Structure, morphology and dynamics of crown ether-based polyrotaxanes

Ph.D.H.W. Beckha

Solid-state NMR investigation of structure and dynamics of polyrotaxanes

M.S.H.W. Beckha

Using Supercritical Fluid Technology as a Green Alternative During the Preparation of Drug Delivery Systems

Micro- and nano-carrier formulations have been developed as drug delivery systems for active pharmaceutical ingredients (APIs) that suffer from poor physico-chemical, pharmacokinetic, and pharmacodynamic properties. Encapsulating the APIs in such systems can help improve their stability by protecting them from harsh conditions such as light, oxygen, temperature, pH, enzymes, and others. Consequently, the API’s dissolution rate and bioavailability are tremendously improved. Conventional techniques used in the production of these drug carrier formulations have several drawbacks, including thermal and chemical stability of the APIs, excessive use of organic solvents, high residual solvent levels, difficult particle size control and distributions, drug loading-related challenges, and time and energy consumption. This review illustrates how supercritical fluid (SCF) technologies can be superior in controlling the morphology of API particles and in the production of drug carriers due to SCF’s non-toxic, inert, economical, and environmentally friendly properties. The SCF’s advantages, benefits, and various preparation methods are discussed. Drug carrier formulations discussed in this review include microparticles, nanoparticles, polymeric membranes, aerogels, microporous foams, solid lipid nanoparticles, and liposomes

Determination of Fragility in Organic Small Molecular Glass Forming Liquids: Comparison of Calorimetric and Spectroscopic Data and Commentary on Pharmaceutical Importance

The fragility index (<i>m</i>) and conversely the strength parameter (<i>D</i>) are widely used to categorize glass forming liquids and are used to characterize temperature dependency of viscosity and relaxation time as the supercooled liquid approaches glass transition. The currently used calorimetric methods in pharmaceutical literature lead to wide variability in measured values of <i>m</i>. In this work, a modulated differential scanning calorimetry (DSC) method is introduced that can directly determine <i>m</i> with minimal variability. Although calorimetric fragility is easy to measure due to availability and ease of use of DSC, there is no correlation between calorimetric and dielectric fragility (calculated spectroscopically from relaxation times). In addition, there is also no correlation between calorimetric fragility and the so-called “thermodynamic fragility” that can be calculated using only thermodynamic parameters. No relationship can be found between the crystallization propensity in the supercooled liquid state and <i>D</i>. However, the crystallization propensity shows a reasonable correlation with the Kohlrausch distribution parameter β_k, which defines the breadth of the relaxation time distribution

J Pharm Sci

Active pharmaceutical ingredients (API) and excipients are often classified as 'brittle' or 'ductile' based on their yield pressure determined through the Heckel analysis. Such a brittle/ductile classification is often correlated to some measure of elasticity, die-wall stresses, and brittle fracture propensities from studies performed with a handful of model excipients. This subsequently gives rise to the presumption that all ductile materials behave similarly to microcrystalline cellulose (MCC) and that all brittle materials to lactose, mannitol, or dicalcium phosphate. Such a 'one-size-fits-all' approach can subsequently lead to inaccurate classification of APIs, which often behave very differently than these model excipients. This study compares the commonly reported mechanical metrics of two proprietary APIs and two classical model excipients. We demonstrate that materials classified as 'ductile' by Heckel's 'standards' may behave very differently than MCC and in some cases may even have a propensity for brittle failure. Our data highlight the complexity of APIs and the need to evaluate a set of mechanical metrics, instead of binary assignments of ductility or brittleness based on quantities that do not fully capture the tableting process, to truly optimize a tablet formulation as part of the overall target product profile

Resonant Acoustic Mixing (RAM) for Efficient Mechanoredox Catalysis without Grinding or Impact Media

Resonant acoustic mixing (RAM) enables mechanoredox catalysis with BaTiO3 as the piezoelectric catalyst on model diazonium coupling reactions. RAM proceeds without formal grinding or impact media, is faster than the analogous ball-milling strategy, and is readily scalable to gram-scale. Combined X-ray diffraction and spectroscopy indicate that reusability of BaTiO3 as a mechanoredox catalyst might be limited by unwanted boration

Simple, Scalable Mechanosynthesis of Metal-Organic Frameworks Using Liquid-Assisted Resonant Acoustic Mixing (LA-RAM)

We present a methodology for the rapid and readily scalable mechanosynthesis of diverse metal-organic frameworks (MOFs) in the absence of milling media, typically required for other types of mechanochemical syntheses. We demonstrate the use of liquid-assisted resonant acoustic mixing (LA-RAM) methodology for the synthesis of two- and three-dimensional MOFs based on Zn, Co(II) and Cu(II), including single- and mixed-ligand systems, imidazolate or carboxylate ligands. The LA-RAM approach also allowed the synthesis of the ZIF-L, a framework never previously obtained in a solventless environment, as well as its Co(II) analogue. Straightforward scale-up from milligrams to at least 25 grams is demonstrated using ZIF-L as the model.<br /

Direct mechanocatalysis using Resonant Acoustic Mixing (RAM)

We demonstrate the first example of direct mechanocatalysis by Resonant Acoustic Mixing (RAM), an emerging mechanochemical methodology that eliminates the need for bulk solvent and milling media. By using a simple copper coil as a catalyst, RAM enables the effective one-pot, 2-step synthesis of triazoles via a combination of benzyl azide formation and copper-catalyzed alkyne-azide click-coupling (CuAAC), on a wide scope of reagents, providing excellent control over reaction stoichiometry, and enabling a simple synthesis of the anticonvulsant drug Rufinamide