12 research outputs found
Characterization of a Water–Solid Interaction in a Partially Ordered System
GNE068-PC,
a developmental compound, was previously characterized to be mesomorphous,
i.e. having long-range order associated with significant local molecular
disorder (Chakravarty et. al., <i>Mol. Pharmaceutics</i>, accepted). The compound was exposed to moisture under different
relative humidity conditions ranging from 11% to 60% RH at room temperature
(RT) for 7 days, and the resultant product phases were characterized.
The partially ordered sample progressively lost crystallinity (long-range
order) and birefringence (orientational order) upon exposure to increasing
RH conditions, leading to the formation of a completely disordered
amorphous phase at 60% RH (RT). Long-range positional order was irrecoverable
even after moisture removal from the sample exposed to 60% RH. This
was attributed to replacement of residual ethyl acetate by water,
the former being critical for maintenance of long-range order in the
material. In addition, water sorption appeared to irreversibly alter
the molecular orientation, thereby affecting sample birefringence.
Solid-state NMR revealed increases in <sup>1</sup>H and <sup>13</sup>C spin–lattice relaxation times (<i>T</i><sub>1</sub>) going from the mesomorphous phase to the fully amorphous phase.
This was indicative of reduction in lattice mobility, likely due to
the decreased motion of the aromatic portions of the molecule, in
particular C17, which showed the most dramatic increase in <sup>13</sup>C <i>T</i><sub>1</sub>. This is likely due to decrease
in available free volume upon water sorption. Drying of the hydrated
disordered phase showed somewhat greater mobility than the hydrated
phase, likely due to increased relative free volume through removal
of water. A water–solid interaction therefore irreversibly
changed the solid-state makeup of GNE068-PC
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<sub>k</sub>, which
defines the breadth of the relaxation time distribution
Using Supercritical Fluid Technology as a Green Alternative During the Preparation of Drug Delivery Systems
Characterization of Pharmaceutical Cocrystals and Salts by Dynamic Nuclear Polarization-Enhanced Solid-State NMR Spectroscopy
Multicomponent solids such as
cocrystals have emerged as a way
to control and engineer the stability, solubility, and manufacturability
of solid active pharmaceutical ingredients (APIs). Cocrystals are
typically formed by solution- or solid-phase reactions of APIs with
suitable cocrystal coformers, which are often weak acids. One key
structural question about a given multicomponent solid is whether
it should be classified as a salt, where the basic API is protonated
by the acid, or as a cocrystal, where the API and coformer remain
neutral and engage in hydrogen bonding interactions. It has previously
been demonstrated that solid-state NMR spectroscopy is a powerful
probe of structure in cocrystals and salts of APIs; however, the poor
sensitivity of solid-state NMR spectroscopy usually restricts the
types of experiments that can be performed. Here, relayed dynamic
nuclear polarization (DNP) was applied to reduce solid-state NMR experiment
times by 1–2 orders of magnitude for salts and cocrystals of
a complex API. The large sensitivity gains from DNP facilitates rapid
acquisition of natural isotopic abundance <sup>13</sup>C and <sup>15</sup>N solid-state NMR spectra. Critically, DNP enables double
resonance <sup>1</sup>H–<sup>15</sup>N solid-state NMR experiments
such as 2D <sup>1</sup>H–<sup>15</sup>N HETCOR, <sup>1</sup>H–<sup>15</sup>N CP-build up, <sup>15</sup>NÂ{<sup>1</sup>H} <i>J</i>-resolved/attached proton tests, <sup>1</sup>H–<sup>15</sup>N DIPSHIFT, and <sup>1</sup>H–<sup>15</sup>N PRESTO.
The latter two experiments allow <sup>1</sup>H–<sup>15</sup>N dipolar coupling constants and H–N bond lengths to be accurately
measured, providing an unambiguous assignment of nitrogen protonation
state and definitive classification of the multicomponent solids as
cocrystals or salts. These types of measurements should also be extremely
useful in the context of polymorph discrimination, NMR crystallography
structure determination, and for probing hydrogen bonding in a variety
of organic materials
Solid-State Characterization of Novel Propylene Glycol Ester Solvates Isolated from Lipid Formulations
Identification of a Potential Conformationally Disordered Mesophase in a Small Molecule: Experimental and Computational Approaches
Monitoring Phase Transformations in Intact Tablets of Trehalose by FT-Raman Spectroscopy
The purpose of this study is to monitor phase transformations in intact trehalose tablets using FT-Raman spectroscopy. Tablets of trehalose dihydrate, amorphous trehalose (obtained by freeze-drying aqueous trehalose solutions), and anhydrous trehalose (β-trehalose) were prepared. The tablets were exposed to different conditions [11% and 0% RH (60°C); 75% RH (25°C)] and monitored periodically over 96 h using Raman spectroscopy. Within 96 h of storage, the following phase transformations were observed: (1) trehalose dihydrate → β-trehalose (11% RH, 60°C), (2) trehalose dihydrate → α-trehalose (0% RH, 60°C), (3) β-trehalose → trehalose dihydrate (75% RH, 25°C), and (4) amorphous trehalose → trehalose dihydrate (75% RH, 25°C). FT-Raman spectroscopy was a useful technique to identify the solid form and monitor multiple-phase transformations in intact trehalose tablets stored at different conditions
Chemically Diverse Group I p21-Activated Kinase (PAK) Inhibitors Impart Acute Cardiovascular Toxicity with a Narrow Therapeutic Window
p21-activated kinase 1 (PAK1) has
an important role in transducing
signals in several oncogenic pathways. The concept of inhibiting this
kinase has garnered significant interest over the past decade, particularly
for targeting cancers associated with PAK1 amplification. Animal studies
with the selective group I PAK (pan-PAK1, 2, 3) inhibitor G-5555 from
the pyridoÂ[2,3-<i>d</i>]Âpyrimidin-7-one class uncovered
acute toxicity with a narrow therapeutic window. To attempt mitigating
the toxicity, we introduced significant structural changes, culminating
in the discovery of the potent pyridone side chain analogue G-9791.
Mouse tolerability studies with this compound, other members of this
series, and compounds from two structurally distinct classes revealed
persistent toxicity and a correlation of minimum toxic concentrations
and PAK1/2 mediated cellular potencies. Broad screening of selected
PAK inhibitors revealed PAK1, 2, and 3 as the only overlapping targets.
Our data suggest acute cardiovascular toxicity resulting from the
inhibition of PAK2, which may be enhanced by PAK1 inhibition, and
cautions against continued pursuit of pan-group I PAK inhibitors in
drug discovery