8 research outputs found
Apigenin Cocrystals: From Computational Prescreening to Physicochemical Property Characterization
Apigenin (4′,5,7-trihydroxyflavone, APG) has many
potential
therapeutic benefits; however, its poor aqueous solubility has limited
its clinical applications. In this work, a large scale cocrystal screening
has been conducted, aiming to discover potential APG cocrystals for
enhancement of its solubility and dissolution rate. In order to reduce
the number of the experimental screening tests, three computational
prescreening tools, i.e., molecular complementarity (MC), hydrogen
bond propensity (HBP), and hydrogen bond energy (HBE), were used to
provide an initial selection of 47 coformer candidates, leading to
the discovery of seven APG cocrystals. Among them, six APG cocrystal
structures have been determined by successful growth of single crystals,
i.e., apigenin–carbamazepine hydrate 1:1:1 cocrystal, apigenin–1,2-di(pyridin-4-yl)ethane
hydrate 1:1:1 cocrystal, apigenin–valerolactam 1:2 cocrystal,
apigenin-(dl) proline 1:2 cocrystal, apigenin-(d) proline/(l) proline 1:1 cocrystal. All of the APG cocrystals
showed improved dissolution performances with the potential to be
formulated into drug products
Crystal or Glass? Chemical and Crystallographic Factors in the Amorphization of Molecular Materials
The creation of long-lived
amorphous phases has potential applications
in numerous fields; for example, the instability of the amorphous
phase leads to higher solubility of pharmaceutical phases, often leading
to higher bioavailability. The rate of recrystallization of an amorphous
phase poses a significant limitation to the application of many such
phases; however, understanding the energetic and structural factors
that control the stability of molecular amorphous phases is limited
by empirical classifications based on thermal analysis used to identify
materials. From a set of molecularly related benzanilides, examples
of all three classes have been identified, allowing use of crystal
structural analysis, Raman spectroscopy, and energetic calculations
to determine the structural factors playing a role in the different
stabilities. While the behavior of most systems reflects the relative
energy of the crystalline phase to the amorphous phase, kinetic factors
based on whether a NH···OC hydrogen bond is
present in the crystalline phase play a key role in stabilizing the
amorphous phase as the loss of this bond reduces the conversion rate.
In contrast, systems without this bond display fast recrystallization
due to the greater structural similarity between the amorphous and
crystalline phases
Solution mediated phase transformations between co-crystals
A solution mediated transformation between two co-crystal phases has been observed for the p-5 toluensulfonamide/triphenylphosphine oxide co-crystal system. This system has two known co-crystals with 1:1 and 3:2 stoichiometry respectively, and the ternary phase diagram (TPD) for the system has been determined in acetonitrile previously. By manipulating the solution composition in this 10 solvent to a region of the TPD where the 1:1 co-crystal is stable, the 3:2 co-crystal could be observed to convert to the 1:1 co-crystal. The corresponding transformation was true for the 1:1 co-crystal in a region of the TPD where the 3:2 co-crystal is stable; the 1:1 co-crystal converted to the 3:2 co-15 crystal
Investigation into solid and solution properties of quinizarin
Polymorphism, crystal shape and solubility of 1,4-dihydroxyanthraquinone (quinizarin) have been investigated in acetic acid, acetone, acetonitrile, n-butanol and toluene. The solubility of FI and FII from 20 degrees C to 45 degrees C has been determined by a gravimetric method. By slow evaporation, pure FI was obtained from n-butanol and toluene, pure FII was obtained from acetone, while either a mixture of the two forms or pure FI was obtained from acetic acid and acetonitrile. Slurry conversion experiments have established an enantiotropic relationship between the two polymorphs and that the commercially available FI is actually a metastable polymorph of quinizarin under ambient conditions. However, in the absence of FII, FI is kinetically stable for many days over the temperature range and in the solvents investigated. FI and FII have been characterized by infrared spectroscopy (IR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), transmission and ordinary powder X-ray diffraction (PXRD) at different temperatures. The crystal structure of FII has been determined by single-crystal XRD. DSC and high-temperature PXRD have shown that both FI and FII will transform into a not previously reported hightemperature form (FIII) around 185 degrees C before this form melts at 200-202 degrees C. By indexing FIII PXRD data, a triclinic P (1) over bar cell was assigned to FIII. The solubility of quinizarin FI and FII in the pure organic solvents used in the present work is below 2.5% by weight and decreases in the order: toluene, acetone, acetic acid, acetonitrile and n-butanol. The crystal shapes obtained in different solvents range from thin rods to flat plates or very flat leaves, with no clear principal difference observed between FI and FII
Investigation of the solid-state polymorphic transformations of piracetam
The solid-state polymorphic transformations of 2-oxo-1-pyrrolidine acetamide (Piracetam) were investigated using a combination of off-line and on-line techniques; Differential Scanning Calorimetry (DSC), High Temperature X-ray Diffraction (HT-XRD), thermal analysis and Hot Stage Optical Microscopy. Form II and Form III were each observed to transform directly to Form I upon heating, with Form II transforming at a slightly lower temperature. The transformation of both polymorphs to Form I was observed to cause physical cracking of the crystals as well as changing the optical properties. Form I consistently transformed to Form II when cooled. The molecular rearrangements required for the transformation from Form I to Form II were found to be more energetically favourable than those required for the transformation to Form III. The
transformation from the metastable Form II to the stable Form III was not observed in the solid state, while the Form II – Form III transition temperature was found to be higher than the transition temperature of both polymorphs to Form I
Insight into the Mechanism of Formation of Channel Hydrates via Templating
Cocrystallization
of modafinil, <b>1</b>, and 1,4-diiodotetrafluorobenzene, <b>2</b>, in toluene leads to the formation of a metastable modafinil
channel hydrate containing an unusual hydrogen bonded dimer motif
involving the modafinil molecules that is not seen in anhydrous forms
of modafinil. Computational methodologies utilizing bias drift-free
differential evolution optimization have been developed and applied
to a series of molecular clusters and multicomponent crystals in the
modafinil/water and modafinil/water/additive systems for the additive
molecules <b>2</b> or toluene. These calculations show the channel
hydrate is less energetically stable than the anhydrous modafinil
but more stable than a cocrystal involving <b>1</b> and <b>2</b>. This provides theoretical evidence for the observed instability
of the channel hydrate. The mechanism for formation of the channel
hydrate is found to proceed via templating of the modafinil molecules
with the planar additive molecules, allowing the formation of the
unusual hydrogen-bonded modafinil dimer. It is envisaged that the
additive is then replaced by water molecules to form the channel hydrate.
The formation of the channel hydrate is more likely in the presence
of <b>2</b> compared to toluene due to the destabilizing effect
of the larger iodine molecules protruding into neighboring modafinil
clusters
Tuning Proton Disorder in 3,5-Dinitrobenzoic Acid Dimers: the Effect of Local Environment
The carboxylic acid dimer is a frequently observed intermolecular
association used in crystal engineering and design, which can show
proton disorder across its hydrogen bonds. Proton disorder in benzoic
acid dimers is a dynamic, temperature-dependent process whose reported
occurrence is still relatively rare. A combination of variable temperature
X-ray and neutron diffraction has been applied to demonstrate the
effect of local crystalline environment on both the degree and onset
of proton disorder in 3,5-dinitrobenzoic acid dimers. Dimers which
have significantly asymmetric local intermolecular interactions are
found to have a higher onset temperature for occupation of a second
hydrogen atom site to be observed, indicating a greater energy asymmetry
between the two configurations. Direct visualization of the electron
density of hydrogen atoms within these dimers using high resolution
X-ray diffraction data to characterize this disorder is shown to provide
remarkably good agreement with that derived from neutron data
Tuning Proton Disorder in 3,5-Dinitrobenzoic Acid Dimers: the Effect of Local Environment
The carboxylic acid dimer is a frequently observed intermolecular
association used in crystal engineering and design, which can show
proton disorder across its hydrogen bonds. Proton disorder in benzoic
acid dimers is a dynamic, temperature-dependent process whose reported
occurrence is still relatively rare. A combination of variable temperature
X-ray and neutron diffraction has been applied to demonstrate the
effect of local crystalline environment on both the degree and onset
of proton disorder in 3,5-dinitrobenzoic acid dimers. Dimers which
have significantly asymmetric local intermolecular interactions are
found to have a higher onset temperature for occupation of a second
hydrogen atom site to be observed, indicating a greater energy asymmetry
between the two configurations. Direct visualization of the electron
density of hydrogen atoms within these dimers using high resolution
X-ray diffraction data to characterize this disorder is shown to provide
remarkably good agreement with that derived from neutron data