Solubility Enhancement and Precipitation Inhibition of Poorly Water Soluble Compounds Utilizing Hot Melt Extrusion Technology

Soluplus® (SOL), a graft amorphous copolymer, composed of polyethylene glycol, vinyl acetate and vinylcaprolactam in a ratio of 13: 30: 57, was utilized to prepare solid dispersions containing felodipine (FEL) or ketoconazole (KTZ) using hot-melt extrusion technology. The melting point depression approach was utilized to determine the miscibility and solubility of the model compounds within Soluplus® , of which felodipine demonstrated higher solubility when compared to ketoconazole (14% vs 4.3% w/w) at room temperature (298K). Moreover, the solubility parameters of FEL, KTZ and SOL were calculated as 21.76, 26.51 and 21.64, respectively. Polarized light microscopy, Fourier transform infrared spectroscopy (FT-IR), Raman microscopy, differential scanning calorimetry (DSC), X-Ray diffraction (XRD), and scanning electron microscopy (SEM) were explored to characterize the FEL-SOL solid dispersions, and FEL was found to be molecularly dispersed in the matrix at a concentration of 10% w/w, which also demonstrated a higher solubility. A central composite design (CCD) was applied to optimize the processing parameters for KTZ-SOL solid dispersions and the final formulation containing 29.8% drug was extruded at a temperature of 140°C and screw speed of 31 rpm. The robustness of the design was also examined. A solid dispersion system of paclitaxel (PTX) was also developed to increase the aqueous solubility in order to overcome the side effects of its commercial products Taxol® , which was accomplished with the addition of a non-ionic surfactant, Cremophor® EL. PolyOx™ WSR N-80 (Molecular weight: 200,000 Da) was utilized as the matrix carrier, in which the concentration of PTX was determined as 30%. Various surfactants and solubilizers, including sodium lauryl sulfate (SLS), Lutrol® F68 (F68) and polyethylene glycol (PEG) 3350 were incorporated into the formulation. Of these, PEG 3350 was found to increase the solubility of PTX to 9.29 μg/ml (9-fold); however, the formulation started to precipitate after 2 hours due to the high energy amorphous state of PTX. 5% hydroxypropyl methylcellulose acetate succinate (HPMCAS-LF) successfully postponed the precipitation and maintained the solubility up to 12 hours by forming hydrogen bonds with PTX. This finding was confirmed by FT-IR analysis

Continuous Monitoring of A/B Tests without Pain: Optional Stopping in Bayesian Testing

A/B testing is one of the most successful applications of statistical theory in modern Internet age. One problem of Null Hypothesis Statistical Testing (NHST), the backbone of A/B testing methodology, is that experimenters are not allowed to continuously monitor the result and make decision in real time. Many people see this restriction as a setback against the trend in the technology toward real time data analytics. Recently, Bayesian Hypothesis Testing, which intuitively is more suitable for real time decision making, attracted growing interest as an alternative to NHST. While corrections of NHST for the continuous monitoring setting are well established in the existing literature and known in A/B testing community, the debate over the issue of whether continuous monitoring is a proper practice in Bayesian testing exists among both academic researchers and general practitioners. In this paper, we formally prove the validity of Bayesian testing with continuous monitoring when proper stopping rules are used, and illustrate the theoretical results with concrete simulation illustrations. We point out common bad practices where stopping rules are not proper and also compare our methodology to NHST corrections. General guidelines for researchers and practitioners are also provided