PurposeDevelopment of a method to assess the drug/polymer miscibility and stability of solid dispersions using a melt-based mixing method.MethodsAmorphous 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.ResultsCombinations 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.ConclusionsThe 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.Electronic Supplementary MaterialThe online version of this article (doi:10.1007/s11095-010-0306-4) contains supplementary material, which is available to authorized users.

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PurposeTo verify the robustness and fundamental value of Atomic Force Microscopy (AFM) and AFM-based assays to rapidly examine the molecular homogeneity and physical stability of amorphous solid dispersions on Hot-Melt-Extrudates.MethodsAmorphous solid dispersions were prepared with a Hot-Melt Extruder (HME) and profiled by Raman Microscopy and AFM following a sequential analytical routine (Multi-Scale-Imaging-of-Miscibiliy (MIMix)). Extrudates were analyzed before and after incubation at elevated temperature and humidity. The data were compared with published results as collected on miniaturized melt models. The value of molecular phase separation rates for long term stability prediction was assessed.ResultsData recorded on the extrudates are consistent with those published, and they can be compared side by side. Such direct data comparisons allow the identification of possible sources of extrudate heterogeneities. The surface roughness analysis of fracture-exposed interfaces is a novel quantitative way to trace on the nanometer scale the efficiencies of differently conducted HME-processes. Molecular phase separation rates are shown to be relevant for long term stability predictions.ConclusionsThe AFM-based assessment of API:excipient combinations is a robust method to rapidly identify miscible and stable solid dispersions in a routine manner. It provides a novel analytical tool for the optimization of HME processes.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-013-1045-0) contains supplementary material, which is available to authorized users.

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Older adults represent the major target population for oral medications, due to the high prevalence of multimorbidity. To allow for successful pharmacological treatments, patients need to adhere to their medication and, thus, patient-centric drug products with a high level of acceptability by the end users are needed. However, knowledge on the appropriate size and shape of solid oral dosage forms, as the most commonly used dosage forms in older adults, is still scarce. A randomized intervention study was performed including 52 older adults (65 to 94 years) and 52 young adults (19 to 36 years). Each participant swallowed four coated placebo tablets differing in weight (250 to 1000 mg) and shape (oval, round, oblong) in a blinded manner on three study days. The choice of tablet dimensions allowed for a systematic comparison between different tablet sizes of the same shape, as well as between different tablet shapes. Swallowability was assessed using a questionnaire-based method. All tested tablets were swallowed by ≥80% of adults, independent of age. However, only the 250 mg oval tablet was classified as well swallowable by ≥80% of old participants. The same was true for young participants; however, they also considered the 250 mg round and the 500 mg oval tablet as well swallowable. Furthermore, swallowability was seen to influence the willingness to take a tablet on a daily basis, especially for an intake over longer time periods.

The purpose of this study was to develop a model to predict (1) air and product temperatures, (2) product moisture, and (3) air humidity during an aqueous coating process using a Bohle Lab-Coater. Because of the geometrical properties and the airflow, the drum of the Bohle Lab-Coater can in principle be divided into 2 zones of equal size-the drying and the spraying zones. For each zone, 4 balance equations could be set up describing the change of the air humidity, the product moisture, the enthalpy of the air, and the enthalpy of the product in each zone. For this purpose, knowledge regarding heat and mass transfer and also the motion of the tablets in drums was used. Based on the considerations of the heat and mass transfer, a set of first-order coupled ordinary differential equations (ODEs) was developed. This set of ODEs can be solved numerically. In this part, the development of the model is described in detail, whereas the application of the model can be found in part 2.

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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.