer. Soluplus® exhibited better stabilization of FEB nanocrystals as compared to other polymeric stabilizers. Formulation was successfully optimized using CCD and was further characterized for solid phase characterization, in vitro drug release as well as in vivo bioavailability study. Results of DSC and XRD are showing reduction in crystallinity of FEB API after milling which resulted

Declaration of interest

The authors report no conflict of interest.

Acknowledgements

The authors would like to thank Dr. Santanu Ghosh, Director, Aculife Healthcare Private Limited, Sachana, Ahmedabad, Gujarat, for carrying out particle size analysis. Authors are thankful to Prof. Jigna Shah, Khushboo Faldu and Dhara Patel for their kind support in carrying out in vivo study. Authors are also thankful to Tejas Dadhaniya, Sr. Executive, Zydus Cadila Healthcare Ltd., Changodar, Gujarat for his aid in carrying out bioanalytical study.

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