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Publikation Multifractal characterization of pharmaceutical hot-melt extrudates(Springer, 2017) Adler, Camille; Kuentz, Martin; Teleki, AlexandraPurpose Multifractal geometry has become a powerful tool to describe complex structures in many fields. Our first aim was to combine imaging and multifractal analysis to better understand the microstructure of pharmaceutical extrudates. A second objective was to study erosion/dispersion behavior of the formulations because it would condition release of any drug. Methods Different formulations containing a lipid, a polymer and different silica based inorganic carriers were produced by hot-melt extrusion at various screw speeds. Multifractal analysis was based on scanning electron microscopy/energy dispersive X-Ray spectroscopy images. This microstructural analysis was complemented with dynamic optical imaging of formulation erosion/dispersion behavior. Results Multifractal analysis indicated that inorganic carrier type and concentration as well as the screw speed affected the microstructure of the extrudates. The aqueous erosion/dispersion study showed that only the type and concentration of inorganic carrier were important. Conclusions The use of microstructural and dispersion analysis appeared to be complementary to better characterize and understand complex formulations obtained by hot-melt extrusion.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Electron microscopy/energy dispersive X-ray spectroscopy of drug distribution in solid dispersions and interpretation by multifractal geometry(Elsevier, 2018) Abreu-Villela, Renata; Adler, Camille; Caraballo, Isidoro; Kuentz, MartinMuch contemporary research of poorly water-soluble drugs focuses on amorphous solid dispersions (SDs) for oral drug delivery. Recently, a multifractal formalism has been introduced to describe the distribution of an inorganic carrier in SDs. The present work attempts to directly image model drugs by means of scanning electron microscopy and energy dispersive X-ray spectroscopy. The compounds amlodipine, felodipine, glyburide, and indomethacine, which include halogens to enable sufficient scattering in energy dispersive X-ray spectroscopy, were employed to prepare SDs with hydroxypropyl methylcellulose acetate succinate (HPMCAS) by using a microwave method. Following chemical imaging, it was demonstrated that drug distribution was best described by multifractals, which was clearly superior to a monofractal assumption. The obtained fractal dimensions were influenced by drug loading and it was possible to detect microstructural changes upon addition of the plasticizer urea. Accordingly, the multifractal approach bears much potential to better explore the analytical results of chemical formulation imaging. Insights can be gained from the microstructural organization of SDs, which is interesting to further study formulation and process factors as well as physical stability.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Multifractal and mechanical analysis of amorphous solid dispersions(Elsevier, 2017) Adler, Camille; Kuentz, Martin; Teleki, AlexandraThe formulation of lipophilic and hydrophobic compounds is a challenge for the pharmaceutical industry and it requires the development of complex formulations. Our first aim was to investigate hot-melt extrudate microstructures by means of multifractal analysis using scanning electron microscopy imaging. Since the microstructure can affect solid dosage form performance such as mechanical properties, a second objective was to study the influence of the type of adsorbent and of the presence of an amorphous compound on extrudate hardness. β-Carotene (BC) was chosen as poorly water-soluble model compound. Formulations containing a polymer, a lipid and two different silica based inorganic carriers were produced by hot-melt extrusion. Based on scanning electron microscopy/energy dispersive X-ray spectroscopy, the obtained images were analyzed using multifractal formalism. The breaking force of the strands was assessed by a three point bending test. Multifractal analysis and three point bending results showed that the nature of interparticle interactions in the inorganic carrier as well as the presence of amorphous BC had an influence on the microstructure and thus on the mechanical performance. The use of multifractal analysis and the study of the mechanical properties were complementary to better characterize and understand complex formulations obtained by hot-melt extrusion.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Molecularly designed lipid microdomains for solid dispersions using a polymer/inorganic carrier matrix produced by hot-melt extrusion(Elsevier, 29.02.2016) Adler, Camille; Schönenberger, Monica; Teleki, Alexandra; Kuentz, MartinAmorphous solid dispersions have for many years been a focus in oral formulations, especially in combination with a hot-melt extrusion process. The present work targets a novel approach with a system based on a fatty acid, a polymer and an inorganic carrier. It was intended to adsorb the acidic lipid by specific molecular interactions onto the solid carrier to design disorder in the alkyl chains of the lipid. Such designed lipid microdomains (DLM) were created as a new microstructure to accommodate a compound in a solid dispersion. Vibrational spectroscopy, X-ray powder diffraction, atomic force microscopy as well as electron microscopic imaging were employed to study a system of stearic acid, hydroxypropylcellulose and aluminum magnesium silicate. β-carotene was used as a poorly water-soluble model substance that is difficult to formulate with conventional solid dispersion formulations. The results indicated that the targeted molecular excipient interactions indeed led to DLMs for specific compositions. The different methods provided complementary aspects and important insights into the created microstructure. The novel delivery system appeared to be especially promising for the formulation of oral compounds that exhibit both high crystal energy and lipophilicity.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Multifractal Characterization of Pharmaceutical Hot-Melt Extrudates(Springer, 2016) Adler, Camille; Kuentz, Martin; Teleki, AlexandraPURPOSE: Multifractal geometry has become a powerful tool to describe complex structures in many fields. Our first aim was to combine imaging and multifractal analysis to better understand the microstructure of pharmaceutical extrudates. A second objective was to study erosion/dispersion behavior of the formulations because it would condition release of any drug. METHODS: Different formulations containing a lipid, a polymer and different silica based inorganic carriers were produced by hot-melt extrusion at various screw speeds. Multifractal analysis was based on scanning electron microscopy/energy dispersive X-Ray spectroscopy images. This microstructural analysis was complemented with dynamic optical imaging of formulation erosion/dispersion behavior. RESULTS: Multifractal analysis indicated that inorganic carrier type and concentration as well as the screw speed affected the microstructure of the extrudates. The aqueous erosion/dispersion study showed that only the type and concentration of inorganic carrier were important. CONCLUSIONS: The use of microstructural and dispersion analysis appeared to be complementary to better characterize and understand complex formulations obtained by hot-melt extrusion.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation 06 - PräsentationPublikation Multifractal Analysis and Dispersion Imaging of Pharmaceutical Hot -Melt E xtrudates (Poster)(2016) Adler, Camille; Teleki, Alexandra; Kuentz, Martin06 - PräsentationPublikation A new polymer/lipid system for hot-melt extrusion by designing a microstructure on an inorganic carrier (Poster)(2016) Adler, Camille; Teleki, Alexandra; Kuentz, Martin; Schönenberger, Monica06 - PräsentationPublikation 06 - PräsentationPublikation Flow-through cross-polarized imaging as a new tool to overcome the analytical sensitivity challenges of a low-dose crystalline compound in a lipid matrix(Elsevier, 10.11.2015) Adler, Camille; Schönenberger, Monica; Teleki, Alexandra; Leuenberger, Bruno; Kuentz, MartinAssessing the physical state of a low-dose active compound in a solid lipid or polymer matrix is analytically challenging, especially if the matrix exhibits some crystallinity. The aim of this study was first to compare the ability of current methods to detect the presence of a crystalline model compound in lipid matrices. Subsequently, a new technique was introduced and evaluated because of sensitivity issues that were encountered with current methods. The new technique is a flow-through version of cross-polarized imaging in transmission mode. The tested lipid-based solid dispersions (SDs) consisted of β-carotene (BC) as a model compound, and of Gelucire 50/13 or Geleol mono- and diglycerides as lipid matrices. The solid dispersions were analyzed by (hyper) differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and microscopic techniques including atomic force microscopy (AFM). DSC and XRPD could analyze crystalline BC at concentrations as low as 3% (w/w) in the formulations. However, with microscopic techniques crystalline particles were detected at significantly lower concentrations of even 0.5% (w/w) BC. A flow-through cross-polarized imaging technique was introduced that combines the advantage of analyzing a larger sample size with high sensitivity of microscopy. Crystals were detected easily in samples containing even less than 0.2% (w/w) BC. Moreover, the new tool enabled approximation of the kinetic BC solubility in the crystalline lipid matrices. As a conclusion, the flow-through cross-polarized imaging technique has the potential to become an indispensable tool for characterizing low-dose crystalline compounds in a lipid or polymer matrix of solid dispersions.01A - Beitrag in wissenschaftlicher Zeitschrift