ABSTRACT
Methane hydrates (MHs) have been considered a promising future energy source due to their vast resource volume and high energy density. Understanding the behavior of MH formation and dissociation at the pore-scale and the effect of MH distribution on the gas-liquid two phase flow is of critical importance for designing effective production strategies from natural gas hydrate (NGH) reservoirs. In this study, we devised a novel high-pressure microfluidic chip apparatus that is capable of direct observation of MH formation and dissociation behavior at the pore-scale. MH nucleation and growth behavior at 10.0 MPa and dissociation via thermal stimulation with gas bubble generation and evolution were examined. Our experimental results reveal that two different MH formation mechanisms co-exist in pores: (a) porous-type MH with a rough surface formed from CH4 gas bubbles at the gas-liquid interface and (b) crystal-type MH formed from dissolved CH4 gas. The growth and movement of crystal-type MH can trigger the sudden nucleation of porous-type MH. Spatially, MHs preferentially grow along the gas-liquid interface in pores. MH dissociation under thermal stimulation practically generates gas bubbles with diameters of 20.0-200.0 µm. Based on a custom-designed image analysis technique, three distinct stages of gas bubble evolution were identified during MH dissociation via thermal stimulation: (a) single gas bubble growth with an expanding water layer at an initial slow dissociation rate, (b) rapid generation of clusters of gas bubbles at a fast dissociation rate, and (c) gas bubble coalescence with uniform distribution in the pore space. The novel apparatus designed and the image analysis technique developed in this study allow us to directly capture the dynamic evolution of the gas-liquid interface during MH formation and dissociation at the pore-scale. The results provide direct first-hand visual evidence of the growth of MHs in pores and valuable insights into gas-liquid two-phase flow behavior during fluid production from NGHs.
ABSTRACT
The skew and shape of the molecular weight distribution (MWD) of polymers have a significant impact on polymer physical properties. Standard summary metrics statistically derived from the MWD only provide an incomplete picture of the polymer MWD. Machine learning (ML) methods coupled with high-throughput experimentation (HTE) could potentially allow for the prediction of the entire polymer MWD without information loss. In our work, we demonstrate a computer-controlled HTE platform that is able to run up to 8 unique variable conditions in parallel for the free radical polymerization of styrene. The segmented-flow HTE system was equipped with an inline Raman spectrometer and offline size exclusion chromatography (SEC) to obtain time-dependent conversion and MWD, respectively. Using ML forward models, we first predict monomer conversion, intrinsically learning varying polymerization kinetics that change for each experimental condition. In addition, we predict entire MWDs including the skew and shape as well as SHAP analysis to interpret the dependence on reagent concentrations and reaction time. We then used a transfer learning approach to use the data from our high-throughput flow reactor to predict batch polymerization MWDs with only three additional data points. Overall, we demonstrate that the combination of HTE and ML provides a high level of predictive accuracy in determining polymerization outcomes. Transfer learning can allow exploration outside existing parameter spaces efficiently, providing polymer chemists with the ability to target the synthesis of polymers with desired properties.
Subject(s)
Polymers , Molecular Weight , Polymerization , Polymers/chemistryABSTRACT
Commercialization of most promising active pharmaceutical ingredients (APIs) is impeded either by poor bioavailability or challenging physical properties leading to costly manufacture. Bioavailability of ionizable hydrophobic APIs can be enhanced by its conversion to salt form. While salt form of the API presents higher solution concentration than the non-ionized form, poor physical properties resulting from particle anisotropy or non-ideal morphology (needles) and particle size distribution not meeting dissolution rate targets can still inhibit its commercial translation. In this regard, API physical properties can be improved through addition of non-active components (excipients or carriers) during API manufacture. In this work, a facile method to perform reactive crystallization of an API salt in presence of the microporous environment of a hydrogel microparticle is presented. Specifically, the reaction between acidic antiretroviral API, raltegravir and base potassium hydroxide is performed in the presence of polyethylene glycol diacrylamide hydrogel microparticles. In this bottom-up approach, the spherical template hydrogel microparticles for the reaction lead to monodisperse composites loaded with inherently micronized raltegravir-potassium crystals, thus improving API physical properties without hampering bioavailability. Overall, this technique provides a novel approach to reactive crystallization while maintaining the API polymorph and crystallinity.
Subject(s)
Hydrogels , Crystallization , Raltegravir Potassium , Particle Size , SolubilityABSTRACT
Co-processing active pharmaceutical ingredients (APIs) with excipients is a promising particle engineering technique to improve the API physical properties, which can lead to more robust downstream drug product manufacturing and improved drug product attributes. Excipients provide control over critical API attributes like particle size and solid-state outcomes. Eudragit E100 is a widely used polymeric excipient to modulate drug release. Being cationic, it is primarily employed as a precipitation inhibitor to stabilize amorphous solid dispersions. In this work, we demonstrate how co-processing of E100 with naproxen (NPX) (a model hydrophobic API) into monodisperse emulsions via droplet microfluidics followed by solidification via solvent evaporation allows the facile fabrication of compact, monodisperse, and spherical particles with an expanded range of solid-state outcomes spanning from amorphous to crystalline forms. Low E100 concentrations (≤26% w/w) yield crystalline microparticles with a stable NPX polymorph distributed uniformly across the matrix at a high drug loading (â¼89% w/w). Structurally, E100 incorporation reduces the size of primary particles comprising the co-processed microparticles in comparison to neat API microparticles made using the same technique and the as-received API powder. This reduction in primary particle size translates into an increased internal porosity of the co-processed microparticles, with specific surface area and pore volume â¼9 times higher than the neat API microparticles. These E100-enabled structural modifications result in faster drug release in acidic media compared to neat API microparticles. Additionally, E100-NPX microparticles have a significantly improved flowability compared to neat API microparticles and as-received API powder. Overall, this study demonstrates a facile microfluidics-based co-processing method that broadly expands the range of solid-state outcomes obtainable with E100 as an excipient, with multiscale control over the key attributes and performance of hydrophobic API-laden microparticles.
Subject(s)
Chemistry, Pharmaceutical , Excipients , Excipients/chemistry , Chemistry, Pharmaceutical/methods , Powders , Solubility , Microfluidics , Naproxen/chemistry , Particle Size , Drug Compounding/methodsABSTRACT
[This corrects the article DOI: 10.1039/C3RA23176C.].
ABSTRACT
PURPOSE: Industrial implementation of continuous oral solid dosage form manufacturing has been impeded by the poor powder flow properties of many active pharmaceutical ingredients (APIs). Microfluidic droplet-based particle synthesis is an emerging particle engineering technique that enables the production of neat or composite microparticles with precise control over key attributes that affect powder flowability, such as particle size distribution, particle morphology, composition, and the API's polymorphic form. However, the powder properties of these microparticles have not been well-studied due to the limited mass throughputs of available platforms. In this work, we produce spherical API and API-composite microparticles at high mass throughputs, enabling characterization and comparison of the bulk powder flow properties of these materials and greater understanding of how particle-scale attributes correlate with powder rheology. METHODS: A multi-channel emulsification device and an extractive droplet-based method are harnessed to synthesize spherical API and API-excipient particles of artemether. As-received API and API crystallized in the absence of droplet confinement are used as control cases. Particle attributes are characterized for each material and correlated with a comprehensive series of powder rheology tests. RESULTS: The droplet-based processed artemether particles are observed to be more flowable, less cohesive, and less compressible than conventionally synthesized artemether powder. Co-processing the API with polycaprolactone to produce composite microparticles reduces the friction of the powder on stainless steel, a common equipment material. CONCLUSIONS: Droplet-based extractive solidification is an attractive particle engineering technique for improving powder processing and may aid in the implementation of continuous solid dosage form manufacturing.
Subject(s)
Antimalarials/chemistry , Artemether/chemistry , Excipients/chemistry , Microfluidic Analytical Techniques , Polyesters/chemistry , Crystallization , Drug Compounding , Emulsions , Friction , Powders , RheologyABSTRACT
Conventional formulation strategies for hydrophobic small-molecule drug products frequently include mechanical milling to decrease active pharmaceutical ingredient (API) crystal size and subsequent granulation processes to produce an easily handled powder. A hydrogel-templated anti-solvent crystallization method is presented for the facile fabrication of microparticles containing dispersed nanocrystals of poorly soluble API. Direct crystallization within a porous hydrogel particle template yields core-shell structures in which the hydrogel core containing API nanocrystals is encased by a crystalline API shell. The process of controllable loading (up to 64% w/w) is demonstrated, and tailored dissolution profiles are achieved by simply altering the template particle size. API release is well described by a shrinking core model. Overall, the approach is a simple, scalable and potentially generalizable method that enables novel means of independently controlling both API crystallization and excipient characteristics, offering a "designer" drug particle system.
Subject(s)
Excipients , Hydrogels , Crystallization/methods , Excipients/chemistry , Particle Size , Solubility , Solvents/chemistryABSTRACT
Inadequate intake of lutein is relevant to a higher risk of age-related eye diseases. However, lutein has been barely incorporated into foods efficiently because it is prone to degradation and is poorly bioaccessible in the gastrointestinal tract. Microfluidics, a novel food processing technology that can control fluid flows at the microscale, can enable the efficient encapsulation of bioactive compounds by fabricating suitable delivery structures. Hence, the present study aimed to evaluate the stability and the bioaccessibility of lutein that is encapsulated in a new noodle-like product made via microfluidic technology. Two types of oils (safflower oil (SO) and olive oil (OL)) were selected as a delivery vehicle for lutein, and two customized microfluidic devices (co-flow and combination-flow) were used. Lutein encapsulation was created by the following: (i) co-flow + SO, (ii) co-flow + OL, (iii) combination-flow + SO, and (iv) combination-flow + OL. The initial encapsulation of lutein in the noodle-like product was achieved at 86.0 ± 2.7%. Although lutein's stability experienced a decreasing trend, the retention of lutein was maintained above 60% for up to seven days of storage. The two types of device did not result in a difference in lutein bioaccessibility (co-flow: 3.1 ± 0.5%; combination-flow: 3.6 ± 0.6%) and SO and OL also showed no difference in lutein bioaccessibility (SO: 3.4 ± 0.8%; OL: 3.3 ± 0.4%). These results suggest that the types of oil and device do not affect the lutein bioaccessibility. Findings from this study may provide scientific insights into emulsion-based delivery systems that employ microfluidics for the encapsulation of bioactive compounds into foods.
ABSTRACT
Recent advances in end-to-end continuous-flow synthesis are rapidly expanding the capabilities of automated customized syntheses of small-molecule pharmacophores, resulting in considerable industrial and societal impacts; however, many hurdles persist that limit the number of sequential steps that can be achieved in such systems, including solvent and reagent incompatibility between individual steps, cumulated by-product formation, risk of clogging and mismatch of timescales between steps in a processing chain. To address these limitations, herein we report a strategy that merges solid-phase synthesis and continuous-flow operation, enabling push-button automated multistep syntheses of active pharmaceutical ingredients. We demonstrate our platform with a six-step synthesis of prexasertib in 65% isolated yield after 32 h of continuous execution. As there are no interactions between individual synthetic steps in the sequence, the established chemical recipe file was directly adopted or slightly modified for the synthesis of twenty-three prexasertib derivatives, enabling both automated early and late-stage diversification.
Subject(s)
Chemistry Techniques, Synthetic/methods , Pyrazines/therapeutic use , Pyrazoles/therapeutic use , Solid-Phase Synthesis Techniques/methods , Humans , Pyrazines/pharmacology , Pyrazoles/pharmacologyABSTRACT
Lipids serve as excellent excipients for drug products. Solid lipid microparticles (SLMs) are relatively underexplored in drug delivery; these particles are conventionally prepared using processes yielding polydisperse size distributions, such as spray congealing or emulsification. In this paper, we demonstrate a microfluidics-enabled process for particle engineering of monodisperse solid lipid microparticles with size and content uniformity. To overcome low solubility, we use a volatile solvent to increase drug loading, making the drug-lipid solution a single phase, enabling identical drug loading across particles. We use microfluidic flow extrusion of the solution to generate uniform drug-loaded SLMs, substantially enhancing monodispersity. This method generalises across three drugs-ibuprofen, 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY), and naproxen, and two lipids-beeswax and hard fat (Suppocire NAI 25A), forming particles of various solid states: amorphous naproxen in crystalline lipids, crystalline ROY in crystalline lipids, and a eutectic mixture of ibuprofen-hard fat. In vitro dissolution studies on the ibuprofen-hard fat SLMs reveal gradual release, fitting the Higuchi model with 50-65% drug released over 72 h. This work expands the drug particle engineering toolbox to enable the formulation of SLMs with high precision in particle size and drug loading. Moreover, the diverse solid-state outcomes enabled by our method makes it applicable to various drugs having different formulation requirements (crystalline/amorphous).
Subject(s)
Lipids , Microfluidics , Delayed-Action Preparations , Drug Carriers , Drug Compounding , Particle Size , SolubilityABSTRACT
Muslim renal transplant recipients often ask their physicians if performing certain lifestyles or religious obligations may be harmful to their health. Permissibility as advised by an expert Muslim physician is considered as being religiously accepted. A cross-sectional, survey-based study was conducted enquiring what nephrologists would advise their transplant recipients to do, about some lifestyles and religious duties. Fifty-eight nephrologists responded to the survey. Of these, 77% routinely follow-up post-transplant patients; 34% were from Saudi Arabia, 18% from the USA, and 20% from Pakistan. Fifty-four percent of the respondents would let patients with stable graft function fast during Ramadan, while 20% would not recommend fasting at any time following transplantation. This response did not change much if the patient was diabetic although in these patients, not recommending fasting at any time increased to 32%. For kidney donors, fasting would be allowed by 58% of the respondents once the kidney function stabilizes. About 50% would let their patients perform Omrah or obligatory Hajj any time after 12 months following transplantation, and only about 3% would not recommend that at any time after transplantation. For nonobligatory Hajj, 37% and 22%, respectively, would allow. Sixty-one percent would delay the pregnancy in nullipara with stable renal function, and none of the nephrologists would deny the opportunity to pregnancy at any time. In multiparous transplant recipients, the respective frequencies would be 45% and 20%. To our knowledge, this the first study exploring the consensus among Muslim nephrologists regarding the advice they would give on performance of potentially risky lifestyles and religious rituals by Muslim posttransplant patients.
Subject(s)
Islam , Kidney Transplantation , Life Style , Nephrologists/statistics & numerical data , Patient Education as Topic , Adolescent , Adult , Aged , Ceremonial Behavior , Cross-Sectional Studies , Fasting , Female , Humans , Male , Middle Aged , Practice Patterns, Physicians'/statistics & numerical data , Pregnancy , Young AdultABSTRACT
Optimized physical properties (e.g., bulk, surface/interfacial, and mechanical properties) of active pharmaceutical ingredients (APIs) are key to the successful integration of drug substance and drug product manufacturing, robust drug product manufacturing operations, and ultimately to attaining consistent drug product critical quality attributes. However, an appreciable number of APIs have physical properties that cannot be managed via routes such as form selection, adjustments to the crystallization process parameters, or milling. Approaches to control physical properties in innovative ways offer the possibility of providing additional and unique opportunities to control API physical properties for both batch and continuous drug product manufacturing, ultimately resulting in simplified and more robust pharmaceutical manufacturing processes. Specifically, diverse opportunities to significantly enhance API physical properties are created if allowances are made for generating co-processed APIs by introducing nonactive components (e.g., excipients, additives, carriers) during drug substance manufacturing. The addition of a nonactive coformer during drug substance manufacturing is currently an accepted approach for cocrystals, and it would be beneficial if a similar allowance could be made for other nonactive components with the ability to modify the physical properties of the API. In many cases, co-processed APIs could enable continuous direct compression for small molecules, and longer term, this approach could be leveraged to simplify continuous end-to-end drug substance to drug product manufacturing processes for both small and large molecules. As with any novel technology, the regulatory expectations for co-processed APIs are not yet clearly defined, and this creates challenges for commercial implementation of these technologies by the pharmaceutical industry. The intent of this paper is to highlight the opportunities and growing interest in realizing the benefits of co-processed APIs, exemplified by a body of academic research and industrial examples. This work will highlight reasons why co-processed APIs would best be considered as drug substances from a regulatory perspective and emphasize the areas where regulatory strategies need to be established to allow for commercialization of innovative approaches in this area.
Subject(s)
Drug Compounding/methods , Drug Industry/methods , Pharmaceutical Preparations/chemistry , Chemical Precipitation , Chemistry, Pharmaceutical/methods , Crystallization , Drug Carriers/chemistry , Excipients/chemistry , Flavoring Agents/chemistry , Particle Size , Quality ControlABSTRACT
Microfluidic tools and techniques for manipulating fluid droplets have become core to many scientific and technological fields. Despite the plethora of existing approaches to fluidic manipulation, non-Newtonian fluid phenomena are rarely taken advantage of. Here we introduce embedded droplet printing-a system and methods for the generation, trapping, and processing of fluid droplets within yield-stress fluids, materials that exhibit extreme shear thinning. This technique allows for the manipulation of droplets under conditions that are simply unattainable with conventional microfluidic methods, namely the elimination of exterior influences including convection and solid boundaries. Because of this, we believe embedded droplet printing approaches an ideal for the experimentation, processing, or observation of many samples in an "absolutely quiescent" state, while also removing some troublesome aspects of microfluidics including the use of surfactants and the complexity of device manufacturing. We characterize a model material system to understand the process of droplet generation inside yield-stress fluids and develop a nascent set of archetypal operations that can be performed with embedded droplet printing. With these principles and tools, we demonstrate the benefits and versatility of our method, applying it toward the diverse applications of pharmaceutical crystallization, microbatch chemical reactions, and biological assays.
ABSTRACT
Latent tracks in pure polymer and its nanohybrid are fabricated by irradiating with swift heavy ions (SHI) (Ag+) having 140 MeV energy followed by selective chemical etching of the amorphous path, caused by the irradiation of SHI, to generate nanochannels of size â¼80 nm. Grafting is done within the nanochannels utilizing free radicals generated from the interaction of high-energy ions, followed by tagging of ionic species to make the nanochannels highly ion-conducting. The uniform dispersion of two-dimensional nanoparticles better controls the size and number density of the nanochannels and, thereby, converts them into an effective membrane. The nanoparticle and functionalization induce a piezoelectric ß-phase in the membrane. The functionalized membrane removes the radioactive nuclide like 241Am+3 (α-emitting source) efficiently (â¼80% or 0.35 µg/cm2) from its solution/waste. This membrane act as a corrosion inhibitor (92% inhibition efficiency) together with its higher proton conduction (0.13 S/m) ability. The higher ion-exchange capacity, water uptake, ion conduction, and high sorption by the nanohybrid membrane are explored with respect to the extent of functionalization and control over nanochannel dimension. A membrane electrode assembly has been fabricated to construct a complete fuel cell, which exhibits superior power generation (power density of 45 mW/cm2 at a current density of 298 mA/cm2) much higher than that of the standard Nafion, measured in a similar condition. Further, a piezoelectric matrix along with its anticorrosive property, high sorption characteristics, and greater power generation makes this class of material a smart membrane that can be used for many different applications.
ABSTRACT
Conventionally Surface-enhanced Raman spectroscopy (SERS) is realized by adsorbing analytes onto nano-roughened planar substrate coated with noble metals (silver or gold) or their colloidal nanoparticles (NPs). Nanoscale irregularities in such substrates/NPs could lead to SERS sensors with poor reproducibility and repeatability. Herein, we demonstrate a suspended core photonic crystal fiber (PCF) based SERS sensor with extremely high reproducibility and repeatability in measurement with a relative SD of only 1.5% and 4.6%, respectively, which makes it more reliable than any existing SERS sensor platforms. In addition, our platform could improve the detection sensitivity owing to the increased interaction area between the guided light and the analyte, which is incorporated into the holes that runs along the length of the PCF. Numerical calculation established the significance of the interplay between light coupling efficiency and evanescent field distribution, which could eventually determine the sensitivity and reliability of the developed SERS active-PCF sensor. As a proof of concept, using this sensor, we demonstrated the detection of haptoglobin, a biomarker for ovarian cancer, contained within the ovarian cyst fluid, which facilitated in differentiating the stages of cancer. We envision that with necessary refinements, this platform could potentially be translated as a next-generation highly sensitive SERS-active opto-fluidic biopsy needle for the detection of biomarkers in body fluids.
Subject(s)
Metal Nanoparticles , Ovarian Neoplasms , Biomarkers, Tumor , Cyst Fluid , Female , Humans , Ovarian Neoplasms/diagnosis , Reproducibility of Results , Spectrum Analysis, RamanABSTRACT
In this paper, we demonstrate FRET-based multicolor lasing within chemically open droplet cavities that allow online modulation of the gain medium composition. To do this, we generated monodisperse microfluidic droplets loaded with coumarin 102 (donor), where the spherical droplets acted as whispering gallery mode (WGM) optical cavities in which coumarin 102 lasing (~ 470 nm) was observed. The lasing color was switched from blue to orange by the introduction of a second dye (acceptor, rhodamine 6 G) into the flowing droplet cavities; subsequent lasing from rhodamine 6 G (~ 590 nm) was observed together with the complete absence of coumarin 102 emission. The ability to control color switching online within the same droplet cavity enables sequential detection of multiple target molecules within or around the cavity. As a demonstration of this concept, we show how the presence of FITC-Dextran and methylene blue (MB) in the medium surrounding the lasing droplets can be sequentially detected by the blue and orange laser respectively. The method is simple and can be extended to a range of water-soluble dyes, thus enabling a wide spectral range for the lasing with the use of a single pump laser source.
ABSTRACT
Microfluidic droplets have been applied extensively as reaction vessels in a wide variety of chemical and biological applications. Typically, once the droplets are formed in a flow channel, it is a challenge to add new chemicals to the droplets for subsequent reactions in applications involving multiple processing steps. Here, we present a novel and versatile method that employs a high strength alternating electrical field to tunably transfer chemicals into microfluidic droplets using nanodroplets as chemical carriers. We show that the use of both continuous and cyclic burst square wave signals enables extremely sensitive control over the total amount of chemical added and, equally importantly, the rate of addition of the chemical from the nanodroplet carriers to the microfluidic droplets. An a priori theoretical model was developed to model the mass transport process under the convection-controlled scenario and compared with experimental results. We demonstrate an application of this method in the controlled preparation of gold nanoparticles by reducing chloroauric acid pre-loaded in microfluidic droplets with l-ascorbic acid supplied from miniemulsion nanodroplets. Under different field strengths, l-ascorbic acid is supplied in controllable quantities and addition rates, rendering the particle size and size distribution tunable. Finally, this method also enables multistep synthesis by the stepwise supply of miniemulsions containing different chemical species. We highlight this with a first report of a three-step Au-Pd core-shell nanoparticle synthesis under continuous flow conditions.
Subject(s)
Metal Nanoparticles/chemistry , Microfluidics/methods , Nanotechnology/methods , Electricity , Emulsions , Gold/chemistry , Models, Theoretical , Particle SizeABSTRACT
Topically administered ocular drug delivery systems typically face severe bioavailability challenges because of the natural protective mechanisms of eyes. The rational design of drug delivery systems that are able to persist on corneal surfaces for sustained drug release is critical to tackle this problem. In this study, we fabricated monodisperse chitosan-coated PLGA microparticles with tailored diameters from 5 to 120 µm by capillary microfluidic techniques and conducted detailed investigations of their mucoadhesion to artificial mucin-coated substrates. AFM force spectroscopy revealed strong instant adhesion to mucins, whereas the adhesion force, rupture length, and adhesion energy were positively correlated to the particle diameter and contact time. Particle detachment tests under shear flow in a microfluidic mucin-coated flow cell were in accord with the AFM measurements and revealed that microparticles smaller than 25 µm exhibited strong persistence in the flow cell, withstanding high shear rates up to 28,750 s-1 which are equivalent to the harshest in vivo ocular conditions. A simple scaling analysis connects the AFM and detachment tests, and reveals the existence of a threshold diameter below which mucoadhesion performance essentially saturates-an important insight in managing the opposing design criteria of enhanced mucoadhesion and slow, sustained drug delivery. Our findings thus pave the way for the rational design of mucoadhesive microparticulate ocular drug delivery systems that are capable of enhancing the bioavailability of topically applied drugs to eyes, as well as to other tissues whose epithelial surfaces contain mucosae.
ABSTRACT
This study presents a novel droplet-templated antisolvent spherical crystallization method applicable to both hydrophilic and hydrophobic drugs. In both cases, an alginate hydrogel binder forms in situ, concurrently with the crystallization process, effectively binding the drug crystals into monodisperse spheres. This study presents a detailed process description with mass transfer modeling, and with characterization of the obtained alginate/drug spheres in terms of morphology, composition, and drug loading. Although glycine and carbamazepine are used as model hydrophilic and hydrophobic drugs, this method is easily generalized to other drugs, and offers several benefits such as minimal thermal impact, fast crystallization rates, high drug-binder loading ratios, and high selectivity toward metastable polymorphs.