Crystalline mesophases: Structure, mobility, and pharmaceutical properties

Shalaev, Evgenyi; Ke, Wu; Shamblin, Sheri L.; Krzyzaniak, Joseph F.; Descamps, Marc

doi:10.1016/j.addr.2016.04.002

Cited by 47 publications

(37 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is expected that the IL state is more reactive than the LC state. [1,2] Subsequently, to identify the phase state and phase transition in these thermal processes, PXRD analysis was conducted ( Figure 3). For the PXRD profiles obtained at temperatures below the T m (AsP), numerous diffraction peaks from the anhydrous Cr phase were confirmed (Figure 3a, black).…”

Section: Resultsmentioning

confidence: 99%

“…The accurate understanding of the states of drug and excipient compounds is essential for rational pharmaceutical formulation. [1,2] For example, the material states kinetically produced under far-from-equilibrium conditions are known to effectively enhance the solubility and dissolution rate of poorly water-soluble drug compounds more than thermodynamically stable crystalline states or hydrate crystals. Despite the significance of ascorbic acid 6-palmitate (AsP; Figure 1), the basic understanding of its solids remains limited.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Thermal Behavior of Anhydrous Ascorbic Acid 6‐Palmitate with Trace of Decomposition

et al. 2020

View full text Add to dashboard Cite

Ascorbic acid 6‐palmitate (AsP) is an industrially utilized antioxidant and amphiphilic lipid, which forms a liquid crystalline (LC) phase. Herein, we describe the basic thermal behavior of AsP under anhydrous condition. Grazing‐incidence wide‐angle X‐ray‐diffraction (GI‐WAXD) measurements using a two‐dimensional detector (2D‐GI‐WAXD) and perpendicularly aligned AsP films, together with thermal analysis, showed that the AsP forms only a lamellar LC phase above its melting point (Tm); however, when the LC phase was cooled to facilitate annealing and recrystallization, crystals (Cr) formed with a low degree of crystallinity. Furthermore, a composite system, consisting of the Cr phase and LC phase of AsP, was obtained upon reheating. These anomalous phenomena were likely caused by trace dimerization and decomposition of AsP at a temperature just above Tm, although thermal decomposition accompanied by weight reduction occurred at a much higher temperature in the isotropic phase (IL). Thus, the basic thermal behavior of AsP, which is essential for its use, was unveiled.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Thermal Behavior of Anhydrous Ascorbic Acid 6‐Palmitate with Trace of Decomposition

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In the pharmaceutical industry, acetaminophen has a metastable form with significantly better tabletability than the globally stable form [33]. Disordered crystals like fenoprofem also have a number of promising uses for drug manufacturing due to their higher stability than amorphous crystals and their higher solubility/dissolution rates compared to crystalline structures [66,67]. Finally, the hydrogel 4,6-O-Benzylidene--D-galactosyl azide becomes stronger after a spontaneous temperature induced polymorphic transformation from the α to β form [35,68].…”

Section: Legal Controversy and Disappearing Polymorphsmentioning

confidence: 99%

“…In these plastic phases, the molecules have 3-dimensional translational order and rotational disorder around their crystallographic positions [67]. Each degenerate structure of these disordered crystals represents a stable lattice minima.…”

Section: Introductionmentioning

confidence: 99%

“…Molecules that form plastic crystals typically have a spherical or disk-like shape. Examples include caffeine [271], cyclopentane [100], ethanol [272], succinonitrile [209], methane [67], C60 [4], and alkali hydroxides [273]. These molecules at ambient temperature will maintain an average spatial position within the crytal lattice, but will freely rotate about one or more axes due to the near-symmetric nature of the electrostatic structure.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Capturing the Role of Temperature and Entropy in Crystal Polymorphs Through Molecular Simulations

Dybeck

View full text Add to dashboard Cite

AcknowledgementsI would like to acknowledge the guidance and support provided by my advisor MichaelShirts. I would also like to thank Levi Naden, Natalie Schieber, Nate Abraham and the entire Shirts group for their help and technical support during my research. I also would like to acknowledge the UVA high performance computing team for the computational resources necessary to complete this work. Finally, I would like to acknowledge the endless love and support that my friends and family provided me during this challenging Ph.D. journey.iii AbstractThe presence of multiple stable crystal structures in solid organic materials can limit their commercial viability when two or more observable polymorphs exhibit markedly different physical properties. Unintended restructuring events have hindered pharmaceutical solid form development in numerous therapeutic candidates and have led to costly market recalls.Conversely, intentional synthesis of a metastable form has led to significantly more favorable performance in numerous materials.Current computational methods for predicting polymorphic behavior evaluate candidate crystal structures based on the minimized lattice energy. However, these static lattice energybased approaches generate far more lattice energy minima than there are experimentally observed structures. Thermal motion of the crystals under working conditions has the potential to explain why many of these lattice minima are not observed experimentally. Lattice minima that are identified from a static crystal structure prediction can ultimately be unstable at experimental conditions through either temperature-mediated stability reranking, kinetic interconversion of multiple minima, or inaccuracies of the energy function in producing the real crystal ensemble.In this work, we explore the role of thermal motion in eliminating candidate crystal structures using fully atomistic molecular dynamics simulations. Enthalpically favorable structures with low entropy will become unfavorable at high temperatures through temperaturemediated stability reranking. Our simulations correctly identify the high temperature solid form as having a larger entropy than the low temperature form in twelve small molecule organic systems with known temperature-mediated transformations. The estimated entropy differences in the classical point-charge potential are significantly closer to experimental measurements than estimated enthalpy differences. This result suggests that entropy difference estimates are less sensitive to the complexity of the simulation potential than the corresponding enthalpy estimates. We additionally find that a cheaper harmonic approximation provides a sufficient estimate of entropic contributions in small rigid molecules. However, entropies with iv the harmonic approximation diverge from molecular dynamics-derived entropies in systems with multiple rotatable degrees of freedom or dynamically disordered crystalline structures.We additionally probe the sensitivity of the stability estimates to the energy function ...

show abstract