Antisolvent Method Research Articles

Effect of particle size on in vivo performances of long-acting injectable drug suspension

Herein, entecavir-3-palmitate (EV-P), an ester prodrug of entecavir (EV), was employed as a model drug, and the effect of drug particle size on in vivo pharmacokinetic profiles and local inflammatory responses, and those associations were evaluated following intramuscular (IM) injection. EV-P crystals with different median diameters (0.8, 2.3, 6.3, 15.3 and 22.6 μm) were prepared using the anti-solvent crystallization method, with analogous surface charges (−10.7 ~ −4.7 mV), and crystallinity (melting point, 160–170 °C). EV-P particles showed size-dependent in vitro dissolution profiles under sink conditions, exhibiting a high correlation between the median diameter and Hixon-Crowell's release rate constant (r2 = 0.94). Following IM injection in rats (1.44 mg/kg as EV), the pharmacokinetic profile of EV exhibited marked size-dependency; 0.8 μm-sized EV-P particles about 1.6-, 3.6-, and 5.6-folds higher systemic exposure, compared to 6.3, 15.3, and 22.6 μm-sized particles, respectively. This pharmacokinetic pattern, depending on particle size, was also highly associated with histopathological responses in the injected tissue. The smaller EV-P particles (0.8 or 2.3 μm) imparted the larger inflammatory lesion after 3 days, lower infiltration of inflammatory cells, and thinner fibroblastic bands around depots after 4 weeks. Conversely, severe fibrous isolation with increasing particle size augmented the drug remaining at injection site over 4 weeks, impeding the dissolution and systemic exposure. These findings regarding the effects of formulation variable on the in vivo behaviors of long-acting injectable suspension, provide constructive knowledge toward the improved design in poorly water-soluble compounds.

Experimental measurement and thermodynamic modeling of solubility of flufenamic acid in different pure solvents

Flufenamic acid (FFA) is a BCS II class drug having low solubility and high permeability in the gastrointestinal tract. The solubility enhancement techniques of BCS II class drugs such as co-crystallization, solid dispersion or fine particle generation by supercritical or liquid antisolvent method require the knowledge of solubility of API in the organic solvent. In the present work, the equilibrium solubility of FFA was determined in methanol, ethanol, 1-propanol and 2-propanol at a temperature ranging from 298 to 318 K. Different models such as the modified Apelblat equation, λh equation, NRTL and Wilson were used to correlate the experimental solubility of FFA in these solvents. The enthalpy of mixing (ΔmH), entropy of mixing (ΔmS) and Gibbs energy of mixing (ΔmG) were computed in the real binary mixture of FFA – solvent to examine the nature of mixing thermodynamically.

Fabrication of Stable Apigenin Nanosuspension with PEG 400 as Antisolvent for Enhancing the Solubility and Bioavailability.

The purpose of this paper is to prepare a stable apigenin nanosuspension with a drug concentration of 1.11mg/mL through green and efficient antisolvent method. Compared with the traditional preparation process that may use toxic reagents, in this study, a green and effective strategy was applied for the preparation of stable apigenin nanosuspension by using an antisolvent method with PEG 400 as antisolvent to improve the solubility and bioavailability. It was found that the particle size of apigenin nanosuspension was about 280nm, and the solubility and dissolution of the nanosuspension were 33 and 3 times higher than that of the apigenin, respectively. Pharmacokinetic study showed that the Cmax and AUC 0-8h values of the nanosuspension in fasting rats achieved about 6- and 2.5-fold enhancement than that of the apigenin, respectively. Stability test showed that the apigenin nanosuspension could be stored stably for 12months at 25℃. Taken together, the antisolvent method with PEG 400 was proven to be a green and effective method to prepare the stable nanosuspension of poorly soluble drugs.

Effect of Sr2+ doping on optical, thermal and photocatalytic behaviour of CsPbBr3

The work delineates synthesis and characterization of phase pure cesium lead bromide-CsPbBr3 and strontium (Sr2+) doped CsPb0.95Sr0.05Br3 based all inorganic perovskite films by anti-solvent assisted method. The CsPb0.95Sr0.05Br3 showed lower band-gap, higher thermal stability, and higher photocatalytic activity compared to CsPbBr3.

A self-powered β-Ga2O3/CsCu2I3 heterojunction photodiode responding to deep ultraviolet irradiation

In this paper, a lead-free halide perovskite CsCu2I3 film with high stability was prepared by the anti-solvent assisted crystallization method. Then, we coupled it with Ga2O3 to prepare a corresponding heterojunction deep ultraviolet (UV) photodetector. After testing, we concluded that the photodetector is sensitive to 254 nm UV light. The photodetector has good reproducibility, and has an ultra-high photo-to-dark current ratio (PDCR) of more than 105. In addition, under a bias of 10 V and an illuminated intensity of 200 μW/cm2, the responsivity (R) and specific detectivity (D*) reached 20 mA/W and 107 cm Hz1/2 W−1 (Jones), and the external quantum efficiency (EQE) is 10%. Meanwhile, the prepared photodetector could operate at zero bias, i.e., self-powered operation, along with a photocurrent of about 1 nA under illumination with UV light intensity of 200 μW/cm2.

(FA0.83MA0.17)0.95Cs0.05Pb(I0.83Br0.17)3 Perovskite Films Prepared by Solvent Volatilization for High‐Efficiency Solar Cells

Perovskite solar cells (PSCs) have attracted significant research efforts due to their remarkable performance. However, most perovskite films are prepared by the antisolvent method which is not suitable for practical applications. Herein, a (FA0.83MA0.17)0.95Cs0.05Pb(I0.83Br0.17)3 (CsFAMA) perovskite film fabrication technique is developed using solvent volatilization without any antisolvents. The films are formed through recrystallization via the intermediate phase CsMAFAPbI x Cl y Br z during annealing, leading to high‐quality perovskite films. The perovskite growth mechanism is investigated in terms of controlling the amount of formamidinium iodide and methylammonium chloride in the precursor solutions. The oriental growth of the films via the intermediate phase is confirmed by the grazing‐incidence wide‐angle X‐ray scattering measurements. The photovoltaic properties of the perovskite films are investigated. The PSCs based on the films fabricated using the method exhibit a high efficiency of 20.6%. The method developed in this work is based on solvent volatilization, which exhibits significant potential in high reproducibility, facile operation, and large‐scale production.

Spray-freeze-dried inhalable composite microparticles containing nanoparticles of combinational drugs for potential treatment of lung infections caused by Pseudomonas aeruginosa

The multi-drug resistance of Pseudomonas aeruginosa is an overwhelming cause of terminal and persistent lung infections in cystic fibrosis (CF) patients. Antimicrobial synergy has been shown for colistin and ivacaftor, and our study designed a relatively high drug-loading dry powder inhaler formulation containing nanoparticles of ivacaftor and colistin. The ivacaftor-colistin nanosuspensions (Iva-Col-NPs) were prepared by the anti-solvent method with different stabilizers. Based on the aggregation data, the formulation 7 (F7) with DSPG-PEG-OMe as the stabilizer was selected for further studies. The F7 consisted of ivacaftor, colistin and DSPG-PEG-OMe with a mass ratio of 1:1:1. The F7 powder formulation was developed using the ultrasonic spray-freeze-drying method and exhibited a rough surface with relatively high fine particle fraction values of 61.4 ± 3.4% for ivacaftor and 63.3 ± 3.3% for colistin, as well as superior emitted dose of 97.8 ± 0.3% for ivacaftor and 97.6 ± 0.5% for colistin. The F7 showed very significant dissolution improvement for poorly water soluble ivacaftor than the physical mixture. Incorporating two drugs in a single microparticle with synchronized dissolution and superior aerosol performance will maximize the synergy and bioactivity of those two drugs. Minimal cytotoxicity in Calu-3 human lung epithelial cells and enhanced antimicrobial activity against colistin-resistant P. aeruginosa suggested that our formulation has potential to improve the treatment of CF patients with lung infections.

Phase control in the synthesis of cesium copper iodide compounds for their photoluminescence and radioluminescence study

Lead-free metal halide perovskites have attracted much attention owing to their non-toxicity and excellent optical properties. Especially, cesium copper iodide compounds exhibit advantages of good environmental stability and low cost, rendering promising potential applications in optoelectronic devices field. Here, we use an anti-solvent assisted crystallization method to realize phase control syntheses of CsCu2I3 and Cs3Cu2I5 by varying the concentrations of precursor solution. Using high precursor solution concentrations, Cs3Cu2I5 with strong blue emission peak at 440 nm is prepared. While the CsCu2I3 is fabricated at low precursor solution concentrations, with the yellow emission peak of 580 nm. Furthermore, the UV-pumped light-emitting diodes (UV-LEDs) are realized by adopting CsCu2I3 and Cs3Cu2I5 powders as phosphors, and we also obverse the scintillation characteristic of the cesium copper iodide powders, showing potential applications for lighting and X-ray detection devices.

Preparation and Pharmacokinetic Characterization of an Anti-Virulence Compound Nanosuspensions.

Antibiotic resistance has become a worldwide public health threat due to the rapid evolution and spread of antibiotic-resistant bacteria. CCG-211790 is a novel anti-virulence compound that does not kill bacteria but could ameliorate human diseases by inhibiting expression of virulence factors, thereby applying less selection pressure for antibiotic resistance. However, its potential clinical use is restricted because of its poor aqueous solubility, resulting in formulation challenges. Nanosuspension technology is an effective way to circumvent this problem. Nanosuspensions of CCG-211790 with two different particle sizes, NanoA (315 ± 6 nm) and NanoB (915 ± 24 nm), were prepared using an antisolvent precipitation-ultrasonication method with Tween 80 as the stabilizer. Particle and pharmacokinetics (PK) of CCG-211790 nanosuspensions were characterized. Both NanoA and NanoB demonstrated remarkable increases in dissolution rate compared with the bulk compound. The PK parameters of NanoA were comparable to those of CCG-211790 solution formulation in intravenous or oral administration, suggesting that CCG-211790 nanosuspensions with smaller particle size improved oral bioavailability and drug exposure compared to traditional formulations of drug candidates.

Ethanol-soluble polysaccharide from sugar beet pulp for stabilizing zein nanoparticles and improving encapsulation of curcumin

Ethanol-soluble polysaccharide (ESP) is a highly ethanol-soluble (85% v/v) fraction from the precipitation process of sugar beet pectin and holds the potential to be utilized for food purposes. This study aimed to explore ESP as a coating polymer to stabilize zein nanoparticles against agglomeration via co-dissolving ESP and zein in an ethanol/water mixture (85% v/v) and subsequently dispersing into the water to form composite nanoparticles. Structural analyses showed that the ESP contained 28.3 wt% galacturonic acid, 45.7 wt% neutral sugar, and 17.6 wt% protein, and that its average molecular weight was 93,157 Da. In this study, we fabricated ESP-coated zein (zein-ESP) nanoparticles with a diameter of around 248 nm using the antisolvent co-precipitation method. These zein-ESP nanoparticles were stable over a wide pH range of 2.0–8.0 when the ESP:zein mass ratio was higher than 0.6:1. Additionally, the nanoparticles exhibited good stability in environmental stresses such as sodium ion concentrations of 400 mM and high temperatures of 90 °C (for 120 min). The encapsulation efficiency of Cur improved significantly, from 68.5% with the zein nanoparticles to 88.7% with the zein-ESP nanoparticles. When encapsulated by zein-ESP nanoparticles, Cur presented as an amorphous form and was released in a sustained and controlled manner after exposure to simulated gastrointestinal fluids, resulting in enhanced solubility and in vitro bioaccessibility, as compared with the free Cur. Altogether, ESP has great potential to stabilize zein nanoparticles-based delivery systems for hydrophobic bioactive compounds with enhanced water solubility and encapsulation efficiency for use in the food and pharmaceutical industries.

Continuous‐Flow Synthesis of Orange Emitting Sn(II)‐Doped CsBr Materials

AbstractAn ongoing demand toward lead‐free all‐inorganic cesium metal halide perovskites has presented Sn(II) as an ideal substitute of Pb(II) for applications in optoelectronic devices. The major concern regarding Sn(II) is the instability due to the ambient oxidation to Sn(IV). To expand the scope of traditional perovskite and analogues, herein the synthesis and optical performance of Sn(II)‐doped CsBr, a new material formed by interstitial doping of Sn(II) into the CsBr matrix, are reported for the first time. This material is prepared following an antisolvent mediated recrystallization method using a continuous flow reactor, which is beneficial for scaling up the production compared to traditional batch reactors. Sn(II)‐doped CsBr exhibits broadband orange emission with full‐width‐half‐maximum of 180 nm and a photoluminescence quantum yield of 21.5%. The emission turned to be highly stable over 7 months despite containing Sn(II). It is suggested that this is due to interstitial location of Sn(II) atoms in bulk of microcrystals. A broadband emission and high aerobic stability are attractive properties of the material for white‐light emitting applications.

Production of Rosuvastatin Calcium Nanoparticles Using Gas Antisolvent Technique

The activity of pharmaceutical substances crucially depends on the bioavailability of the substances. The bioavailability of drugs in body and their rate of dissolution in the biological fluids are increased if the particle size is decreased. In the present paper, the Gas Anti-Solvent (GAS) method was used to lower the size of rosuvastatin particles. The effects of temperature (313–338 K), pressure (105–180 bar) and initial solute concentration (20–60 mg/ml) were evaluated by Response Surface Methodology (RSM). The optimum initial solute concentration, temperature and pressure were found to be 20 mg/ml, 313 K and 180 bar, respectively which resulted in the minimum particle size. Furthermore, the particles were characterized by Differential Scanning Calorimetry (DSC), Dynamic Light Scattering (DLS), Fourier Transform Infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and X-Ray Diffraction (XRD). The analyses showed that the rosuvastatin particles (60.3 nm) precipitated by GAS process become significantly smaller than the initial particles (45.8 µm).

Ultrasound-based one-step fabrication of nobiletin particle: A facile stabilization strategy

As a typical representative of polymethoxylated flavones, nobiletin (NOB) is beneficial to health but hard to be processed, stored, and absorbed, due to its hydrophobicity and crystallinity. Herein, we developed a stabilization system based on an efficient manufacturing procedure of NOB nanocrystal by anti-solvent method combined with ultrasonic treatment. Metal-phenolic networks composed of tannic acid and metal ions were introduced to conformally coat on formed nanocrystal for further stabilization. From the results, the size and morphology of the prepared particles could be altered by the amount, ratio, and kind of the coating materials. The optimized samples could be redispersed after centrifugation, and keep stable at 4 ℃ for at least 120 days. Moreover, they possessed higher acid stability and more effective release than the control sample during the in vitro digestion experiment. Therefore, this work provided a promising idea for overcoming storage and delivery obstacle of hydrophobic crystalline bioactive components.

Revealing phase evolution mechanism for stabilizing formamidinium-based lead halide perovskites by a key intermediate phase

Revealing phase evolution mechanism for stabilizing formamidinium-based lead halide perovskites by a key intermediate phase

Extraction of diterpenes from spent coffee grounds and encapsulation into polyvinylpyrrolidone particles using supercritical carbon dioxide

ABSTRACT In this study, supercritical carbon dioxide (SC-CO2) was used to extract diterpenes from spent coffee grounds (SCGs) and it is followed by the encapsulation of SCG extract into polyvinylpyrrolidone particles using a supercritical antisolvent crystallization method. In the extraction process using SC-CO2, the effects of three independent variables – temperature (40‒80°C), pressure (10‒30 MPa), and the ratio of ethanol as a modifier (0%‒10% v/v), on dependent variables: extraction yield and total diterpene content – were investigated using the response surface methodology and Box – Behnken design. The optimal conditions for the extraction yield and total diterpene content were predicted to be 40°C/30 MPa/10% v/v of ethanol and 80°C/25 MPa/6% v/v of ethanol, respectively. Notably, the predicted maximum total diterpene content was 15 times the amount obtained by the Soxhlet method using n-hexane, thereby confirming the selectivity of ethanol-modified SC-CO2 toward diterpenes. Subsequently, based on the supercritical antisolvent crystallization process, the SCG extract was successfully encapsulated into polyvinylpyrrolidone particles with an average particle size of 140 nm, and the water dispersibility of the SCG extract was enhanced by this encapsulation process. The encapsulation of SCG extract with water-soluble polymers enables the further use of SCG extract in food, cosmetic, and pharmaceutical industries.

Femtosecond relaxation dynamics of two‐dimensional BiOI nanoplatelets as efficient photocatalysts

AbstractThe structural and optical properties of pristine and photoactivated surfaces of facet [001] of 2D BiOI nanoplatelet powders synthesized with an antisolvent method were studied using X‐ray diffraction (XRD), a scanning electron microscope, X‐ray photoelectron spectra (XPS), visible–near infrared (vis–NIR) absorption, and transient absorption spectroscopic techniques. The synthesized BiOI nanoplatelets possessed a tetragonal structure with length 200–400 nm and thickness less than 50 nm. XRD analysis showed that the photoactivation did not affect the crystal structure. In contrast, the XPS analysis showed vacancies associated with elements Bi, I, and O. The band gaps estimated from the diffuse reflectance spectra of pristine and photoactivated samples are 1.83 and 1.80 eV, respectively. Femtosecond transient‐absorption spectra measured in the vis–NIR (2.25–0.9 eV) region showed photobleach bands associated with the band edge, shallow trap, and deep trap states. A global fit of the transient spectral profiles showed that all bands decay synchronously for both pristine and photoactivated samples, but the photoactivated samples showed a greater magnitude of carrier‐carrier annihilation following photoexcitation due to photodoping caused by defects. A carrier‐relaxation model involving thermal equilibrium between band‐edge, shallow, and deep trap states is proposed to explain the synchronous decay of all bands.

Water-driven CsPbBr3 nanocrystals and poly(methyl methacrylate)-CsPbBr3 nanocrystal films with bending-endurable photoluminescence

Perovskite nanocrystals are regarded as next-generation functional materials for display applications, especially for flexible liquid crystal displays (LCDs). As a potential component of flexible LCD backlights, perovskite nanocrystal films are facing a challenge issue of deformation-induced shift of photoluminescence, leading to an image distortion. To date, most synthesis methods have involved the use of organic solvent in precursor solutions, such as N,N-dimethylformamide and dimethyl sulfoxide, which poses a potential threat to the environment, health and security. In this work, we demonstrate the feasibility to produce microsized CsPbBr3 crystals with deionized water as the precursor solvent via an environmental-friendly and cost-efficient approach and CsPbBr3 nanocrystals with green (~522 nm) and blue (~493 nm) emissions from the microsized CsPbBr3 crystals in toluene under sonication. The blue-emitting nanocrystals exhibit a photoluminescence (PL) quantum yield of 80%, much larger than 61.4% of the CsPbBr3 nanocrystals made by an anti-solvent method; the green-emitting nanocrystals exhibit better stability than those made by the antisolvent method over 9 days. Using the green-emitting CsPbBr3 nanocrystals, we prepare a bilayer structure with a poly(methyl methacrylate)-CsPbBr3 nanocrystal film on a polyethylene terephthalate plate. The films exhibit bending-endurable photoluminescence, i.e. the wavelength of the PL peak remains unchanged, for local radius of curvature of the bilayer up to 10.07 mm under bending. This study opens a new avenue to potentially produce microsized perovskite crystals without harmful organic solvents and bending-endurable backlight films for the applications in flexible display.

Formulation, Optimization and Evaluation of Nanoparticulate Oral Fast Dissolving Film Dosage Form of Nitrendipine

The primary objective of the present research work was to develop nanoparticles incorporating (nanoparticulate) fast dissolving (orodispersible) film evincing enhanced solubility and bioavailability of nitrendipine (NIT). An antisolvent sonoprecipitation method was employed to produce the NIT nanosuspension (NS), which was optimized using the 32 optimal response surface design and then the optimized one was evaluated for various parameters (Gandhi et al., AAPS PharmSciTech 22 (1):1-15, 2021). The NIT nanoparticulate orodispersible film (N-ODF) was prepared utilizing the nanosuspension by the solvent casting method using the Vijay film-forming instrument. The N-ODF was optimized by the 23 full factorial design and was evaluated for several parameters. The optimized NS depicted a particle size of 505.74 ± 15.48 nm with a polydispersity index (PDI) of 0.083 ± 0.006 (Fig. 1b). The NIT nanoparticles showed a striking increment in saturation solubility (26.14 times), when compared with plain NIT (2). The developed NIT N-ODF exhibited thickness (0.148 ± 0.008 mm), folding endurance (280.33 ± 5.51 times), surface pH (6.86 ± 0.05), tensile strength (8.25 ± 0.13 kg/cm2), % elongation (63.5 ± 1.97%), and disintegration time (24.60 ± 1.31 s) to be within the standard intended limit. The in vitro dissolution study unveiled 100.28 ± 2.64% and 100.68 ± 2.50% of NIT release from lyophilized nanocrystals (in 8 min) and N-ODF (in 3.5 min), respectively, whereas the conventional NIT tablet took 30 min to release 99.94 ± 1.57% of NIT (Gandhi et al., AAPS PharmSciTech 22 (1):1-15, 2021). The in vivo pharmacokinetic study in rabbits inferred the achievement of significantly (p < 0.05) higher bioavailability of NIT on release from N-ODF in comparison to the conventional NIT tablet. Thus, the generation of N-ODF can be considered as a propitious move toward improving the efficacy of NIT to treat hypertension and angina pectoris.

Surface Decoration via Physical Interaction of Cupric Diethyldithiocarbamate Nanocrystals and Its Impact on Biodistribution and Tumor Targeting.

The vascular wall is the first physiologic barrier that circulating nanoparticles (NPs) encounter, which also is a key biological barrier to cancer drug delivery. NPs can continually scavenge the endothelium for biomarkers of cancer, and the chance of NPs' extravasation into the tumors can be enhanced. Here, we envision P-selectin as a target for specific delivery of drug nanocrystals to tumors. The cupric diethyldithiocarbamate nanocrystals (CuET NCs) were first prepared by an antisolvent method, and then nanocrystals were coated with fucoidan via physical interaction. The fucoidan-coated CuET nanocrystals (CuET@Fuc) possess high drug loading and have the ability to interact with human umbilical vein endothelial cells expressing P-selectin, which transiently enhances the endothelial permeability and facilitates CuET@Fuc extravasation from the peritumoral vascular to achieve higher tumor accumulation of drugs than bare CuET NCs. The CuET NC shows poorer anticancer efficacy than CuET@Fuc at the same dose of CuET. Upon repeated dosing of CuET@Fuc for 2 weeks, no mortality was observed in treated melanoma-bearing mice, while the mortality in the control group and excipient-treated groups reached 23%. The growth rate of melanoma in the CuET@Fuc-treated group was significantly lower than those in other groups. Furthermore, an acute toxicity study revealed that CuET@Fuc is a safe formulation for cancer treatment.

Optically Clear Films of Formamidinium Lead Bromide Perovskite for Wide-Band-Gap, Solution-Processed, Semitransparent Solar Cells.

Solvent engineering and antisolvent methods have been used extensively to achieve high-quality, homogeneous, and crystalline perovskite thin films. Usually, highly concentrated (>1.1 M) precursor solutions are used to achieve the maximum power conversion efficiency (PCE), and most fabrication studies focus on iodide-based metal halide perovskites (MHPs). However, high concentrations of precursors are not suitable for semitransparent (ST) MHP solar cells (STPSCs), which require thinner films to achieve a high average visible transmittance (AVT). The deposition of high-quality perovskites with variable concentrations in a one-step method is challenging due to the complexity of the antisolvent crystallization process. Here, we have developed an in situ technique based on photoluminescence (PL) measurements to identify the optimum delay time for antisolvent crystallization in formamidinium lead bromide (FAPbBr3). By monitoring the in situ PL, the nucleation, crystal growth, and early perovskite formation phases are easily identified for a range of concentrations. Subsequently, we fabricated opaque and ST solar cells with optically clear, ST perovskite films formed from precursors with varying concentrations. These all-solution-processed STPSCs achieved AVTs of up to 35.6, 42.5, and 49.2%, with the corresponding PCEs of 5.71, 3.25, and 1.86% in p-i-n type, FAPbBr3 perovskite solar cells with transparent Ag nanowire electrodes. These devices show good stability over several weeks and an impressive Voc as high as 1.24 V for STPSCs and 1.38 V for opaque cells produced with a thick Ag electrode. This work demonstrates the potential use of in situ spectroscopy to tailor the film growth of halide perovskites with varying concentrations and the feasibility of using wide-band-gap perovskites for ST solar cells with exceptional clarity and higher Voc.