Abstract. Atomic force microscopy (AFM) and modulated differential scanning calorimetry (mDSC) were used to evaluate the extent of mixing of a hot melt extrusion process for producing solid dispersions of copovidone and D-α-tocopherol polyethylene glycol 1000 succinate (TPGS 1000). In addition to composition, extrusion process parameters of screw speed and thermal quench rate were varied. The data indicated that for 10% TPGS and 300 rpm screw speed, the mixing was insufficient to yield a singlephase amorphous material. AFM images of the extrudate cross section for air-cooled material indicate round domains 200 to 700 nm in diameter without any observed alignment resulting from the extrusion whereas domains in extrudate subjected to chilled rolls were elliptical in shape with uniform orientation. Thermal analysis indicated that the domains were predominantly semi-crystalline TPGS. For 10% TPGS and 600 rpm screw speed, AFM and mDSC data were consistent with that of a single-phase amorphous material for both thermal quench rates examined. When the TPGS concentration was reduced to 5%, a single-phase amorphous material was achieved for all conditions even the slowest screw speed studied (150 rpm).

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Optical techniques for the particle size characterization of metered dose inhaler (MDI) suspensions have been developed as an alternative to the labor-intensive and time-consuming impaction method. In this study, a laser diffraction (LD) apparatus with a liquid cell ("wet cell" method) and a "time-of-flight" apparatus named aerodynamic particle sizer (APS) were utilized to assess MDI suspensions with varied formulation compositions and storage conditions. The results were compared with the conventional Anderson cascade impaction (ACI) data. The two optical methods were able to detect the changes in particle size distributions between formulations, yet to a lesser extent than those observed using the cascade impaction methodology. The median aerodynamic particle size measured by the APS method and the median geometric particle size obtained from the LD method were linearly correlated with the corresponding ACI results in the range of 2-5 µm. It was also found that the APS measurement was biased towards the finer particle size region and resulted in overestimated fine particle fraction (FPF) values which were 2-3 times folds of the ACI results. In conclusion, the optical particle sizing techniques may, under some circumstances, be viable techniques for the rapid assessment of MDI suspensions. The "wet cell" LD method, in particular, is found to be a valuable means of detecting active pharmaceutical ingredient (API) particle size changes in an MDI suspension. Using both the LD and the APS methods in early formulation screening followed by a final assessment with cascade impaction analysis can improve the efficiency of MDI formulation development.

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Cryogenic-Scanning Electron Microscopy (cryo-SEM) is a technique which unlike standard SEM, allows the imaging of samples in their hydrated state. This technique was used to image dense nanosuspensions. Standard SEM images were captured previously, however, were questionable in value, because the sample needed to be dried prior to measurement. There were concerns that the particles could be altered upon drying, especially in the presence of surfactant. By using the cryo-SEM technique, this drying step was eliminated and the particles were able to be viewed in situ. The nanosuspension particle morphology, imaged with a Hitachi SU 5000 scanning electron microscope equipped with a Quorum PP3010T cryo unit, correlated with particle size measurements obtained with an orthogonal Dynamic Light Scattering (DLS) technique. It was also previously shown for these nanosuspensions that rheological measurements correlated with median particle size as measured by DLS.The DLS measurements for one nanosuspension formulation exhibited a median particle size growth and a corresponding increase in viscosity during accelerated stability studies. Two theories were hypothesized as to the cause for this phenomenon: aggregation of particles or Ostwald ripening. With the availability of cryo-SEM images, aggregation was ruled out. It is suspected that the morphology and size differences between these batches, observed by SEM and DLS, resulted in an increased viscosity (Figure 1). In general, cryo-SEM was able to provide unique images that could not have been produced using traditional microscopy techniques, proving to be a useful tool for viewing nanoparticles in situ.