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Instruments / Technical Area	Publication Details	Published
I22-Small angle scattering & Diffraction	“Plurethosome” as vesicular system for cutaneous administration of mangiferin: Formulative study and 3D skin tissue evaluation Maddalena Sguizzato , Francesca Ferrara , Paolo Mariani , Alessia Pepe , Rita Cortesi , Nicolas Huang , Fanny Simelière , Paola Boldrini , Anna Baldisserotto , Giuseppe Valacchi , Elisabetta Esposito Pharmaceutics 13 DOI: 10.3390/pharmaceutics13081124 Diamond Proposal Number(s): [28022] Open Access Show Abstract ▼ Abstract: Human skin is dramatically exposed to toxic pollutants such as ozone. To counteract the skin disorders induced by the air pollution, natural antioxidants such as mangiferin could be employed. A formulative study for the development of vesicular systems for mangiferin based on phosphatidylcholine and the block copolymer pluronic is described. Plurethosomes were designed for mangiferin transdermal administration and compared to ethosome and transethosome. Particularly, the effect of vesicle composition was investigated on size distribution, inner and outer morphology by photon correlation spectroscopy, small angle X-ray diffraction, and transmission electron microscopy. The potential of selected formulations as vehicles for mangiferin was studied, evaluating encapsulation efficiency and in vitro diffusion parameters by Franz cells. The mangiferin antioxidant capacity was verified by the 2,2-diphenyl-1-picrylhydrazyl assay. Vesicle size spanned between 200 and 550 nm, being influenced by phosphatidylcholine concentration and by the presence of polysorbate or pluronic. The vesicle supramolecular structure was multilamellar in the case of ethosome or plurethosome and unilamellar in the case of transethosome. A linear diffusion of mangiferin in the case of ethosome and transethosomes and a biphasic profile in the case of plurethosomes indicated the capability of multilamellar vesicles to retain the drug more efficaciously than the unilamellar ones. The antioxidant and anti-inflammatory potential effect of mangiferin against pollutants was evaluated on 3D human skin models exposed to O3. The protective effect exerted by plurethosomes and transethosomes suggests their possible application to enhance the cutaneous antioxidant defense status.	Jul 2021
B23-Circular Dichroism	Interaction of a short peptide with G-quadruplex-forming sequences: An SRCD and CD study Claudia Honisch , Eugenio Ragazzi , Rohanah Hussain , John Brazier , Giuliano Siligardi , Paolo Ruzza Pharmaceutics 13 DOI: 10.3390/pharmaceutics13081104 Diamond Proposal Number(s): [21245] Open Access Show Abstract ▼ Abstract: G-quadruplex (G4) forming DNA sequences were recently found to play a crucial role in the regulation of genomic processes such as replication, transcription and translation, also related to serious diseases. Therefore, systems capable of controlling DNA and RNA G-quadruplex structures would be useful for the modulation of various cellular events. In particular, peptides represent good candidates for targeting G-quadruplex structures, since they are easily tailored to enhance their functionality. In this work, we analyzed, by circular dichroism and synchrotron radiation circular dichroism spectroscopies, the interaction of a 25-residue peptide deriving from RHAU helicases (Rhau25) with three G-quadruplex-forming oligonucleotide sequences, in both sodium- and potassium-containing buffers, the most relevant monovalent cations in physiological conditions. The peptide displayed greater affinity for the G4 sequences adopting a parallel structure. However, it showed the ability to also interact with antiparallel or hybrid G-quadruplex structures, inducing a conformation conversion to the parallel structure. The stability of the oligonucleotide structure alone or in presence of the Rhau25 peptide was studied by temperature melting and UV denaturation experiments, and the data showed that the interaction with the peptide stabilized the conformation of oligonucleotide sequences when subjected to stress conditions.	Jul 2021
I12-JEEP: Joint Engineering, Environmental and Processing	A simultaneous differential scanning calorimetry–X-ray diffraction study of olanzapine crystallization from amorphous solid dispersions Sean Askin , Andrea D. Gonçalves , Min Zhao , Gareth R. Williams , Simon Gaisford , Duncan Q. M. Craig Molecular Pharmaceutics DOI: 10.1021/acs.molpharmaceut.0c00846 Diamond Proposal Number(s): [17450] Show Abstract ▼ Abstract: Amorphous solid dispersions (ASDs) of class II and IV biopharmaceutics classification system drugs in water-miscible polymers are a well-recognized means of enhancing dissolution, while such dispersions in hydrophobic polymers form the basis of micro- and nanoparticulate technologies. However, drug recrystallization presents significant problems for product development, and the mechanisms and pathways involved are poorly understood. Here, we outline the use of combined differential scanning calorimetry (DSC)-synchrotron X-ray diffraction to monitor the sequential appearance of polymorphs of olanzapine (OLZ) when dispersed in a range of polymers. In a recent study (Cryst. Growth Des.2019,19, 2751–2757), we reported a new polymorph (form IV) of OLZ which crystallized from a spray-dried dispersion of OLZ in polyvinylpyrrolidone. Here, we extend our earlier study to explore OLZ dispersions in poly(lactide-co-glycolide) (PLGA), polylactide (PLA), and hydroxypropyl methyl cellulose acetate succinate (HPMCAS), with a view to identifying the sequence of form generation on heating each dispersion. While spray-dried OLZ results in the formation of crystalline form I, the spray-dried material with HPMCAS comprises an ASD, and forms I and IV are generated upon heating. PLGA and PLA result in a product which contains both amorphous OLZ and the dichloromethane solvate; upon heating, the amorphous material converts to forms I, II, and IV and the solvate to forms I and II. Our data show that it is possible to quantitatively assess not only the polymorph generation sequence but also the relative proportions as a function of temperature. Of particular note is that the sequence of form generation is significantly more complex than may be indicated by DSC data alone, with coincident generation of different polymorphs and complex interconversions as the material is heated. We argue that this may have implications not only for the mechanistic understanding of polymorph generation but also as an aid to identifying the range of polymorphic forms that may be produced by a single-drug molecule.	Oct 2020
B21-High Throughput SAXS	Design and characterization of ethosomes for transdermal delivery of caffeic acid Supandeep Singh Hallan , Maddalena Sguizzato , Paolo Mariani , Rita Cortesi , Nicolas Huang , Fanny Simelière , Nicola Marchetti , Markus Drechsler , Tautgirdas Ruzgas , Elisabetta Esposito Pharmaceutics 12 DOI: 10.3390/pharmaceutics12080740 Diamond Proposal Number(s): [21035] Open Access Show Abstract ▼ Abstract: The present investigation describes a formulative study aimed at designing ethosomes for caffeic acid transdermal administration. Since caffeic acid is characterized by antioxidant potential but also high instability, its encapsulation appears to be an interesting strategy. Ethosomes were produced by adding water into a phosphatidylcholine ethanol solution under magnetic stirring. Size distribution and morphology of ethosome were investigated by photon correlation spectroscopy, small-angle X-ray spectroscopy, and cryogenic transmission electron microscopy, while the entrapment capacity of caffeic acid was evaluated by high-performance liquid chromatography. Caffeic acid stability in ethosome was compared to the stability of the molecule in water, determined by mass spectrometry. Ethosome dispersion was thickened by poloxamer 407, obtaining an ethosomal gel that was characterized for rheological behavior and deformability. Caffeic acid diffusion kinetics were determined by Franz cells, while its penetration through skin, as well as its antioxidant activity, were evaluated using a porcine skin membrane–covered biosensor based on oxygen electrode. Ethosome mean diameter was ≈200 nm and almost stable within three months. The entrapment of caffeic acid in ethosome dramatically prolonged drug stability with respect to the aqueous solution, being 77% w/w in ethosome after six months, while in water, an almost complete degradation occurred within one month. The addition of poloxamer slightly modified vesicle structure and size, while it decreased the vesicle deformability. Caffeic acid diffusion coefficients from ethosome and ethosome gel were, respectively, 137- and 33-fold lower with respect to the aqueous solution. At last, the caffeic acid permeation and antioxidant power of ethosome were more intense with respect to the simple solution.	Aug 2020
I11-High Resolution Powder Diffraction	Elucidating an Amorphous Form Stabilization Mechanism for Tenapanor Hydrochloride: Crystal Structure Analysis using X-ray Diffraction, NMR Crystallography and Molecular Modelling Sten O. Nilsson Lill , Cory M. Widdifield , Anna Pettersen , Anna Svensk Ankarberg , Maria Lindkvist , Peter Aldred , Sandra Gracin , Norman Shankland , Kenneth Shankland , Staffan Schantz , Lyndon Emsley Molecular Pharmaceutics DOI: 10.1021/acs.molpharmaceut.7b01047 Diamond Proposal Number(s): [5018] Show Abstract ▼ Abstract: By the combined use of powder and single crystal X-ray diffraction, solid-state NMR, and molecular modelling, the crystal structures of two systems containing the unusually large tenapanor drug molecule have been determined: the free form, ANHY and a dihydrochloride salt form, 2HCl. Dynamic nuclear polarization (DNP) assisted solid-state NMR (SSNMR) crystallography investigations were found essential for the final assignment, and were used to validate the crystal structure of ANHY. From the structural informatics analysis of ANHY and 2HCl, conformational ring differences in one part of the molecule were observed which influences the relative orientation of a methyl group on a ring nitrogen and thereby impacts the crystallizability of the dihydrochloride salt. From quantum chemistry calculations, the dynamics between different ring conformations in tenapanor is predicted to be fast. Addition of HCl to tenapanor results in general in a mixture of protonat-ed ring conformers and hence a statistical mix of diastereoisomers which builds up the amorphous form, a-2HCl. This was qualitatively verified by 13C CP/MAS NMR investigations of the amorphous form. Thus, to form any significant amount of the crystalline material 2HCl, which originates from the minor (i.e., energetically less stable) ring conformations, one needs to involve nitrogen deprotonation to allow exchange between minor and major conformations of ANHY in solution. Thus, by controlling the solution pH value to well below the pKa of ANHY, the equilibrium between ANHY and 2HCl can be con-trolled and by this mechanism the crystallization of 2HCl can be avoided and the amorphous form of the dichloride salt can therefore be stabilized.	Feb 2018
I19-Small Molecule Single Crystal Diffraction	Sulfamerazine: Understanding the Influence of Slip Planes in the Polymorphic Phase Transformation through X-Ray Crystallographic Studies and ab Initio Lattice Dynamics Anuradha R. Pallipurath , Jonathan M. Skelton , Mark R. Warren , Naghmeh Kamali , Patrick Mcardle , Andrea Erxleben Molecular Pharmaceutics 12 (10), 3735 - 3748 DOI: 10.1021/acs.molpharmaceut.5b00504 PMID: 26317333 Show Abstract ▼ Abstract: Understanding the polymorphism exhibited by organic active-pharmaceutical ingredients (APIs), in particular the relationships between crystal structure and the thermodynamics of polymorph stability, is vital for the production of more stable drugs and better therapeutics, and for the economics of the pharmaceutical industry in general. In this article, we report a detailed study of the structure–property relationships among the polymorphs of the model API, Sulfamerazine. Detailed experimental characterization using synchrotron radiation is complemented by computational modeling of the lattice dynamics and mechanical properties, in order to study the origin of differences in millability and to investigate the thermodynamics of the phase equilibria. Good agreement is observed between the simulated phonon spectra and mid-infrared and Raman spectra. The presence of slip planes, which are found to give rise to low-frequency lattice vibrations, explains the higher millability of Form I compared to Form II. Energy/volume curves for the three polymorphs, together with the temperature dependence of the thermodynamic free energy computed from the phonon frequencies, explains why Form II converts to Form I at high temperature, whereas Form III is a rare polymorph that is difficult to isolate. The combined experimental and theoretical approach employed here should be generally applicable to the study of other systems that exhibit polymorphism.	Oct 2015
B23-Circular Dichroism	Application of circular dichroism and magnetic circular dichroism for assessing biopharmaceuticals formulations photo-stability and small ligands binding properties Edoardo Longo , Rohanah Hussain , Giuliano Siligardi International Journal Of Pharmaceutics 480, 84 - 91 DOI: 10.1016/j.ijpharm.2015.01.026 PMID: 25596417 Diamond Proposal Number(s): [7559, 8714, 9786, 10484] Open Access Show Abstract ▼ Abstract: Synchrotron radiation circular dichroism (SRCD) is a powerful tool for photo-stability assessment of proteins. Recently our research has been interested in applying SRCD to develop screening methodologies for accelerated photo-stability assessment of monoclonal antibody formulations. Despite it was proven to be reliable and applicable within a wide range of salts and excipients containing solutions, the presence of far-UV (<260 nm) strong absorbing species (e.g., sodium chloride, histidine, arginine) in common formulations completely prevent the analysis. Herein, we propose a new method based on CD coupled with magnetic CD (MCD) to address the problem and offer an additional versatile tool for monitoring the photo-stability. This is done by assessing the stability of the samples by looking at the near-UV band, as well as giving insights in the denaturation mechanism. We applied this method to four mAbs formulations and correlated the results with dynamic light scattering data. Finally, we applied MCD in ligand interaction to key proteins such as lysozyme, comparing the human with the hen enzyme in the binding of N,N′,N′′-triacetylchitotriose.	Mar 2015
B23-Circular Dichroism	The effect of palmitoylation on the conformation and physical stability of a model peptide hormone Edoardo Longo , Emiliana De Santis , Rohanah Hussain , Chris Van Der Walle , Jose Casas-finet , Shahid Uddin , Ana Dos Santos , Giuliano Siligardi International Journal Of Pharmaceutics 472, 156 - 164 DOI: 10.1016/j.ijpharm.2014.06.008 PMID: 24928136 Diamond Proposal Number(s): [7559, 8082] Show Abstract ▼ Abstract: Peptides are ideal drug candidates due to their potency and specificity, but suffer from a short half-life and low membrane permeability. Acylation can overcome these limitations but the consequences to stability under different formulation conditions and stresses are largely unreported. Using synchrotron radiation circular dichroism (SRCD), we show that palmitoylation of a 28 amino acid peptide hormone (pI 9.82) induced a structural transition from 310-helix to α-helix, irrespective of buffer type and pH investigated (5.5–8.0) when compared to the non acylated analogues. These conformational preferences were retained in the presence of non-ionic micelles but not anionic micelles, which induced an α-helical structure for all peptides. Palmitoylation promoted an irreversible peptide denaturation under thermal stress at pH ≥ 6.5 and increased the propensity for loss of helical structure under high photon flux (here used as a novel accelerated photostability test). The presence of either ionic or non-ionic micelles did not recover these conformational changes over the same irradiation period. These results demonstrate that acylation can change peptide conformation and decrease thermal-/photo-stability, with important consequences for drug-development strategies.	Sep 2014

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