The potential implications of these findings when applied to a non-ambient processing method such as Hot Melt Extrusion (HME) are also discussed.

The formulation of BCS Class II drugs as amorphous solid dispersions has been shown to provide advantages with respect to improving the aqueous solubility of these compounds. While hot melt extrusion (HME) and spray drying (SD) are among the most common methods for the production of amorphous solid dispersions (ASDs), the high temperatures often required for HME can restrict the processing of thermally labile drugs, while the use of toxic organic solvents during SD can impact on end-product toxicity. In this study, we investigated the potential of supercritical fluid impregnation (SFI) using carbon dioxide as an alternative process for ASD production of a model poorly water-soluble drug, indomethacin (INM). In doing so, we produced ASDs without the use of organic solvents and at temperatures considerably lower than those required for HME. Previous studies have concentrated on the characterization of ASDs produced using HME or SFI but have not considered both processes together. Dispersions were manufactured using two different polymers, Soluplus and polyvinylpyrrolidone K15 using both SFI and HME and characterized for drug morphology, homogeneity, presence of drug-polymer interactions, glass transition temperature, amorphous stability of the drug within the formulation, and nonsink drug release to measure the ability of each formulation to create a supersaturated drug solution. Fully amorphous dispersions were successfully produced at 50% w/w drug loading using HME and 30% w/w drug loading using SFI. For both polymers, formulations containing 50% w/w INM, manufactured via SFI, contained the drug in the γ-crystalline form. Interestingly, there were lower levels of crystallinity in PVP dispersions relative to SOL. FTIR was used to probe for the presence of drug-polymer interactions within both polymer systems. For PVP systems, the nature of these interactions depended upon processing method; however, for Soluplus formulations this was not the case. The area under the dissolution curve (AUC) was used as a measure of the time during which a supersaturated concentration could be maintained, and for all systems, SFI formulations performed better than similar HME formulations.

Current experimental methodologies used to determine the thermodynamic solubility of an API within a polymer typically involves establishing the dissolution/melting end point of the crystalline API within a physical mixture or through the use of the glass transition temperature measurement of a demixed amorphous solid dispersion. The measurable "equilibrium" points for solubility are normally well above the glass transition temperature of the system, meaning extrapolation is required to predict the drug solubility at pharmaceutically relevant temperatures. In this manuscript, we argue that the presence of highly viscous polymers in these systems results in experimental data that exhibits an under or overestimated value relative to the true thermodynamic solubility. In previous work, we demonstrated the effects of experimental conditions and their impact on measured and predicted thermodynamic solubility points. In light of current understanding, we have developed a new method to limit error associated with viscosity effects for application in small-scale hot-melt extrusion (HME). In this study, HME was used to generate an intermediate (multiphase) system containing crystalline drug, amorphous drug/polymer-rich regions as well as drug that was molecularly dispersed in polymer. An extended annealing method was used together with high-speed differential scanning calorimetry to accurately determine the upper and lower boundaries of the thermodynamic solubility of a model drug-polymer system (felodipine and Soluplus). Compared to our previously published data, the current results confirmed our hypothesis that the prediction of the liquid-solid curve using dynamic determination of dissolution/melting end point of the crystalline API physical mixture presents an underestimation relative to the thermodynamic solubility point. With this proposed method, we were able to experimentally measure the upper and lower boundaries of the liquid-solid curve for the model system. The relationship between inverse temperature and drug-polymer solubility parameter (χ) remained linear at lower drug loadings. Significantly higher solubility and miscibility between the felodipine-Soluplus system were derived from the new χ values.

The Coxian phase-type distribution is a special type of Markov model which can be utilised both to uncover underlying stages of a survival process and to make inferences regarding the rates of flow of individuals through these latent stages before an event of interest occurs. Such models can be utilised, for example, to identify individuals who are likely to deteriorate faster through a series of disease states and thus require more aggressive medical intervention. Within this paper, a two-stage approach to the analysis of longitudinal and survival data is presented. In Stage 1, a linear mixed effects model is first used to represent how some longitudinal response of interest changes through time. Within this linear mixed effects model, the individuals' random effects can be considered as a proxy measure for the effect of the individuals' genetic profiles on the response of interest. In Stage 2, the Coxian phase-type distribution is employed to represent the survival process. The individuals' random effects, estimated in Stage 1, are incorporated as covariates within the Coxian phase-type distribution so as to evaluate their effect on the individuals' rates of flow through the system represented by the Coxian. The approach is illustrated using data collected on individuals suffering from chronic kidney disease, where focus is given to an emerging longitudinal biomarker of interest -an individual's haemoglobin level.

The ELSO Supplies Platform (Supplies.ELSO.org) was created out of Extracorporeal Membrane Oxygenation (ECMO) disposable product deficiency prior to and during the Coronavirus Disease 2019 (COVID-19) pandemic. This novel Platform supports Centers in obtaining disposables when alternative avenues are exhausted. Driven by the opportunity for increased patient care by using the product availability of the 962 ELSO centers worldwide was the motivation to form an efficient online supply sharing platform. The pandemic created by COVID-19, became a catalyst to further recognize the magnitude of the supply disruption on a global scale, impacting allocations and guidelines for institutions, practice, and patient care. Records kept on the platform website are helpful to industry by providing insights where difficulties exist in the supply chain for needed equipment. Yet, the common thread is awareness, how critical situations can stretch resources and challenge our resolve for best patient care. ELSO is proud to support member centers in these situations, by providing a means of attaining needed ECMO life support products to cover supply deficiencies.