Influence of redox initiator component ratios on the emulsion copolymerisation of vinyl acetate and neodecanoic acid vinyl ester.

Redox initiated emulsion polymerisation of vinyl acetate and neodecanoic acid vinyl ester was investigated at temperatures ranging from -1 °C to 87 °C (initiation temperature between -1 °C and 60 °C), using varying molar ratios of the following redox components: l-ascorbic acid, tert-butyl hydroperoxide and ammonium iron(iii) sulfate dodecahydrate as a catalyst. The high flexibility of redox initiators enables product properties, as well as space-time-yield, to be adjusted as required. Polymers being products by process, it was presumed that modifying the conversion rate would lead to a different product. However, it was shown that the reaction rate is adjustable by varying the catalyst amount without changing the product properties, such as molecular weight, particle size, glass transition temperature and polymer structure, while reducing the overall process time by 40-86% (at equimolar ratios of reducing and oxidising agent). In contrast, variation of the tert-butyl hydroperoxide content resulted in changes of the molecular weight. The influence of the initiation temperature and of the redox system on the reaction rate was determined, enabling control over the reaction rate in the whole temperature range. Meanwhile, overall process times of approximately 2-240 min and high conversions of 90-99% could be achieved. Statistical modelling confirmed the results and facilitated predictions, enabling the conversion rate to be adjusted to the desired properties. The possibility of being able to adjust the conversion rate and product properties independently of each other creates additional degrees of freedom in process design.

Scale-up of Emulsion Polymerisation up to 100 L and with a Polymer Content of up to 67 wt%, Monitored by Photon Density Wave Spectroscopy.

The scale-up process of the high solid content (up to 67 wt%) emulsion polymerisation of vinyl acetate and Versa®10 from 1 L over 10 L to 100 L was investigated. An emulsion copolymerisation of vinyl acetate and neodecanoic acid vinyl ester in a molar ratio of 9:1 was carried out in a starved-fed semi-batch operation. As a radical source, a redox initiator system consisting of L-ascorbic acid, tert-butyl hydroperoxide and ammonium iron (III) sulphate was used. The process parameters, such as the required stirring speed and heat dissipation, were determined and adjusted beforehand via reaction calorimetry to ensure a successful scale-up without safety issues. In addition, the emulsion polymerisation was monitored inline by Raman (qualitative monomer accumulation), as well as Photon Density Wave spectroscopy (particle size and scattering coefficient) and temperature measurements. The data provided by Raman spectroscopy and temperature measurements revealed mixing difficulties due to an insufficient stirring rate, while the inline measurement with Photon Density Wave spectroscopy offered an insight into the development of the product properties. It proved to be reliable and precise throughout the entire scale-up process, especially compared to conventional offline methods, such as dynamic light scattering or sedimentation analysis by means of a disc centrifuge, both of which encountered issues when using higher polymer contents.

In-line monitoring of latex-particle size during emulsion polymerizations with a high polymer content of more than 60.

The photon density wave (PDW) spectroscopy is established in the fields of biochemistry and food chemistry as an online analytical method for the determination of mean particle sizes. This work examines PDW spectroscopy regarding its potential in high solid content emulsion polymerization. For this reason, emulsion copolymerization with a tendency for agglomeration of vinyl acetate and Versa® 10 in a molar ratio of 9 : 1, and with varying emulsifier content, was carried out in semi-batch operation mode with different target particle sizes from 50 to 325 nm. A redox initiator system, consisting of l-ascorbic acid, tert-butyl hydroperoxide and ammonium iron(iii) sulfate, was used as a radical source. The mean particle sizes of PDW spectroscopy were compared with those of conventional offline measurement methods, such as dynamic light scattering (DLS) and sedimentation analysis, by means of a disc centrifuge. The determined mean particle sizes show a very good reproducibility and agreement between DLS and sedimentation analysis up to a polymer content of 36%, after which measurements were rendered difficult due to agglomeration. Nevertheless, PDW spectroscopy was able to continue providing reproducible measurements until reaching a polymer content of 63%.

Formulating Amorphous Solid Dispersions: Impact of Inorganic Salts on Drug Release from Tablets Containing Itraconazole-HPMC Extrudate.

Amorphous solid dispersions (ASD) are increasingly used to improve the oral bioavailability of poorly water-soluble compounds. However, hydrophilic polymers in ASD have high water-binding properties and, upon water contact, they often form a gel on the surface of the tablet, impacting the rate and extent of drug release. Most inorganic salts decrease water solubility of organic solutes, changing the gel properties of hydrophilic polymers. In this study, the effect of inorganic salts on drug release from a tablet formulation containing an itraconazole (ITZ)-hydroxypropyl methyl cellulose (HPMC) extrudate was investigated. The cloud point of a 1% HPMC solution with and without inorganic salts (KCl, KH2PO4, KHCO3, and potassium iodate (KI)) was determined to classify the salts according to their salting-out or salting-in effect. A kosmotropic effect on HPMC was observed for KCl, KH2PO4, and KHCO3, whereas KI exhibited a chaotropic effect. To prove the effect of these salts on drug release, tablets containing 66% of ITZ-HPMC extrudate (20:80 w/w %), 4% croscarmellose sodium, 30% microcrystalline cellulose, and different types and amounts of KHCO3, KH2PO4, KCl, and KI were compressed (same solid fraction of 0.83-0.85). Tablets without salts showed a slow release and low peak concentrations during dissolution in simulated gastric fluids. By adding the kosmotropic salts to the tablets, the rate and extent of drug release were increased, whereas the chaotropic anion iodide had no effect. The effect was pronounced even with the addition of as little as 2% of inorganic salts and tended to increase with the increasing amount of salt in the formulation. Tablets without salt stored under either dry or humid conditions exhibited a large difference in dissolution profiles, whereas little variation was observed for tablets with kosmotropic salts. In conclusion, the effect of inorganic salts was mechanistically clarified on ASD containing commonly used HPMC. This approach can be beneficial to successfully develop robust formulations containing ASD.

A Miniaturized Extruder to Prototype Amorphous Solid Dispersions: Selection of Plasticizers for Hot Melt Extrusion.

Hot-melt extrusion is an option to fabricate amorphous solid dispersions and to enhance oral bioavailability of poorly soluble compounds. The selection of suitable polymer carriers and processing aids determines the dissolution, homogeneity and stability performance of this solid dosage form. A miniaturized extrusion device (MinEx) was developed and Hypromellose acetate succinate type L (HPMCAS-L) based extrudates containing the model drugs neurokinin-1 (NK1) and cholesterylester transfer protein (CETP) were manufactured, plasticizers were added and their impact on dissolution and solid-state properties were assessed. Similar mixtures were manufactured with a lab-scale extruder, for face to face comparison. The properties of MinEx extrudates widely translated to those manufactured with a lab-scale extruder. Plasticizers, Polyethyleneglycol 4000 (PEG4000) and Poloxamer 188, were homogenously distributed but decreased the storage stability of the extrudates. Stearic acid was found condensed in ultrathin nanoplatelets which did not impact the storage stability of the system. Depending on their distribution and physicochemical properties, plasticizers can modulate storage stability and dissolution performance of extrudates. MinEx is a valuable prototyping-screening method and enables rational selection of plasticizers in a time and material sparing manner. In eight out of eight cases the properties of the extrudates translated to products manufactured in lab-scale extrusion trials.

Virtual faces expressing emotions: an initial concomitant and construct validity study.

BACKGROUND: Facial expressions of emotions represent classic stimuli for the study of social cognition. Developing virtual dynamic facial expressions of emotions, however, would open-up possibilities, both for fundamental and clinical research. For instance, virtual faces allow real-time Human-Computer retroactions between physiological measures and the virtual agent. OBJECTIVES: The goal of this study was to initially assess concomitants and construct validity of a newly developed set of virtual faces expressing six fundamental emotions (happiness, surprise, anger, sadness, fear, and disgust). Recognition rates, facial electromyography (zygomatic major and corrugator supercilii muscles), and regional gaze fixation latencies (eyes and mouth regions) were compared in 41 adult volunteers (20 ♂, 21 ♀) during the presentation of video clips depicting real vs. virtual adults expressing emotions. RESULTS: Emotions expressed by each set of stimuli were similarly recognized, both by men and women. Accordingly, both sets of stimuli elicited similar activation of facial muscles and similar ocular fixation times in eye regions from man and woman participants. CONCLUSION: Further validation studies can be performed with these virtual faces among clinical populations known to present social cognition difficulties. Brain-Computer Interface studies with feedback-feedforward interactions based on facial emotion expressions can also be conducted with these stimuli.

Miniaturized screening of polymers for amorphous drug stabilization (SPADS): rapid assessment of solid dispersion systems.

PURPOSE: Development of a novel, rapid, miniaturized approach to identify amorphous solid dispersions with maximum supersaturation and solid state stability. METHOD: Three different miniaturized assays are combined in a 2-step decision process to assess the supersaturation potential and drug-polymer miscibility and stability of amorphous compositions. Step 1: SPADS dissolution assay. Drug dissolution is determined in 96-well plates to detect systems that generate and maintain supersaturation. Promising combinations graduate to step 2. Step 2: SPADS interaction and SPADS imaging assays. FTIR microspectroscopy is used to study intermolecular interactions. Atomic force microscopy is applied to analyze molecular homogeneity and stability. Based on the screening results, selected drug-polymer combinations were also prepared by spray-drying and characterized by classical dissolution tests and a 6-month physical stability study. RESULTS: From the 7 different polymers and 4 drug loads tested, EUDRAGIT E PO at a drug load of 20% performed best for the model drug CETP(2). The classical dissolution and stability tests confirmed the results from the miniaturized assays. CONCLUSION: The results demonstrate that the SPADS approach is a useful de-risking tool allowing the rapid, rational, time- and cost-effective identification of polymers and drug loads with appropriate dual function in supersaturation performance and amorphous drug stabilization.

Atomic force microscopy-based screening of drug-excipient miscibility and stability of solid dispersions.

PURPOSE: Development of a method to assess the drug/polymer miscibility and stability of solid dispersions using a melt-based mixing method. METHODS: Amorphous fractured films are prepared and characterized with Raman Microscopy in combination with Atomic Force Microscopy to discriminate between homogenously and heterogeneously mixed drug/polymer combinations. The homogenous combinations are analyzed further for physical stability under stress conditions, such as increased humidity or temperature. RESULTS: Combinations that have the potential to form a molecular disperse mixture are identified. Their potential to phase separate is determined through imaging at molecular length scales, which results in short observation time. De-mixing is quantified by phase separation analysis, and the drug/polymer combinations are ranked to identify the most stable combinations. CONCLUSIONS: The presented results demonstrate that drug/polymer miscibility and stability of solid dispersions, with many mechanistic details, can be analyzed with Atomic Force Microscopy. The assay allows to identify well-miscible and stable combinations within hours or a few days.