(T1530-01-04) Design of Experiment Multi-level Categoric Design Model for Formulation Parameters’ Optimization of Raloxifene Hydrochloride Solid Dispersion Produced by Hot-Melt Extrusion

Purpose: It is known that RLH relative bioavailability is about 2% because of poor solubility and glucuronidation with metabolic enzymes. The present study develops Raloxifene Hydrochloride (RLH) amorphous solid dispersion (ASD) with polyvinylpyrrolidone (PVP) K30 by hot-melt extrusion (HME). Amorphization of RLH and conjugation with hydrophilic polymers are expected to enhance the drug solubility and accelerate its release. PVP K30 and surfactants included in the formulas are also known to inhibit the metabolism of RLH.

Methods: Design of experiment multi-level categoric model was employed to investigate the impact of different formulation variables on the drug release profiles, and to select the optimized formula. Two independent variables were fitted in the model; level of Polyethylene Oxide (PEO) N80, and type of surfactant with three and two levels respectively. Amount of drug released in 30, and 60 minutes (DR30, DR60) were the dependent variables (responses). PEO N80 was included as a copolymer to facilitate the extrusion process and reduce the torque level. Tween 80 and Cremophor RH 40 (C RH40) surfactants were added to enhance the solubility and inhibit RLH metabolism. PVP K30 was used due to its high solubilizing efficiency and high compatibility with the drug. Six different formulas were computed by the DOE software version 13 (Stat-ease, Inc., Minneapolis, MN, USA). The ingredients were extruded with 11 mm-twin screw extruder (11 mm Process 11™, Thermo Fisher Scientific, Waltham, MA, USA) at 165 °C and 150 rpm. The formulas were further characterized using Differential Scanning Calorimetry (TA DSC 25) with a heating rate of 10 °C/min from 25 °C to 300 °C, and powder X-ray diffraction >(Rikagu Miniflex II). Drug content uniformity was examined and dissolution study was performed on pure drug and samples of milled extrudates (equivalent to 60 mg RLF) using USP apparatus II, 1000 mL of 0.1% polysorbate 80 solution. RLH was quantified using Waters HPLC-UV system (Waters Corporation, Milford, MA, USA). An accelerated stability study in 40 °C for three months was performed to support the quality and robustness of the optimized formula.

Results: Formulas were extruded successfully as in (Table 1). DSC thermograms of the extrudates depicted the absence of RLH endothermic peak at 270 °C in all formulas. XRD of the extrudates confirmed the drug amorphization since the distinctive crystalline diffraction pattern was not visible. The average drug content of all formulas was 96.58% ± 3.97. Dissolution results are shown in Figure (1). The release data was fitted in the DOE model, and it was concluded from the surface plots that the amount of PEO significantly impacted DR 30. However, both independent variables had a significant impact on DR 60 as illustrated in Figure (2). The considerably slower drug release from formulas with PEO could be due to the formation of a gel layer that extend the time for the drug to diffuse into the dissolution media. Higher release rates from tween 80 than C RH40 could be a result of increased solubilization efficiency. SD2 was selected as the optimized formula and its stability was supported by consistent drug content and release data that was found to be significantly similar to the initial formulas as confirmed by f2 similarity factor.

Conclusion: The ASDs of RLH-PVP K30 exhibited a significant increase in the drug release profile. Enhanced bioavailability is expected to be a result of RLH amorphous nature, hydrophilic excipients, and metabolism inhibitors included.

References: Kim, A. R., Lim, S. J., & Lee, B. J. (2009). Metabolic inhibition and kinetics of raloxifene by pharmaceutical excipients in human liver microsomes. International Journal of Pharmaceutics, 368(1-2), 37-44.
Tran, T. H., Poudel, B. K., Marasini, N., Chi, S. C., Choi, H. G., Yong, C. S., & Kim, J. O. (2013). Preparation and evaluation of raloxifene-loaded solid dispersion nanoparticle by spray-drying technique without an organic solvent. International journal of pharmaceutics, 443(1-2), 50-57.

Table 1. Design of experiments for the investigated formulation

Figure 1. Dissolution release profiles of the pure drug and the six formulas

Figure 2. Surface plot for the effect of the independent variables on the % drug release in 60 minutes