Antisolvent Addition Research Articles

Polymorphic Control and Scale-Up Strategy for Antisolvent Crystallization Using Direct Nucleation Control

In this work, a scale-up strategy based on the principles of direct design and quality-by-control (QbC) was applied and investigated using direct nucleation control (DNC). Process analytical technologies (PATs) were implemented for process monitoring and control. Antisolvent crystallization of indomethacin (IMC) was performed in a ternary solvent and antisolvent system. Mixture of acetone–methanol (66.5–33.5 wt %) was used as solvent and water as antisolvent since the mixed solvent system provides increased process yield and facilitates the suppression of the undesired acetone solvate. The effect of different process parameters, such as seed load, seed size, and initial concentration was investigated on process time, solid form and particle size distribution (PSD). The simplified solvent and antisolvent addition profiles obtained from the DNC were implemented directly in open-loop control to investigate reproducibility of the designed process. The open-loop operation was successfully scaled up by 1 order of magnitude, obtaining crystalline products with similar properties (solid form and PSD) as in the small-scale experiments. The results provide a proof-of-concept showing how the direct design approach can be applied in the rapid development of a robust crystallization process and efficient scale-up to yield the desired solid form with desired particulate properties (unimodal PSD and no agglomeration).

Pure, stable and highly antioxidant lignin nanoparticles from elephant grass

Finding renewable and green resources for nanomaterial preparation is a compelling topic concerning the sustainability in nanotechnological applications. In particular, lignin-based nanoparticles are pivotal for unlocking the use of lignin in value added products. In this paper, we isolated pure lignin (ca. 98 % of purity) from elephant grass (Pennisetum purpureum) using two simple extractions with diluted acid and alkali solutions and prepared lignin and lignin acetate nanoparticles dispersed in water-basis by anti-solvent addition. Elephant grass in natura contains ca. 25 % of lignin, which could be converted into lignin nanoparticles with a 37 % yield. Spherical lignin and lignin acetate nanoparticles were revealed by electron microscopies (TEM and FESEM) and proved to be stable in a wide pH range (5–11) and ionic strength lower than 0.01. Lignin nanoparticles showed higher antioxidant activity (RSI of ca. 82) as compared to lignin in solution and to the commercial antioxidants (BHT and BHA). These nanoparticles were successfully incorporated in a neutral cream, resulting in a tinted sunscreen formulation with both ultraviolet and visible absorption. Altogether, we present here an effective method to isolate pure lignin from a non-food biomass and to prepare stable and highly antioxidant lignin nanoparticles that can be applied in dermocosmetics and are intrinsically non-toxic to the environment.

Reproducible Crystallization of Sodium Dodecyl Sulfate·1/8 Hydrate by Evaporation, Antisolvent Addition, and Cooling.

Sodium dodecyl sulfate (SDS)·1/8 hydrate (NaC12H25SO4·1/8H2O) crystals were successfully produced by evaporation, antisolvent addition, cooling crystallization, and isothermal aging in a common stirred tank. A clear 33.3 wt % SDS aqueous solution was concentrated by evaporation to a 60 wt % coagel consisting of numerous SDS hydrates and water. The coagel was transformed to a clear solution when two times the volume of acetone relative to the water remaining were added. By this fluid property, a controlled crystallization was made possible in a homogeneous solution. Moreover, acetone with a water-to-acetone volume ratio of 1:15 was then added as an antisolvent to induce crystallization of SDS·1/8 hydrate by cubic addition. Finally, cooling crystallization and isothermal aging were carried out to further increase the yields and gave monodispersed particle size. The stability test showed that the produced SDS·1/8 hydrate could be stored at various relative humidity environments for at least 5 days.

Acetylated lignin nanoparticles as a possible vehicle for photosensitizing molecules.

Lignins are underused and abundant bio-sourced polymers with various potential applications. An attractive one is the development of nanoparticles for bioactive compound delivery. Here, we optimized the synthesis of hydrodispersible nanoparticles of acetylated lignin by comparing different lignin sources, degrees of acetylation and preparation methods. The formation of acetylated lignin nanoparticles in various solvents was probed by both experiments and, for the first time, a molecular dynamics simulation. We showed that dialysis is more suitable to obtain these nanoparticles than anti-solvent addition. The encapsulation of hydrophobic photosensitizing porphyrin in these nanoparticles was also demonstrated and rationalized at the molecular level, together with experiments, docking and molecular dynamics simulations. As acetylated lignin has been demonstrated to exhibit photosensitizing activity, the encapsulation of bioactive compounds in lignin nanoparticles opens the doors to a broad range of potential applications.

Perovskite Ink with an Ultrawide Processing Window for Efficient and Scalable Perovskite Solar Cells in Ambient Air.

Perovskite solar cells (PSCs) have attracted tremendous attention because of their rapidly growing efficiency and low cost. However, the efficiency of scalably deposited PSCs, especially spray-coated devices, is still lagging far behind that of spin-coated devices because of the complicated crystallization of coated precursor ink. Here, we show a precursor ink with an ultrawide processing window (more than 40 min) for spray-coating by adjusting the precursor component, which benefits the scalable deposition of perovskite films. Coupled with antisolvent extraction and addition of methylamine chloride to perovskite ink, high-quality perovskite films were achieved with large-scale uniformity. A power conversion efficiency (PCE) of 18.5% for rigid sprayed PSCs and 16.15% for flexible sprayed PSCs were achieved. At the square-centimeter level, sprayed PSCs on rigid and flexible substrates were achieved with PCEs of 15.07 and 13.21%, respectively. The one-step single-pass spraying method for versatility substrates at a deposition rate of 540 m h-1 brings great prospects for commercialization of PSCs.

Badanie wpływu szybkości dozowania nierozpuszczalnika na przebieg krystalizacji CL-20

In this paper, the effect of antisolvent addition rate on the yield and polymorphic purity of the obtained product, in order to optimise the 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20) precipitation process using a solvent/antisolvent system, was determined. It was found that increased dispensing rate of the antisolvent results in increased supersaturation in the mother liquor. This, in turn, increases the nucleation rate. The prevalence of the process of creating new seeds reduces the growth rate of the crystal, which affects the size distribution of the final crystallisation product. Reducing the time of the process results in the transformation of the initially formed, kinetically stable polymorph β, into the thermodynamically stable ε form with a lower yield, than the yield obtained after increased time.

Production of the metastable δ-polymorphic form of pyrazinamide by isothermal internal seeding anti-solvent crystallization

Pyrazinamide, an important drug for treatment of tuberculosis, crystallizes in four different polymorphic forms: commercially available needle-like α-polymorph, plate-like metastable δ-polymorph, prism shaped γ-polymorph, and the highly unstable β-polymorph. Since the fine needle shaped crystals of α-form of pyrazinamide easily agglomerate rendering downstream processing inefficient, the manufacture of plate-like δ-form of pyrazinamide is of significant importance in pharmaceutical industries. In this work, an isothermal internal seeding anti-solvent crystallization is proposed to selectively obtain metastable δ-polymorph of pyrazinamide with desired particle size distribution. The polymorphic purity and the final crystal size distribution can be influenced by careful selection of solvents, anti-solvents, anti-solvent addition rate, stirring rate, and seeding. After a series of screening experiments, 1,4-dioxane and cyclohexane were chosen as solvent and anti-solvent, respectively for the isothermal anti-solvent crystallization at 30 °C. The solubility of pyrazinamide in various 1,4-dioxane-cyclohexane mixtures in the range of 0–50 wt% of cyclohexane was determined gravimetrically at a temperature of 30 °C. A central composite design was then employed to investigate the effects of important process variables such as anti-solvent addition rate, stirring rate, and internal seeding on the process yield and the final crystal size distribution. An empirical model was developed that correlated the mean particle size with these variables and such a model can be used to determine the operating parameters for obtaining a target product size.

Review and Modeling of Crystal Growth of Atropisomers from Solutions

In this paper, theories on anisotropic crystal growth and crystallization of atropisomers are reviewed and a model for anisotropic crystal growth from solution containing slow inter-converting conformers is presented. The model applies to systems with growth-dominated crystallization from solutions and assumes that only one conformation participates in the solute integration step and is present in the crystal lattice. Other conformers, defined as the wrong conformers, must convert to the right conformer before they can assemble to the crystal lattice. The model presents a simple implicit method for evaluating the growth inhibition effect by the wrong conformers. The crystal growth model applies to anisotropic growth in two main directions, namely a slow-growing face and a fast-growing face and requires the knowledge of solute crystal face integration coefficients in both directions. A parameter estimation algorithm was derived to extract those coefficients from data about temporal concentration and crystal size during crystallization and was designed to have a short run time, while providing a high-resolution estimation. The model predicts a size-dependent growth rate and simulations indicated that for a given seed size and solvent system and for an isothermal anti-solvent addition crystallization, the seed loading and the supersaturation at seeding are the main factors impacting the final aspect ratio. The model predicts a decrease of the growth inhibition effect by the wrong conformer with increasing temperature, likely due to faster equilibration between conformers and/or a decrease of the population of the wrong conformer, if of low energy, at elevated temperatures. Finally, the model predicts that solute surface integration becomes the rate-limiting mechanism for high solute integration activation energies, resulting in no impact of the WC on the overall crystal growth process.

Incorporating Solvent-Dependent Kinetics To Design a Multistage, Continuous, Combined Cooling/Antisolvent Crystallization Process

Combined cooling and antisolvent crystallization enables crystallization of many pharmaceutical products, but its process design typically neglects solvent composition influences on crystallization kinetics. This paper evaluates the influence of solvent-dependent nucleation and growth kinetics on the design of optimal, multistage mixed-suspension, mixed-product removal (MSMPR) crystallization cascades. The ability to independently select temperature and solvent compositions in each stage of the cascade serves to greatly expand the attainable region for a two-stage cascade, with diminishing returns for additional stages. Failure to include solvent-dependent kinetics can result in simulating incorrect attainable regions, active pharmaceutical ingredient (API) yields, and crystal size distributions. This work also demonstrates that commonly employed crystallization process design heuristics, such as equal antisolvent addition and decreasing temperature in successive stages, can result in suboptimal process d...

Isothermal by Design: An Accelerated Approach to the Prediction of the Crystallizability of Slowly Nucleating Systems

A route to the accelerated nucleation of α-para-aminobenzoic acid in ethanol/water (EtOH/H2O) mixed solvent solutions, using antisolvent crystallization, is presented. An isothermal by design approach is adopted, whereby the exothermic enthalpy of mixing associated with antisolvent addition is offset by the control of the temperature of the antisolvent added. Induction times (τ) are found to be reduced by 4 orders of magnitude using this methodology, consistent with the use of this approach as a nucleation acceleration technique. Calculation of the nucleation kinetic parameters for a range of solution concentrations, compositions, and supersaturations (S) reveal that effective interfacial tensions (γeff) vary from 8.4 to 2.3 mJ m–2 from solutions in H2O solvent and EtOH solvent, respectively, in line with the trend in solubility. The critical nucleus radius (r*) decreases from 1.98 to 0.40 nm associated with a decrease in the number of molecules in the critical nucleus (i*) from 196 to 2 molecules. A change in nucleation mechanism from heterogeneous nucleation to homogeneous nucleation is observed to take place at S ≈ 1.5. Limitations, particularly with focus toward larger-scale operation, are highlighted together with potential solutions to overcome such aspects.

Energy saving integrated membrane crystallization: A sustainable technology solution

An integrated membrane system for crystallization has been studied experimentally. Performance of two membrane based processes; Osmotic Crystallization (OC) and Ultrafiltration (UF) were compared by using different membrane configurations (flat sheet and hollow fibre). Possibility of reduction in crystallization time by antisolvent addition was also explored. Different process combinations were developed for comparative performance analysis. For macromolecular feeds, it was seen UF see was more viable; though FO was attractive with respective to operation at ambient temperature and pressure. Integrated membrane based antisolvent crystallization did not affect the purity of the crystals as is evident from the X-Ray Diffraction analysis of the obtained crystals. The integrated membrane system showed an energy saving of 33.33% while antisolvent addition decreased energy consumption by 16.7%. Combination of membrane based and antisolvent crystallization further lowered the energy consumption by a whopping 36%. This was accompanied with a proportional reduction of 17% of crystallization time with respect to conventional evaporative crystallization. The competitive flux and energy saving quotient makes the system techno-economically viable.

A Purified, Solvent-Intercalated Precursor Complex for Wide-Process-Window Fabrication of Efficient Perovskite Solar Cells and Modules.

A high-purity methylammonium lead iodide complex with intercalated dimethylformamide (DMF) molecules, CH3 NH3 PbI3 ⋅DMF, is introduced as an effective precursor material for fabricating high-quality solution-processed perovskite layers. Spin-coated films of the solvent-intercalated complex dissolved in pure dimethyl sulfoxide (DMSO) yielded thick, dense perovskite layers after thermal annealing. The low volatility of the pure DMSO solvent extended the allowable time for low-speed spin programs and considerably relaxed the precision needed for the antisolvent addition step. An optimized, reliable fabrication method was devised to take advantage of this extended process window and resulted in highly consistent performance of perovskite solar cell devices, with up to 19.8 % power-conversion efficiency (PCE). The optimized method was also used to fabricate a 22.0 cm2 , eight-cell module with 14.2 % PCE (active area) and 8.64 V output (1.08 V/cell).

A Purified, Solvent‐Intercalated Precursor Complex for Wide‐Process‐Window Fabrication of Efficient Perovskite Solar Cells and Modules

AbstractA high‐purity methylammonium lead iodide complex with intercalated dimethylformamide (DMF) molecules, CH3NH3PbI3⋅DMF, is introduced as an effective precursor material for fabricating high‐quality solution‐processed perovskite layers. Spin‐coated films of the solvent‐intercalated complex dissolved in pure dimethyl sulfoxide (DMSO) yielded thick, dense perovskite layers after thermal annealing. The low volatility of the pure DMSO solvent extended the allowable time for low‐speed spin programs and considerably relaxed the precision needed for the antisolvent addition step. An optimized, reliable fabrication method was devised to take advantage of this extended process window and resulted in highly consistent performance of perovskite solar cell devices, with up to 19.8 % power‐conversion efficiency (PCE). The optimized method was also used to fabricate a 22.0 cm2, eight‐cell module with 14.2 % PCE (active area) and 8.64 V output (1.08 V/cell).

Antisolvent addition at extreme conditions

Antisolvent addition at high pressure (0.8 GPa) allows crystallization and recovery to ambient pressures of metastable form II paracetamol.

Ultrasound exposure ameliorates the hepatoprotective effect of herpetrione nanosuspension via oral delivery

The present study was performed to investigate the influence of ultrasound exposure on liver distribution and hepatoprotective effect of herpetrione nanosuspension (HPE NS) via oral administration. HPE NS was prepared by nanoprecipitation method and then characterized by particle size analysis, TEM, SEM and XRD. The pharmacokinetics and liver distribution of HPE NS after oral administration with the ultrasound exposure were evaluated and the protective effect of HPE NS against acute liver injury induced by CCl4 was also evaluated in a rat model. HPE NS with particle size of 213 ± 18 nm was successful prepared using nanoprecipitation method (bottom-up) by solvent–antisolvent addition. The images of TEM and SEM showed HPE NS were regular round shape with uniform and narrow size distribution. Results of XRD showed that HPE was amorphous state in both coarse powder and nanosuspension. In the in vivo pharmacokinetics and liver distribution studies in rats, ultrasound exposure had no influence on the pharmacokinetic characteristics of HPE NS after oral administration, but significantly increased the liver distribution of HPE NS. As evidenced by the lowering serum levels of ALT and AST and mitigating pathological lesions, the oral administration of HPE NS with the ultrasound exposure showed a superior hepatoprotective effect against CCl4 induced acute liver injury in rats as compared to oral administration of HPE NS without ultrasound exposure. These results revealed that ultrasound exposure could increase the liver distribution of HPE NS via oral delivery and ameliorate its hepatoprotective effect against CCl4 induced acute liver injury.

Comparison of particle size methodology and assessment of nanoparticle tracking analysis (NTA) as a tool for live monitoring of crystallisation pathways

Sample complexity and polydispersity presents challenges surrounding particle size measurements for nanoparticles (NPs). To ensure the delivery of high quality products to the marketplace it is imperative that this task is performed with the greatest accuracy and certainty. For this reason, particle sizing via more than one technique is critical to the success of the formulation process. Dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA) are techniques that size particles based on their Brownian motion in liquid medium. However, each technique has advantages and disadvantages associated with its application. This study was designed with the intent of comparing these techniques in a critical manner. NPs were formed using three Biopharmaceutics Classification System class II compounds: itraconazole, ketoconazole and posaconazole, using an anti-solvent addition, bottom up method. The impact of polyethylene glycol, polyethylene glycol methyl ether and polyethylene glycol dimethyl ether with a molecular weight 2000 Da, as stabilizers, was assessed using these two particle sizing techniques. Mie light scattering theory was successfully used to explain the relationship between material composition and particle scattering power. A change in material refractive index, associated with an amorphous to crystalline solid state transformation, was predominantly responsible for the observed change in the light scattering power of posaconazole nano-dispersions. The innovative application of NTA for the live tracking of these physical processes was explored for the first time. This novel finding can serve to deepen our understanding of the dynamic crystallisation pathway undertaken by a nanoparticle.

Isothermal crystallization of glycine in semi-continuous mode by anti-solvent addition

This article focuses on the isothermal semi-continuous crystallization of glycine aqueous solution by adding an anti-solvent, ethanol. The effect of the ethanol concentration on solubility and the impact of the ethanol flow rate on the metastable zone width and on the size distribution of the crystals were investigated. The study showed that increasing the ethanol concentration in the medium decreases solubility for the studied temperatures and that increasing the ethanol flow rate causes a widening of the metastable zone without inducing any noticeable effect on the crystals’ size distribution. In addition, nucleation kinetic models were determined for two temperatures (30 and 56 °C).

Modeling, Simulation, and Influence of Operational Parameters on Crystal Size and Morphology in Semibatch Antisolvent Crystallization of α-Lactose Monohydrate

This work summarizes the study of semibatch antisolvent crystallization of α-lactose monohydrate using ethanol as an antisolvent. The main objective of the work is to study the impact of operational parameters such as antisolvent flow rate, initial concentration of the solute, and the application of ultrasound on the crystal size and morphology. Mathematical modeling of semibatch antisolvent crystallization was formulated comprising a population balance equation (PBE) and material balance. The growth and nucleation kinetic parameters were estimated by fitting the model estimates to the experimental data. It was found that with an increase in antisolvent addition rate and initial lactose concentration the crystal morphology changed from polyhedral shape (α-lactose monohydrate) to curved needle/rod shape (β-lactose). The application of ultrasound led to the formation of smaller size crystals; however, no change in the morphology was observed. The work shows that there is a potential to engineer the shape, s...

In situ monitoring of nanoparticle formation: Antisolvent precipitation of azole anti-fungal drugs

In this work we report the effect of stabilizer choice and concentration on nanoparticle (NP) stability over time. Three different BCS class II active pharmaceutical ingredient (APIs): itraconazole (ITR), ketoconazole (KETO) and posaconazole (POS) were chosen due to their poor aqueous solubility and closely related chemical structures. Polyethylene glycol, polyethylene glycol methyl ether and polyethylene glycol dimethyl ether (DMPEG) with a molecular weight of 2000 Da were included as stabilisers. NPs were formed in situ using an anti-solvent addition, bottom up method at 25 °C. Colloidal stability was monitored using dynamic light scattering (DLS), accompanied by morphological examination of the NPs using scanning electron microscopy. Kinetic modelling indicates nanoparticle growth is driven by Ostwald ripening (OR). The presence of DMPEG causes OR growth to become an interface controlled process following a parabola trend. DMPEG encourages OR for POS NPs whilst driving the crystallisation process. The rate of OR appears to be inherent of the crystallisation pathway by which these APIs proceed. Crystallisation mechanisms are API, stabilizer type and concentration dependent. DLS is suitable as an initial systematic screening method for stabilizer selection, aiding the pharmaceutical scientist in the optimisation of nano-formulations.

Mechanistic understanding of the phase behavior of supersaturated solutions of poorly water-soluble drugs

Amorphous solid dispersions (ASDs) are a promising formulation strategy to increase both the apparent aqueous solubility and bioavailability of poorly water-soluble drugs. Upon dissolution under nonsink conditions, ASDs can generate highly supersaturated drug solutions which can undergo liquid–liquid phase separation (LLPS) and/or crystallization. In this study, the phase behavior of supersaturated solutions generated by antisolvent addition and upon the dissolution of ASDs was evaluated using fluorescence lifetime measurements and several other orthogonal techniques, including steady-state fluorescence spectroscopy, ultraviolet (UV) extinction and concentration profiles, ultracentrifuge measurements and nanoparticle tracking analysis. Ritonavir and lopinavir were chosen as poorly water-soluble model drugs, and the polymer, Kollidon VA64, was selected to form the dispersions. The fluorescence lifetime of the environment-sensitive fluoroprobe, PRODAN, was monitored to determine the occurrence of LLPS and crystallization. It was found that only the 10% w/w drug loading ASDs dissolved to a concentration in solution higher than the LLPS concentration and this led to an increase in the lifetime of PRODAN due to partitioning of the fluoroprobe into the drug-rich phase. In contrast, the 50% w/w drug loading ASDs did not reach the amorphous solubility, pointing to a dissolution behavior controlled by the low water solubility and high hydrophobicity of the drug. Fluorescence lifetime measurements were demonstrated to be extremely useful for the characterization of the phase behavior of supersaturated solutions of poorly water-soluble drugs.