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 solid–liquid 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 bar­(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 product’s 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 μm) 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 polymer–solute 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 ∼80% 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, Δ<i><i>T</i></i>_f, described by the Gibbs–Thomson (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, Δ<i><i>H</i></i>_m, and the solid–liquid surface energy, γ_SL, 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 Δ<i><i>T</i></i>_f. This analysis provides a straightforward method to estimate Δ<i><i>T</i></i>_f 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 Δ<i><i>T</i></i>_f of nanoconfined ibuprofen

CO₂‑Reactive 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 do­decyl­tri­methyl­am­mmonium bromide (DTAB) by substitution of the halide counterion with counterions such as 2-cyano­pyrrolide, 1,2,3-tri­azolide, and <i>L</i>-proline that complex reversibly with CO₂. 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 CO₂ 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 surfactant–DNA complexes upon alternate bubbling of the solution with CO₂ and N₂