Investigating the Physical Stability of Amorphous Pharmaceutical Formulations

Amorphous formulations, including amorphous solid dispersions (ASDs), consisting of the active pharmaceutical ingredient (API) intimately mixed in a polymeric matrix, are an attractive formulation approach to improve drug delivery, dissolution, and solubility. However, an amorphous API in an ASD is in a higher energy state compared to the crystalline drug and results in most ASDs being inherently unstable. The polymer helps to stabilize the amorphous drug against crystallization such that the resulting homogenous mixture maintains its solubility advantage relative to the crystalline form. One challenge of ASDs is that the presence of impurities including crystals or residual solvent, variations in the ingredients, or changes in storage conditions can all affect physical stability and bioavailability. There is a clear need for advanced analytical techniques that can both detect, characterize, and quantify the components of amorphous formulations, especially ASDs. This research focuses on methods to detect and quantify crystallinity, ensure consistency between manufactured lots of amorphous formulations, and predict shelf life and drug substance properties. Poorly soluble model drug compounds such as nifedipine, indomethacin, and patiromer were studied using multiple analytical techniques including solid-state nuclear magnetic resonance (SSNMR) spectroscopy. First, SSNMR was used to develop a method to quantify the monomeric makeup of an insoluble polymeric API which can be used to demonstrate API sameness during generic drug development. Second, crystallinity was detected, quantified, and compared using a variety of analytical techniques with SSNMR and powder X-ray diffraction being used to predict drug-polymer solubility form the first time. Third, an extensive investigation into the effect of hydrogen bonding, drug loading, and storage temperature on crystallization tendency was conducted around the glass transition temperature (Tg) and found that hydrogen bonding plays a particularly important role in stability near Tg. Lastly, the impact of multiple absorbed solvents on the physicochemical properties of pharmaceutical polymers was investigated using dynamic vapor sorption. In conclusion, this research proposes new methods and new applications of existing analytical techniques for the advanced characterization of pharmaceutical amorphous formulations. The results provide an improved understanding of the factors affecting the physical stability of ASDs and should aid in their successful formulation

Dynamics on the Way to Forming Glass: Bubbles in Space-time

We review a theoretical perspective of the dynamics of glass forming liquids and the glass transition. It is a perspective we have developed with our collaborators during this decade. It is based upon the structure of trajectory space. This structure emerges from spatial correlations of dynamics that appear in disordered systems as they approach non-ergodic or jammed states. It is characterized in terms of dynamical heterogeneity, facilitation and excitation lines. These features are associated with a newly discovered class of non-equilibrium phase transitions. Equilibrium properties have little if anything to do with it. The broken symmetries of these transitions are obscure or absent in spatial structures, but they are vivid in space-time (i.e., trajectory space). In our view, the glass transition is an example of this class of transitions. The basic ideas and principles we review were originally developed through the analysis of idealized and abstract models. Nevertheless, the central ideas are easily illustrated with reference to molecular dynamics of more realistic atomistic models, and we use that illustrative approach here.Comment: 21 pages, 8 figures. Submitted to Annu. Rev. Phys. Che

LiSc(BH_4)_4 as a Hydrogen Storage Material: Multinuclear High-Resolution Solid-State NMR and First-Principles Density Functional Theory Studies

A lithium salt of anionic scandium tetraborohydride complex, LiSc(BH_4)_4, was studied both experimentally and theoretically as a potential hydrogen storage medium. Ball milling mixtures of LiBH_4 and ScCl_3 produced LiCl and a unique crystalline hydride, which has been unequivocally identified via multinuclear solid-state nuclear magnetic resonance (NMR) to be LiSc(BH_4)_4. Under the present reaction conditions, there was no evidence for the formation of binary Sc(BH_4)_3. These observations are in agreement with our first-principles calculations of the relative stabilities of these phases. A tetragonal structure in space group I (#82) is predicted to be the lowest energy state for LiSc(BH_4)_4, which does not correspond to structures obtained to date on the crystalline ternary borohydride phases made by ball milling. Perhaps reaction conditions are resulting in formation of other polymorphs, which should be investigated in future studies via neutron scattering on deuterides. Hydrogen desorption while heating these Li−Sc−B−H materials up to 400 °C yielded only amorphous phases (besides the virtually unchanged LiCl) that were determined by NMR to be primarily ScB_2 and [B_(12)H_(12)]^(−2) anion containing (e.g., Li_2B_(12)H_(12)) along with residual LiBH_4. Reaction of a desorbed LiSc(BH_4)_4 + 4LiCl mixture (from 4LiBH_4/ScCl_3 sample) with hydrogen gas at 70 bar resulted only in an increase in the contents of Li_2B_(12)H_(12) and LiBH_4. Full reversibility to reform the LiSc(BH_4)_4 was not found. Overall, the Li−Sc−B−H system is not a favorable candidate for hydrogen storage applications

The molecular organisation in starch based products : the influence of polyols used as a plasticisers

Ageing causes retrogradation or recrystallisation of starch, which leads to staling of food products and embrittlement of non-food starch products. Some plasticisers are known to reduce retrogradation, but it is not clear how. In chapter 1, an overview is given of the present knowledge of starch. In chapter 2, the analytical techniques and their applicabilities in starch research are presented. In chapter 3, retrogradation and sub-Tg physical ageing are described of gelatinised starch, as studied with infrared and NMR relaxation spectroscopy. The influence of processing temperature on initial crystallinity and subsequent recrystallisation (by X-ray diffraction) are described of compression moulded starch, plasticised by water and glycerol. In chapters 4-6, the interaction between starch and the plasticisers glycerol or ethylene glycol in the absence of water are described. In chapter 4, the interaction is described to cause a strong exothermal DSC transition. With solid state NMR spectroscopy, an immobilisation of the plasticisers and mobilisation of starch were observed. Upon storage at room temperature, the interaction also occurred, but faster for ethylene glycol than for glycerol, and glycerol interacted mainly with amorphous starch. Less plasticiser molecules interacted with more of their hydroxy groups than upon heating. In chapter 5, the interaction between dry amylopectin and ethylene glycol is described as studied by dielectric relaxation spectroscopy. Ethylene glycol was suggested to form intra-chain H-bonded bridges between the amylopectin chains, increasing chain stiffness and increasing the glass transition. Ethylene glycol was confined to nanometer sized droplets, as the dynamics changed from VFT towards Arrhenius behaviour. In chapter 6, the interaction was studied by Inverse Recovery Cross Polarisation NMR spectroscopy. At room temperature, the plasticiser mobility decreased and the amylopectin C6 mobility increased. The mobilities of the other amylopectin carbons did not change. The interaction mainly occurs at C6. Upon heating, the interaction develops fast, after which crystal perfection is assumed to take place. Crystal perfection is slower for glycerol than for ethylene glycol. In chapters 7 and 8, retrogradation is described of fully and partly gelatinised starch with several plasticisers. Due to partial gelatinisation, some granular structure remained, appearing as non-crystalline ghosts. These may act as nuclei for crystallisation. In chapter 7, systems are described with a range of plasticisers, increasing in size and number of hydroxy groups (ethylene glycol, glycerol, threitol, xylitol, glucose and for potato starch also maltose). The larger the number of OH groups, the better the plasticiser reduced the crystallisation inducing effect of ghosts in potato starch. Wheat starch recrystallised to a lesser extent (X-ray crystallinity indices of ~0.4 vs. ~0.5 for potato starch), probably because of the shorter amylopectin chains. Wheat starch did not show clear trends for the influence of plasticiser size and of ghosts. In chapter 8, retrogradation is described of wheat starch with a range of malto-oligosaccharides (maltose, maltotriose, maltotetraose, maltopentaose and maltohexaose). Malto-oligosaccharides substantially reduced retrogradation (crystallinity indices of ~0.2). No trend was found for the influence of ghosts. The finding that maltose reduced retrogradation substantially better than glucose (chapter 7), is of practical importance for starch based foods. Malto-oligosaccharides consisting of 6 or more glucose residues (6 residues are needed for helix formation) were proposed to increase retrogradation because of co-crystallisation. The smaller malto-oligosaccharides were assumed to reduce retrogradation by intruding between the starch chains

Crystal nucleation as the ordering of multiple order parameters

Nucleation is an activated process in which the system has to overcome a free energy barrier in order for a first-order phase transition between the metastable and the stable phases to take place. In the liquid-to-solid transition the process occurs between phases of different symmetry, and it is thus inherently a multi-dimensional process, in which all symmetries are broken at the transition. In this Focus Article, we consider some recent studies which highlight the multi-dimensional nature of the nucleation process. Even for a single-component system, the formation of solid crystals from the metastable melt involves fluctuations of two (or more) order parameters, often associated with the decoupling of positional and orientational symmetry breaking. In other words, we need at least two order parameters to describe the free-energy of a system including its liquid and crystalline states. This decoupling occurs naturally for asymmetric particles or directional interactions, focusing here on the case of water, but we will show that it also affects spherically symmetric interacting particles, such as the hard-sphere system. We will show how the treatment of nucleation as a multi-dimensional process has shed new light on the process of polymorph selection, on the effect of external fields on the nucleation process, and on glass-forming ability.Comment: 20 pages, 10 figure

Understanding the relaxation spectra of neat and mixed ionic liquids

Due to their unique properties, ionic liquids are promising candidates for various applications. The possibility to combine cations and anions almost arbitrarily leads to a virtually infinite number of different ionic liquids. The hope is that one could tailor an ionic liquid for a specific need in this way. However, to achieve a particular property, it would be essential to understand the ionic liquids on a microscopy level and not rely on trial and error. One crucial point is the dynamics of the ions, for example, concerning reaction media or electrolytes. However, the ion dynamics are quite complex due to the balanced interplay between Coulomb, hydrogen-bonding, and van der Waals interactions. Furthermore, in cases where cations are equipped with long, non-polar chains, it was found that nanosized aggregates form in neat ionic liquids. In this way, rotational and translational motions of cations and anions together with motions of aggregates possibly show up in the spectra of dynamical measurements. This has led to dynamic processes in the spectra being interpreted differently in the literature with respect to their microscopic origin. Therefore, this work aims to combine dielectric spectroscopy and depolarized light scattering to disentangle the rotational and translational contributions found in the relaxation spectra of ionic liquids. This is done for various neat ionic liquids, where the cations are equipped with non-polar chains of different lengths, thus varying the size ratio between cations and anions. Measurements are performed from far above room temperature down to the glass transition. In the case of dielectric spectroscopy, also pressures up to 550 MPa are applied. In this way, it could be shown that the dynamics of cations and anions separate in the case of a large size difference between the two ion species. Rotational motions of the cations are revealed to be the origin of a slow dielectric relaxation process, which was formerly often ascribed to motions of aggregates. It could be shown that such aggregates show up only in rare cases in the light scattering spectra at low frequencies, not accessible by dielectric spectroscopy. Furthermore, mixtures of an ionic liquid with water or 1-propanol are considered. The rotational contribution of the admixtures is discriminated from the ion dynamics and from signatures of hydrogen-bonding mediated orientational cross-correlations. Additionally, an ionic gel is prepared by mixing an ionic liquid with water and gelatin, and it is shown that the rotational and translational dynamics of the ions are hardly affected by the presence of the gelatin, although macroscopically, mechanical rigidity is introduced. More fundamental questions regarding the intensity of the scattered light and the shape of the rotational spectra, which have arisen during this work, are also addressed based on non-ionic systems

38th Rocky Mountain Conference on Analytical Chemistry

Final program, abstracts, and information about the 38th annual meeting of the Rocky Mountain Conference on Analytical Chemistry, co-sponsored by the Colorado Section of the American Chemical Society and the Rocky Mountain Section of the Society for Applied Spectroscopy. Held in Denver, Colorado, July 21-26, 1996

Synthesis, Relaxation Dynamics and Rheology of Supramolecular Polymers

A supramolecular polymer is a complex assembly of molecules held together by noncovalent bonds, such as hydrogen bonding, host-guest interactions or coordinative bonds. The last few decades great developments have been made in the research and application of supramolecular polymers, and a wide variety of supramolecular polymers have been prepared. These supramolecular polymers have been applied within many application areas, especially for medical applications such as drug or DNA delivery into living cells, and controlled drug release. However, many fundamental aspects such as the relaxation dynamics and rheological properties over a wide temperature range as well as the detailed structure-properties relationships are still not well understood for supramolecular polymers. This thesis addresses this, and aims at a better understanding of how the supramolecular interactions affect the structure, relaxation dynamics and rheological properties of different supramolecular polymer systems over a wide timescale or temperature range ranging from the glassy to the melt states. The goal is to determine the structure-property relationships, and to provide guidelines for the design and synthesis of new supramolecular polymers. In this thesis, the dynamics of four different supramolecular polymers are investigated. The first system is based on a comb-like polymeric backbone of poly(2-ethylhexyl acrylate) (PEHA) to which a random distribution of 2-ureido-4[1H]-pyrimidinone (UPy) supramolecular side-groups are added. A series of polymers with varying side-group UPy contents have been synthesised using the reversible addition fragmentation chain transfer (RAFT) polymerization. The second system is based on poly(propylene glycol) (PPG) for which the chain ends were functionalised using supramolecular hydrogen-bonding UPy-groups. The unfunctionalized PPG is a viscous liquid at room temperature whereas the end-functionalised UPyPPG is a rubbery material due to the formation of long extended chains formed through multiple hydrogen bonds. For this supramolecular polymer system, we have investigated two possible application areas: (i) the use of blends of PPG and UPyPPG with lithium salts in polymer electrolytes for Li-ion batteries and (ii) the use together with UV curable components for self-healing coatings. The third system is based on hydroxyl-capped polytetrahydrofuran (PTHF) with varying molecular weights and the fourth is a set of alkane diols of different chain-length. For both these systems, intermolecular supramolecular hydrogen bond interactions via the chain-ends will become more important for shorter chains. Generally, the relaxation dynamics, thermodynamic response and rheological response were determined using a range of experimental techniques, including broadband dielectric relaxation spectroscopy, differential scanning calorimetry (both in the standard and modulated mode), shear and extensional rheology and nuclear magnetic resonance relaxometry