King Saud University Riyadh, Ar Riyad, Saudi Arabia
Purpose: The concept of quality by design has recently been adopted in the pharmaceutical industry as it encompasses designing and optimizing formulations and manufacturing processes that ensures meeting predefined product specifications. Lornoxicam (LX), is a nonsteroidal anti-inflammatory drug (NSAID) of the oxicam class with analgesic, anti-inflammatory and antipyretic properties. LX differs from other oxicam compounds in its potent inhibition of prostaglandin biosynthesis. Formation of LX as dispersible tablet (DT) is expected to provide quick dissolution and rapid absorption, which may produce rapid onset of action with less gastric irritation. The aim of the present study is to design and optimize lornoxicam dispersible tablet (LXDT) formulation using the Quality by design approach. Methods: A randomized Box-Behnken experimental design was used to characterize the effect of the critical factors such as filler (MCC/ Mannitol) ratio (X1), Mixing time (X2), and disintegrant concentration (X3), on tablet properties. The tablets were assessed for their impacts on the critical quality attributes (responses) of DT including dispersibility time (Y1), friability (Y2), dissolution efficiency (Y3) and content uniformity (Y4). The drug-excipients interaction and morphology of the formulation were investigated using Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), Scanning Electron Microscopy (SEM). The optimized formula was subjected for taste masking and palatability enhancement. Stability studies were carried out for LXDT according to ICH guidelines at accelerated conditions (40°C ± 2°C/75% RH ± 5% RH) for 6 months. Results: FTIR revealed an absence of any significant chemical interaction in solid state. DSC thermogram of LX alone has an endothermic peak at 225 °C, but LX endothermic peak was slightly decreased due to dilution effect in case of the physical mixture. The statistical analysis revealed that the filler ratio (X1) and the disintegrant concentration (X3) has a significant negative effect on dispersibility time (P < 0.002 & P < 0.0001 respectively). All DT formulations exhibited acceptable friability, ranged from 0.2 to 0.9 %, represented a significant effect of the corresponding factors on tablet friability. The actual model R2, adjusted R2, and R2 predicted, for tablet friability (Y2) were 0.9119, 0.8879, and 0.8242, respectively. The dissolution efficiency (DE%) of LXDT formulations was ranged from 72.21 % to 93.63 %, respectively. The actual model R2, adjusted R2, and R2 predicted, for content uniformity (Y4) were 0.9586, 0.8841, and 0.4805, respectively. The most significant effect on the content uniformity among the studied variables suggested that the mixing time was inversely proportional to the content uniformity, whilst the filler ratio and disintegrant concentration were directly proportional to the content uniformity. The palatability test of optimized formulation was found acceptable in most of the volunteers (n=18). Accelerated stability studies showed the acceptable dispersabilty time, friability value less than 1%, and all tablets were non-sticky. LXDT content was reduced to 98٫05 ±1.03 and 95٫14 ±3.03 after storage for 3 and 6 months, respectively, with %DE60 values of 93.84 ±0.94 and 92.37 ±1.59 respectively. Conclusion: The overall results of LXDT formulations suggested less disintegration time, acceptable hardness and friability and showed better in vitro dissolution profiles as compared with commercial tablet (Xefo® 8 mg). The application of QbD approach in the formulation of LXDT can help formulators a detailed understanding of the effect of CMAs and CPPs on the CQAs of the final product.
