6 research outputs found
On the Hofmeister Effect: Fluctuations at the ProteināWater Interface and the Surface Tension
We performed molecular dynamics simulations
on the tryptophane-cage
miniprotein using a nonpolarizable force field, in order to model
the effect of concentrated water solutions of neutral salts on protein
conformation, which is a manifestation of Hofmeister effects. From
the equilibrium values and the fluctuations of the solvent accessible
surface area of the miniprotein, the salt-induced changes of the mean
value of proteināwater interfacial tension were determined.
At 300 K, the chaotropic ClO<sub>4</sub><sup>ā</sup> and NO<sub>3</sub><sup>ā</sup> decreased the interfacial tension according
to their position in the Hofmeister series (by approximately 5 and
2.7 mN/m, respectively), while the kosmotropic F<sup>ā</sup> increased it (by 1 mN/m). These values were compared to those obtained
from the Gibbs equation using the excess surface adsorption calculated
from the probability distribution of the water molecules and ions
around the miniprotein, and the two sets were found to be very close
to each other. Our results present a direct evidence for the central
role of interfacial tension and fluctuations at the proteināwater
interface in Hofmeister phenomena, and provide a computational method
for the determination of the proteināwater interfacial tension,
establishing a link between the phenomenological and microscopic description
of proteināwater interfaces
Electrospun Polymer Blend Nanofibers for Tunable Drug Delivery: The Role of Transformative Phase Separation on Controlling the Release Rate
Electrospun
fibrous materials have a wide range of biomedical applications,
many of them involving the use of polymers as matrices for incorporation
of therapeutic agents. The use of polymer blends improves the tuneability
of the physicochemical and mechanical properties of the drug loaded
fibers. This also benefits the development of controlled drug release
formulations, for which the release rate can be modified by altering
the ratio of the polymers in the blend. However, to realize these
benefits, a clear understanding of the phase behavior of the processed
polymer blend is essential. This study reports an in depth investigation
of the impact of the electrospinning process on the phase separation
of a model partially miscible polymer blend, PVP K90 and HPMCAS, in
comparison to other conventional solvent evaporation based processes
including film casting and spin coating. The nanoscale stretching
and ultrafast solvent removal of electrospinning lead to an enhanced
apparent miscibility between the polymers, with the same blends showing
micronscale phase separation when processed using film casting and
spin coating. Nanoscale phase separation in electrospun blend fibers
was confirmed in the dry state. Rapid, layered, macroscale phase separation
of the two polymers occurred during the wetting of the fibers. This
led to a biphasic drug release profile from the fibers, with a burst
release from PVP-rich phases and a slower, more continuous release
from HPMCAS-rich phases. It was noted that the model drug, paracetamol,
had more favorable partitioning into the PVP-rich phase, which is
likely to be a result of greater hydrogen bonding between PVP and
paracetamol. This led to higher drug contents in the PVP-rich phases
than the HPMCAS-rich phases. By alternating the proportions of the
PVP and HPMCAS, the drug release rate can be modulated
Mechanistic and Kinetic Insight into Spontaneous Cocrystallization of Isoniazid and Benzoic Acid
Solid-state
cocrystallization is of contemporary interest because
it offers an easy and efficient way to produce cocrystals, which are
recognized as prospective pharmaceutical materials. Research explaining
solid-state cocrystallization mechanisms is important but still too
scarce to give a broad understanding of factors governing and limiting
these reactions. Here we report an investigation of the mechanism
and kinetics of isoniazid cocrystallization with benzoic acid. This
reaction is spontaneous; however, its rate is greatly influenced by
environmental conditions (humidity and temperature) and pretreatment
(milling) of the sample. The acceleration of cocrystallization in
the presence of moisture is demonstrated by kinetic studies at elevated
humidity. The rate dependence on humidity stems from moisture facilitated
rearrangements on the surface of isoniazid crystallites, which lead
to cocrystallization in the presence of benzoic acid vapor. Furthermore,
premilling the mixture of the cocrystal ingredients eliminated the
induction time of the reaction and considerably increased its rate
Identification and Characterization of Stoichiometric and Nonstoichiometric Hydrate Forms of Paroxetine HCl: Reversible Changes in Crystal Dimensions as a Function of Water Absorption
Paroxetine hydrochloride (HCl) is an antidepressant drug,
reported to exist in the anhydrous form (form II) and as a stable
hemihydrate (form I). In this study, we investigate the hydration
behavior of paroxetine HCl form II with a view to understanding both
the nature of the interaction with water and the interchange between
forms II and I as a function of both temperature and water content.
In particular, we present new evidence for both the structure and
the interconversion process to be more complex than previously recognized.
A combination of characterization techniques was used, including thermal
(differential scanning calorimetry (DSC) and thermogravimetric analysis
(TGA)), spectroscopic (attenuated total reflectance Fourier transform
infrared spectroscopy (ATR-FTIR)), dynamic vapor sorption (DVS) and
X-ray powder diffraction (XRPD) with variable humidity, along with
computational molecular modeling of the crystal structures. The total
amount of water present in form II was surprisingly high (3.8% w/w,
0.8 mol of water/mol of drug), with conversion to the hemihydrate
noted on heating in hermetically sealed DSC pans. XRPD, supported
by ATR-FTIR and DVS, indicated changes in the unit cell dimensions
as a function of water content, with clear evidence for reversible
expansion and contraction as a function of relative humidity (RH).
Based on these data, we suggest that paroxetine HCl form II is not
an anhydrate but rather a nonstoichiometric hydrate. However, no continuous
channels are present and, according to molecular modeling simulation,
the water is moderately strongly bonded to the crystal, which is in
itself an uncommon feature when referring to nonstoichiometric hydrates.
Overall, therefore, we suggest that the anhydrous form of paroxetine
HCl is not only a nonstoichiometric hydrate but also one that shows
highly unusual characteristics in terms of gradual unit cell expansion
and contraction despite the absence of continuous channels. These
structural features in turn influence the tendency of this drug to
convert to the more stable hemihydrate. The study has implications
for the recognition and understanding of the behavior of pharmaceutical
nonstoichiometric hydrates
Utilizing SulfoxideĀ·Ā·Ā·Iodine Halogen Bonding for Cocrystallization
The propensity of a range of different sulfoxides and
sulfones
to cocrystallize with either 1,2- or 1,4-diiodotetrafluorobenzene,
via IĀ·Ā·Ā·O=S
halogen bonding, was investigated. Cocrystallization occurred exclusively
with 1,4-diiodotetrafluorobenzene in either a 1:1 or 1:2 stoichiometry
of the organohalide and the sulfoxide, respectively, depending on
the sulfoxide used. It was found that the stoichiometry observed was
not necessarily related to whether the oxygen acts as a single halogen
bond acceptor or if it is bifurcated; with IĀ·Ā·Ā·Ļ
interactions observed in two of the cocrystals synthesized. Only those
cocrystals with a 1:2 stoichiometry exhibit CāHĀ·Ā·Ā·O
hydrogen bonding in addition to IĀ·Ā·Ā·O=S halogen bonding.
Examination of the Cambridge Structural Database shows that (i) the
IĀ·Ā·Ā·O=S interaction is similar to other IĀ·Ā·Ā·O
interactions, and (ii) the IĀ·Ā·Ā·Ļ interaction
is significant, with the distances in the two cocrystals among the
shortest known
Utilizing SulfoxideĀ·Ā·Ā·Iodine Halogen Bonding for Cocrystallization
The propensity of a range of different sulfoxides and
sulfones
to cocrystallize with either 1,2- or 1,4-diiodotetrafluorobenzene,
via IĀ·Ā·Ā·O=S
halogen bonding, was investigated. Cocrystallization occurred exclusively
with 1,4-diiodotetrafluorobenzene in either a 1:1 or 1:2 stoichiometry
of the organohalide and the sulfoxide, respectively, depending on
the sulfoxide used. It was found that the stoichiometry observed was
not necessarily related to whether the oxygen acts as a single halogen
bond acceptor or if it is bifurcated; with IĀ·Ā·Ā·Ļ
interactions observed in two of the cocrystals synthesized. Only those
cocrystals with a 1:2 stoichiometry exhibit CāHĀ·Ā·Ā·O
hydrogen bonding in addition to IĀ·Ā·Ā·O=S halogen bonding.
Examination of the Cambridge Structural Database shows that (i) the
IĀ·Ā·Ā·O=S interaction is similar to other IĀ·Ā·Ā·O
interactions, and (ii) the IĀ·Ā·Ā·Ļ interaction
is significant, with the distances in the two cocrystals among the
shortest known