6 research outputs found
Continuous Spherical Crystallization of Albuterol Sulfate with Solvent Recycle System
Spherical crystallization enables
the direct preparation of crystal
agglomerates of active pharmaceutical ingredients (APIs) with improved
crystal handling properties. The continuous spherical crystallization
of albuterol sulfate as a model API was developed using a mixed-suspension,
mixed-product removal (MSMPR) crystallizer. The application of a solvent
recycling system for reuse of the antisolvent in the single-stage
MSMPR crystallizer was also demonstrated. Spherical agglomerates of
albuterol sulfate were obtained via antisolvent crystallization using
the MSMPR crystallizer with water as the solvent and an ethyl acetate/emulsifier
(Pluronic L-121) mixture as the antisolvent. Steady-state continuous
spherical crystallization was rapidly achieved after 30 min, and a
yield of >95% was obtained. The influence of process parameters
such
as the solvent/antisolvent ratio, emulsifier concentration, residence
time, and reactor scale on the properties of the agglomerates formed
during the crystallization process was examined. In the MSMPR crystallizer,
the desired solvent to antisolvent ratio was maintained by controlling
the flow rates of the feed, antisolvent, and recycle stream, and 90%
of the mother liquor was recycled during the continuous spherical
crystallization of albuterol sulfate by optimizing the rate of each
stream
Custom-Built Miniature Continuous Crystallization System with Pressure-Driven Suspension Transfer
At
the bench scale, the transfer of solidâliquid streams
between reaction vessels or crystallizers that operate continuously
poses a significant problem. Reduced equipment size of pumps and valves
(i.e., approaching that on the microfluidic scale) means even further
reduced orifices in which suspensions must attempt to flow. It forces
bridging of solids and leads to blockages in flow. This study presents
a new pressure-driven flow crystallizer (PDFC) with a custom-built
suspension transfer pumping system. In the system, a dip tube is used
to carry suspension between crystallizers by controlling the pressure
differences of the crystallizers. This novel system has a small footprint
on the scale of similar benchtop flow synthesis systems and has been
demonstrated to operate continuously with intermittent withdrawal
for at least 24 h. The system accommodates both cooling and antisolvent
crystallization. It is compatible with a variety of solvents, can
handle crystals with large and small aspect ratios, and can also handle
a large range of crystal sizes and suspension density. The miniature
design of the system requires as little as 0.36 psig (0.025 barÂ(g))
pressure to operate and a design equation can be used to guide the
estimation of the minimum pressure needed for the transfer of suspensions
at larger scales
Composite Hydrogels Laden with Crystalline Active Pharmaceutical Ingredients of Controlled Size and Loading
Efficient control of crystallization
and crystal properties still
represents a bottleneck in the manufacturing of crystalline materials
ranging from pigments to semiconductor particles. In the case of pharmaceutical
drug manufacture, current methods for controlling critical crystal
properties such as size and morphology that dictates the productâs
efficacy are inefficient and often lead to the generation of undesirable
solid states such as metastable polymorphs or amorphous forms. In
this work, we propose an approach for producing crystals of a poorly
water-soluble pharmaceutical compound embedded in a polymer matrix.
Taking advantage of the composite hydrogel structure, we control the
crystallization of the active pharmaceutical ingredient (API), within
the composite hydrogel, generating crystalline API of controlled crystal
size and loading. The composite hydrogels initially consist of organic
phase droplets, acting as crystallization reactors, embedded in an
elastic hydrogel matrix. By controlled evaporation of this composite
material, crystals of controlled size (330 nm to 420 ÎŒm) and
loading (up to 85%w/w) are produced. Through the interplay of elasticity
and confinement, composite hydrogels control the crystal size and
morphology via a two-step mechanism. First, the elastic matrix counteracts
evaporation-induced coalescence of the emulsion droplets, keeping
droplets isolated. Second, a confinement-induced elastic energy barrier,
limits the growth of crystals beyond the size designated by the droplets.
The proposed approach can be applied to production of a wide range
of crystalline materials
Biocompatible Alginate Microgel Particles as Heteronucleants and Encapsulating Vehicles for Hydrophilic and Hydrophobic Drugs
Biocompatible materials that can
control crystallization while
carrying large amounts of active pharmaceutical ingredients (APIs)
with diverse chemical properties are in demand in industrial practice.
In this study, we investigate the utility of biocompatible alginate
(ALG) hydrogels as a rational material for crystallizing and encapsulating
model APIs that present drastically different solubilities in water.
Acetaminophen (ACM) and fenofibrate (FEN) are utilized as the model
hydrophilic and hydrophobic moieties, respectively. ALG hydrogels
with different ALG concentrations (hence different mesh sizes) are
utilized as heteronucleants to control the nucleation kinetics of
ACM from solution. ALG hydrogels with smaller mesh sizes showed faster
nucleation kinetics. We hypothesize that this behavior is due to the
interplay between the polymerâsolute interactions and the mesh-induced
confinement effects. The loading of ACM into hydrogels by equilibrium
partitioning is quantified and found to be inversely proportional
to ALG concentration. For hydrophobic model APIs, loading via equilibrium
partitioning is inefficient; hence, we suggest emulsion-laden hydrogels
where emulsion droplets are encapsulated inside the hydrogel matrix.
The incorporation of emulsion droplets inside hydrogels enables the
high loading of the hydrophobic API leveraging the high solubility
of the hydrophobic API in the dispersed emulsion droplets. By carefully
choosing the emulsification method and the dispersed phase, we demonstrate
significant loading (up to âŒ80% w/w) and crystallization of
the stable form of FEN. Our results provide new insights for designing
biocompatible nucleation-active materials capable of carrying industrially
significant amounts of water-soluble and insoluble APIs in the crystalline
form
Understanding and Analyzing Freezing-Point Transitions of Confined Fluids within Nanopores
Understanding phase transitions of
fluids confined within nanopores
is important for a wide variety of technological applications. It
is well known that fluids confined in nanopores typically demonstrate
freezing-point depressions, Î<i><i>T</i></i><sub>f</sub>, described by the GibbsâThomson (GT) equation.
Herein, we highlight and correct several thermodynamic inconsistencies
in the conventional use of the GT equation, including the fact that
the enthalpy of melting, Î<i><i>H</i></i><sub>m</sub>, and the solidâliquid surface energy, Îł<sub>SL</sub>, are functions of pore diameter, complicating their prediction.
We propose a theoretical analysis that employs the Turnbull coefficient,
originally derived from metal nucleation theory, and show its consistency
as a more reliable quantity for the prediction of Î<i><i>T</i></i><sub>f</sub>. This analysis provides a straightforward
method to estimate Î<i><i>T</i></i><sub>f</sub> of nanoconfined organic fluids. As an example, we apply this
technique to ibuprofen, an active pharmaceutical ingredient (API),
and show that this theory fits well to the experimental Î<i><i>T</i></i><sub>f</sub> of nanoconfined ibuprofen
CO<sub>2</sub>âReactive Ionic Liquid Surfactants for the Control of Colloidal Morphology
This article reports
on a new class of stimuli-responsive surfactant
generated from commercially available amphiphiles such as doÂdecylÂtriÂmethylÂamÂmmonium
bromide (DTAB) by substitution of the halide counterion with counterions
such as 2-cyanoÂpyrrolide, 1,2,3-triÂazolide, and <i>L</i>-proline that complex reversibly with CO<sub>2</sub>. Through
a combination of small-angle neutron scattering (SANS), electrical
conductivity measurements, thermal gravimetric analysis, and molecular
dynamics simulations, we show how small changes in charge reorganization
and counterion shape and size induced by complexation with CO<sub>2</sub> allow for fine-tunability of surfactant properties. We then
use these findings to demonstrate a range of potential practical uses,
from manipulating microemulsion droplet morphology to controlling
micellar and vesicular aggregation. In particular, we focus on the
binding of these surfactants to DNA and the reversible compaction
of surfactantâDNA complexes upon alternate bubbling of the
solution with CO<sub>2</sub> and N<sub>2</sub>