A quality-by-design study to develop Nifedipine nanosuspension: examining the relative impact of formulation variables, wet media milling process parameters and excipient variability on drug product quality attributes

Abstract

Wet milling is a multifunctional and the most common method to prepare a drug nanosuspension for improving the bioavailability of poorly water soluble drugs. A suitable way of preparing a high drug-loaded nifedipine nanosuspension using wet stirred media milling was investigated in the present study. Nifedipine, a poorly water soluble drug, was selected as a model drug to enhance its dissolution rate and oral bioavailability by preparing an appropriate crystalline nanosuspension. Process parameters, such as milling media volume, milling speed and milling time, were optimized using the one variable at a time (OVAT) approach. A similar method was used to select an appropriate polymeric stabilizer and a surfactant from different categories of polymeric stabilizers (HPC SL, HPC SSL Soluplus®, Kollidon VA 64 and HPMC E 15) and surfactants (Poloxamer 407, Kolliphor TPGS and Docusate sodium). A systematic optimization of critical formulation parameters (such as drug concentration, polymer concentration and surfactant concentration) was performed with the aid of the Box-Behnken design. Mean particle size, polydispersity index and zeta potential as critical quality attributes (CQAs) were selected in the design for the evaluation and optimization of the formulation and validation of the improved product. The nifedipine nanosuspension that was prepared using HPC and poloxamer 407 was found to be most stable with the lowest mean particle size as compared with the formulations prepared using other polymeric stabilizers and surfactants. The optimized formulation was further spray-dried and characterized using the Fourier Transform Infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), polarized light microscopy (PLM) and in-vitro dissolution study. Results have shown no interaction between the drug particles and stabilizers, nor a reduction in the crystallinity of drug, nor an increase in the saturation solubility and rapid in vitro dissolution as compared with pure nifedipine crystals. Thus, the current study supports the suitability of the wet stirred media milling method and a combination of HPC SSL and poloxamer 407 as stabilizers for the preparation of nifedipine nanosuspension.

Ternary Solid Dispersion Strategy for Solubility Enhancement of Poorly Soluble Drugs by Co-Milling Technique

“…In the case of the binary mixture (IB/βCD), the frequency shift of the carbonyl group of IB (Table 4) [29], could be attributed to the breaking of certain intermolecular bonds (hydrogen bonds) associated with IB dimmers, largely described in the literature [33]. The shift of the CO (primary alcohol) band and the OH (associated) band of βCD compared to physical mixtures, as well as the disappearance of the NMR proton of the carboxylic group of IB and the hydroxyls peaks of βCD (2,3,6) suggested the presence of hydrogen bonds between the carboxylic group of IB and hydroxyl groups of βCD [29]. DSC results ( Table 5) have shown that the ternary mixture (IB/βCD/PVP) exhibited higher glass transition temperature (Tg˃250°C).…”

“…The presence of these two carriers has increased the glass transition temperature of Indomethacin, the Tg of ternary system was higher than that of binary ground mixtures (IM-SiO 2 , Table 1. Some examples of drug molecules exhibiting solubility enhancement by binary solid dispersion using co-milling technique [1][2][3][4][5][6][7][8][9]. IM-Mg(OH) 2 ).…”

“…In recent years, solid dispersion technology by milling technique was largely utilized by researchers in order to enhance dissolution rate, bioavailability and thus therapeutic efficiency of several poorly water-soluble drugs ( Table 1), as it represents a simple, economic and environmental process without using solvents [1][2][3][4][5][6][7][8][9]. In fact, millings enable particle size reduction and promote the formation of drug nanoparticles, which enhance solubility, flow properties and content uniformities of pharmaceutical dosage forms [10].…”

Isoliquiritigenin Nanosuspension Enhances Cytostatic Effects in A549 Lung Cancer Cells

“…Both nanosuspensions prepared with stabilizer showed a surface charge of approximately − 20 mV, whereas a neutral charge was observed in ISL-MS. The negative surface charge of the nanosuspensions prepared with HPC SSL and PVP K30 as stabilizers has been reported in many studies [24][25]. The morphology of all samples were assessed by SEM and TEM, presented in ▶ Fig.…”

Design, Preparation, and Characterization of Dioscin Nanosuspensions and Evaluation of Their Protective Effect against Carbon Tetrachloride-Induced Acute Liver Injury in Mice

“…The advent of nanotechnology, which can produce nanoscale particles with novel functional properties, offers a potential solution to the aforementioned drawbacks. Nanotechnology has, for example, been used to enhance the bioavailability of certain antibiotics [14] and has also been applied to produce different targeted drugs for the treatment of different diseases [15–17], and various nanosuspensions have been successfully applied [18, 19]. Nanoparticles can also be prepared using a variety of different processes, including reverse solvent, homogenization pressure, milling, and the production of self-nanoemulsifying self-nanosuspensions [20].…”