Susanne Page

Atomic Force Microscopy-Based Screening of Drug-Excipient Miscibility and Stability of Solid Dispersions

ABSTRACTPurposeDevelopment 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.

Rapid Assessment of Homogeneity and Stability of Amorphous Solid Dispersions by Atomic Force Microscopy—From Bench to Batch

ABSTRACTPurposeTo 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.

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.

Structured Development Approach for Amorphous Systems

A structured development approach is presented to guide the development of stable and commercially viable polymer based amorphous formulations. The proposed approach should not only enable the delivery of poorly soluble drugs but also help to reduce the API needs, reduce in vivo screening, minimize risks for late-stage development, and should ensure consistent quality. During initial assessment, a guided evaluation of the physicochemical properties of the API helps to assess the degree of difficulty for the development. A range of tests including in silico evaluation, high-throughput screening assays, and miniaturized screening tools provide a road map for selecting the appropriate polymer, drug loading, and suitable manufacturing process. A dedicated section provides a review of the characterization tools to assess and quantify the crystallinity, understanding the phase behavior of amorphous solid dispersions, and designing the in vitro dissolution methods. Finally, a reference chart is provided that summarizes the key concepts proposed as part of the structured development approach that can serve as a blueprint for the development of amorphous formulations. The current authors would like to thank and acknowledge the significant contribution of the previous authors of this chapter from the first edition. This current second edition chapter is a revision and update of the original authors’ work.

Influence of process parameters and equipment on dry foam formulation properties using indomethacin as model drug.

Dry foam technology was developed to overcome insufficient oral bioavailability of poorly soluble and wettable active pharmaceutical ingredients (APIs). It is intended to enable a faster and more efficient dissolution by avoiding API agglomeration and floating of non-wetted API particles. The aim of this study was to investigate the influence of process parameters, such as paste water content and type of equipment used on dry foam morphology, granule characteristics and dissolution behavior of the corresponding tablets using indomethacin as model compound. Multiple analytical methods, namely scanning electron microscopy, X-ray micro-computed tomography and mercury porosimetry, specific surface area analysis and sieve analysis were employed. Dissolution of dry foam formulation tablets was compared to a reference formulation in biorelevant media. Process parameters proved to have a distinct influence on dry foam morphology and granule characteristics, correlations between paste viscosity and pore size distribution could be observed. Dissolution behavior of indomethacin was improved by dry foam technology compared to the reference formulation. Variation of process parameters within the studied ranges did not alter the characteristics of the dry foam formulation dissolution behavior. Therefore, dry foam technology seems a promising future technology with the option of continuous manufacturing.

Impact of fillers on dissolution kinetic of fenofibrate dry foams.

Abstract Dry foam technology reveals the opportunity to improve the dissolution behavior of poorly soluble drugs tending to agglomeration due to micronization. In this study, the impact of fillers on the manufacturability, the properties of dry foams and granules as well as the dissolution kinetics of dry foam tablets was investigated using fenofibrate as a model compound. Different maltodextrins and dried glucose syrups, a maltodextrin–phosphatidylcholine complex, isomalt and a 1:1 mixture of mannitol/glucose syrup were used as filler. Within the group of maltodextrins and glucose syrups, the influences of dextrose equivalent (DE), particle morphology and botanical source of starch were investigated. Comparable macroscopic foam structures were obtained with maltodextrins and glucose syrups whereas different foam morphologies were obtained for the other fillers tested. Regarding the maltodextrins and glucose syrups, different physicochemical and particle properties had a minor impact on granule characteristics and tablet dissolution. Using the maltodextrin–phosphatidylcholine complex resulted in a low specific surface area of the granules and a slow tablet dissolution caused by a slow disintegration. In contrast, a high specific surface area and a fast release were obtained with isomalt and glucose syrup/mannitol mixture indicating that high soluble low molecular weight fillers enable the development of fast dissolving dry foam tablets.

Downstream Processing Considerations

Successful development of a drug product containing the drug in the amorphous form would not be feasible without a deeper understanding of all parameters having an influence on the critical quality attributes of the final dosage form. For amorphous systems in particular, the desired degree of supersaturation and the physical and chemical stability need to be ensured when formulating the amorphous solid dispersion. Based on the quality target product profile (QTPP), several aspects need to be taken into consideration, such as the desired release profile of the drug and the size of capsule or tablet acceptable from a patient’s perspective.

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.