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Vanillin crystals undergo needle-like morphology that results in poor flowability, crystal breakage, and low packing density. The spherical crystallization technology can produce particles with improved flowability and stability. A reverse antisolvent crystallization based on liquid-liquid phase separation is proposed in this work to produce vanillin spherical agglomerates. Hansen Solubility Parameters are applied to explain the liquid-liquid phase separation (LLPS) phenomenon. The Pixact Crystallization Monitoring system is applied to in-situ monitor the whole process. A six-step spherical crystallization mechanism is revealed based on the recorded photos, including the generation of oil droplets, nucleation inside oil droplets, the coalescence and split of oil droplets, crystal growth and agglomeration, breakage of oil droplets, and attrition of agglomerates. Different working conditions are tested to explore the best operation parameters and a frequency-conversion stirring strategy is proposed to improve the production of spherical crystals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. All rights reserved.)

The utilization of biocompatible drug delivery systems with extended drug release capabilities is highly advantageous in cancer therapy, as they can mitigate adverse effects. To establish such a biocompatible system with prolonged drug release behavior, researchers developed an innovative drug carrier. In this study, a sustainable approach was employed to synthesize a new zinc-based metal-organic framework (Zn-MOF) through the reaction between synthesized Schiff base ligands and zinc ions. Comprehensive analyses, including FT-IR, XRD, SEM, BET surface area, and TGA techniques, were employed to thoroughly characterize the frameworks. Following comprehensive characterization, curcumin (CUR) was loaded onto the Zn-MOF, resulting in CUR entrapment efficiency and loading capacity of 79.23 % and 26.11 %, respectively. In vitro evaluations of CUR release from CUR@MOF exhibited controlled release patterns, releasing 78.9 % and 50.0 % of CUR at pH 5.0 and pH 7.4, respectively. To mitigate initial burst release, a coating of the biopolymer sodium alginate (SA) was applied to CUR@Zn-MOF. In vitro CUR release tests indicated that SA/CUR@Zn-MOF outperformed pristine CUR@Zn-MOF. The release of CUR conformed to the Korsmeyer-Peppas model, displaying non-Fickian diffusion. Furthermore, an in vitro cytotoxicity study clearly demonstrated the potent anti-tumor activity of the synthesized CUR@Zn-MOF attributed to its controlled release of CUR. This led to the induction of apoptotic effects and cell death across HeLa, HEK293, and SH-SY5Y cell lines. These findings strongly suggest that the developed pH-sensitive carriers hold remarkable potential as targeted vehicles for drug delivery in cancer therapy., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Zinc phenylacetate (Zn-PA), a substitute for sodium phenylacetate as an ammonia-scavenging drug is hydrophobic, which poses problems for drug dissolution and solubility. We were able to co-crystallize the zinc phenylacetate with isonicotinamide (INAM) and produce a novel crystalline compound (Zn-PA-INAM). The single crystal of this new crystal was obtained, and its structure is reported here for the first time. Zn-PA-INAM was characterized computationally by ab initio, Hirshfeld calculations, CLP-PIXEL lattice energy calculation, and BFDH morphology analysis, and experimentally by PXRD, Sc-XRD, FTIR, DSC, and TGA analyses. Structural and vibrational analyses showed a major modification in intermolecular interaction of Zn-PA-INAM compared to Zn-PA. The dispersion-based pi-stacking in Zn-PA is replaced by coulomb-polarization effect of hydrogen bonds. As a result, Zn-PA-INAM is hydrophilic, improving the wettability and powder dissolution of the target compound in an aqueous solution. Morphology analysis revealed, unlike Zn-PA, Zn-PA-INAM has polar groups exposed on its prominent crystalline faces, reducing the hydrophobicity of the crystal. The shift in average water droplet contact angle from 128.1° (Zn-PA) to 27.1° (Zn-PA-INAM) is strong evidence of a marked decrease in hydrophobicity of the target compound. Finally, HPLC was used to obtain the dissolution profile and solubility of Zn-PA-INAM compared to Zn-PA., Competing Interests: Declaration of Competing Interest The authors certify that there re are no conflicts to declare., (Copyright © 2023. Published by Elsevier Inc.)

The global water crisis reflects the necessity of exploring the best approaches for the water supply. Therefore, for the first time, the current study compares nitrogen removal systems (NRSs) from life cycle assessment (LCA), economic, kinetic, thermodynamic, and synergistic perspectives. The assessed systems were sequential batch reactor (SBR), oxic/anoxic (OA), and oxic/anaerobic/oxic (OAO) bioreactors. Among all, the SBR configuration showed the best efficiency (98.74 %) for nitrogen removal. The environmental impacts notably presented by marine + freshwater ecotoxicity (53.76 %), and climate change categories (16.39 %), significantly because of metal emissions. Non-renewable sources supplied 95 % of total energy demand. The operation of NRSs showed the most impact on human health (63.67 %) through CH 4 and CO 2 emissions. The total costs significantly belonged to the construction (<86.37 %) > amortization> operation. The influent COD illustrated the most role in environmental burdens (16.44 %) based on the sensitivity analysis. The removal reaction was endothermic, physical, non-spontaneous, and followed a pseudo-second-order kinetic model (R 2 > 0.98). The chemical exergy provided the major portion of the total calculated exergy (83 %). The exergetic efficiency of the system was 69 %, which was predominantly supplied by biogas (∼50.75 %). Accordingly, this study can present a stepwise guideline for further related investigations., Competing Interests: Declaration of competing interest There was no conflict of interest in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Magnetic nanocarriers have been extensively used as a potential drug release system for breast cancer therapy. This work investigates drug release kinetics and transport mechanisms of dasatinib (DAS) anticancer drugs encapsulated in nanomagnetic self-assembled micelles. The drug release kinetics of DAS from the nanomagnetic micelles (NMM) was predicted by fitting the drug release experimental data to four different empirical models at pH values 7.4 and 5. Moreover, a simple mathematical model that can predict the drug release from bulk eroding polymer matrices has been developed using the COMSOL Multiphysics® program. The diffusional egress of the DAS release through the NMM was carried out by evaluating the diffusion coefficients inside NMM using Fick's second law and diffusion coefficients in the solution utilizing the Stokes-Einstein equation. The results revealed that NMM exhibited a superior sustained drug release rate in acidic conditions compared to the neutral state. The Peppas-Sahlin and COMSOL models gave the best fitting for the experimental drug release data and eroding matrices obtained from free DAS, DAS-micelles, and DAS-magnetic micelles at both pH values with correlation coefficients reached to 0.99. The transport mechanisms results showed a Fickian diffusion mechanism controlled with the highest diffusion coefficients of NMM in acidic conditions, while a significant relaxation contribution was observed at the neutral state., Competing Interests: Conflict of Interest The authors of this research acknowledge the originality of their research. This research has not been published before. It is not under consideration for publication elsewhere. The authors approved the submission of this article to the Journal of Pharmaceutical Sciences., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Spheroidal microparticles versatility as a drug carrier makes it a real workhorse in drug delivery applications. Despite of their long history, few research publications emphasize on how to improve their potential targeting ability, production rate, and dissolution characteristics. The current research presents an example of the combined state of the art of nano- and microparticles development technologies. Here in a novel on-chip, microfluidics approach is developed for encapsulating amphiphilic nanomicelles-in-sodium alginate spheroid. The designed nano-in-micro drug delivery system revealed a superior cytotoxicity against triple-negative human breast cancer cell line (MDA-MB-231), besides, a more sustained release of the drug. Hydrodynamics of the designed microchip was also investigated as a function of different flow rates with an insight on the dimensionless numbers; capillary number and Weber number throughout the microchannels. Our study confirmed the efficient encapsulation of nanomicelles within the alginate shell. The current microfluidics approach can be efficiently applied for uniform production of nano-in-microparticles with potential anticancer capability., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Magnetic nanocarriers are useful in targeted cancer therapy. Dasatinib (DAS)-loaded magnetic micelles were prepared for magnetically guided drug delivery. The magnetic nanoplatform is composed of hydrophobic oleic acid-coated magnetite (Fe 3 O 4 ) core along with DAS encapsulated in amphiphilic zein-lactoferrin self-assembled polymeric micelles. Transmission electron microscope analysis manifested formation of these magnetic micelles with a mean diameter of about 100 nm. In addition, drug-loaded magnetic micelles displayed a saturation magnetization of about 10.01 emu.g -1 with a superparamagnetic property. They also showed good in vitro serum stability and hemocompatibility accompanied with a sustained release of DAS in acidic pH. More importantly, they exhibited 1.35-fold increase in their in vitro cytotoxicity against triple-negative human breast cancer cell line (MDA-MB-231) using an external magnetic field compared to drug-loaded magnetic micelles in the absence of a magnetic field. Enhanced inhibition of p-c-Src protein expression level and in vitro cellular migration under the effect of magnetic field was noted owing to the dual-targeting strategy offered by the presence of a magnetic sensitive core, as well as the active targeting property of lactoferrin corona. Taken all together, these results suggest that DAS-loaded magnetic micelles possess a great potential for targeted therapy of breast cancer., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Conventional drug administration suffers from several drawbacks, including a lack of specificity for diseased tissue, the necessity of large and frequent doses, and adverse side effects. Great effort is currently being devoted to developing nanoparticle-based therapeutics capable of prolonging drug administration and providing better control. Here we demonstrate the use of flexible microporous MIL-53(Fe) and mesoporous MIL-101 and SBA-15 as matrices for the adsorption and in vitro drug delivery of acetaminophen, progesterone, and stavudine. A drug loading of 20 wt.% was achieved for each of the nanomaterials using an incipient wetness impregnation procedure. BET, DSC, and XRPD analyses indicated that the entire loaded amount of each of the model drugs had successfully been incorporated within the mesoporous channels of both MIL-101 and SBA-15. DSC analysis evidenced that a portion of each of the model drugs had deposited onto the outer surface of MIL-53(Fe) particles; however, the portion of each drug that had incorporated within the microporous channels was slowly delivered in a diffusion-controlled process, which occurred over a period of up to six days for acetaminophen. These results demonstrate the unique ability of MIL-53(Fe) to adapt its porosity and optimize drug-matrix interactions. Owing to its larger pore diameters and weaker host-guest interactions, MIL-101 release times were shorter, yet still prolonged, as evidenced by the complete release of stavudine after five days. Complete release of each of the drugs from SBA-15 occurred very quickly as a result of rapid drug dissolution and diffusion out of the mesopores., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Cocrystal forming ability of antiviral drug acyclovir (ACV) with different coformers was studied. Three cocrystals containing ACV with fumaric acid, malonic acid, and DL-tartaric acid were isolated. Methods of cocrystallization included grinding with dropwise solvent addition and solvent evaporation. The cocrystals were characterized by powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. The crystal structure of the cocrystal with fumaric acid as conformer was determined by single crystal X-ray diffraction. Formation of supramolecular synthon was observed in the cocrystal. Stability with respect to relative humidity for the three cocrystals was evaluated. The aqueous solubility of the ACV-cocrystal materials was significantly improved with a maximum of malonic acid cocrystal, which was about six times more soluble at 35°C compared with that of parent ACV. The dissolution profile indicates that at any particular dissolution time, the concentration of cocrystals in the solution was higher than that of the parent ACV, and malonic acid cocrystals had a maximum release of about twice than the hydrated ACV., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Co-crystals containing active pharmaceutical ingredients (APIs) represent a new type of pharmaceutical materials. In this work, sulfamethazine (STH) and theophylline (TP) were employed as the co-crystal formers. Neat cogrinding, solvent-drop cogrinding and slow evaporation were applied to synthesize the sulfamethazine-theophylline co-crystal (hereafter STH-TP co-crystal). The co-crystalline phase was characterized by DSC, TGA, Raman, PXRD, and dynamic vapor sorption (DVS) techniques. The STH-TP co-crystal structure was determined from single crystal X-ray diffraction data. The results show that, the STH-TP co-crystal, obtained in a 2:1 molar ratio of sulfamethazine and theophylline only by slow evaporation, possesses unique thermal, spectroscopic, and X-ray diffraction properties. Besides, in the STH-TP co-crystal, the sulfamethazine molecules form a dimer through the intermolecular hydrogen bonding (O ... H -- N), and two intermolecular hydrogen bonds (O ... H -- N and N ... H -- N) keep the theophylline attached the dimer.

The purpose of this study is to investigate the suitability of the crystallization process to produce microcrystals of progesterone for respiratory drug delivery. Crystallization of progesterone was carried out from water-isopropanol (IPA) mixture. The antisolvent (water) was added at two different addition rates (10 and 100 mL/min). The mass percentage of antisolvent was varied between (50% and 75%), and the initial drug concentration was adjusted at (0.5 and 1 g/L). The effect of crystallization method (antisolvent precipitation or combined cooling and antisolvent) was also examined. These operating conditions were investigated in a 2(4) factorial design in an effort to optimize the process. Different solid-state and surface characterization techniques were applied in conjunction with measurements of powder flow properties using aerodynamic particle sizer (APS). Powder dispersibility and aerosol performance were analyzed using Anderson Cascade Impactor (ACI). Antisolvent addition rate, initial drug concentration and dynamic solvent composition are shown to have a significant effect on the aerosol characteristics of progesterone microcrystals. An increase of 38.73% in the fine particle fraction (FPF) was demonstrated for some powders produced by combined cooling and antisolvent crystallization. In conclusion, it was possible to control particle size and hence, pulmonary deposition using process parameters alone, and produce particles with a narrow particle size distribution and a mean particle size of 5 microm with nearly no particles larger than 10 microm by direct crystallization. The suitability of deep pulmonary deposition was proved by the platelet-like morphology of processed microcrystals and greater surface-to-volume ratio than spherical particles., (2009 Wiley-Liss, Inc. and the American Pharmacists Association)

The racemate and enantiomers of 2-chloromandelic acid were characterized by SS-NMR, XRPD, and FTIR. The binary melting point phase diagram was constructed by DSC (differential scanning calorimetry). The solid-state nature of 2-chloromandelic acid was identified to be a racemic compound. The crystal structure of racemic compound was determined to be monoclinic P2(1)/c.

The use of inverse method for the determination of competitive adsorption isotherm of mandelic acid enantiomers on cellulose tris(3,5-diethylphenyl carbamate) stationary phase is proposed in this work. Non-dominated sorting genetic algorithm with jumping genes (NSGA-II-JG) was applied to acquire the isotherm parameters by minimizing the sum of square deviations of the model predictions from the measured elution profiles. Three different competitive isotherm models, i.e., Langmuir, biLangmuir and Tóth, combined with transport-dispersive chromatographic model were used in predicting the elution profiles. Orthogonal collocation on finite element (OCFE) method was applied to obtain the calculated elution profiles. Results indicate that biLangmuir isotherm and Tóth isotherm give remarkably similar equilibrium isotherms within the investigated liquid concentration range. Band profiles calculated from both isotherm models are in good agreement with the experimental data. The validity of the determined parameters was verified by comparing the model predictions with experimental elution profiles at various experimental conditions.

A new activity coefficient model was developed from excess Gibbs free energy in the form G(ex) = cA(a) x(1)(b)...x(n)(b). The constants of the proposed model were considered to be function of solute and solvent dielectric constants, Hildebrand solubility parameters and specific volumes of solute and solvent molecules. The proposed model obeys the Gibbs-Duhem condition for activity coefficient models. To generalize the model and make it as a purely predictive model without any adjustable parameters, its constants were found using the experimental activity coefficient and physical properties of 20 vapor-liquid systems. The predictive capability of the proposed model was tested by calculating the activity coefficients of 41 binary vapor-liquid equilibrium systems and showed good agreement with the experimental data in comparison with two other predictive models, the UNIFAC and Hildebrand models. The only data used for the prediction of activity coefficients, were dielectric constants, Hildebrand solubility parameters, and specific volumes of the solute and solvent molecules. Furthermore, the proposed model was used to predict the activity coefficient of an organic compound, stearic acid, whose physical properties were available in methanol and 2-butanone. The predicted activity coefficient along with the thermal properties of the stearic acid were used to calculate the solubility of stearic acid in these two solvents and resulted in a better agreement with the experimental data compared to the UNIFAC and Hildebrand predictive models.

The solubility of stearic acid, ranitidine hydrochloride, and stavudine were predicted in selected organic solvents. The experimental solubility data of stearic acid and ranitidine hydrochloride were reported in previous work of the authors and stavudine's solubility was measured in this work. Equilibrium aqueous solubility of crystalline stauvudine was determined at controlled temperatures by stirring and filtration, with spectrophotometric quantification. The new model developed in Part 11 of this communication was modified as a semipredictive model with two adjustable parameters. Predicting the solubility data with the NRTL model using just one experimental point resulted in a big error while the modified new model and the UNIQUAC model showed much smaller errors. A new method was proposed in this work for predicting the solubility data of all polymorphs of a given compound using the experimental solubility data of one of the polymorphs of the same chemical compound. Although in general, the UNIQUAC model predictions were marginally superior, the new model is simpler and does not require the molecular parameters such as Van der Waals area and volume. The solubility prediction in a mixture of solvents using the NRTL and UNIQUAC models was also discussed.

It is desirable to have a systematic approach for predicting or interpreting the effect of the solvents on the production of polymorphs. A method based on the atomic electronegativity is suggested that calculates the partial charge distribution in the solute and solvent molecules. Using the calculated partial charges, correlations are developed to predict the hydrogen bonding ability of the solute and/or solvent molecules. The predictive capability of the proposed correlations is compared with the results of a quantum mechanics approach. Selection of the right solvent may play a significant role in the formation of a desirable polymorph or solvate. The most important properties of class 2 and 3 solvents of International Conference on Harmonization (ICH) for crystallization of polymorphic compounds are listed in this paper. The partial charge calculation has been used as a tool for analyzing the solvent impact on polymorphic isolation of two compounds: ranitidine hydrochloride (H2 receptor antagonist) and stearic acid (used as excipients or in coating the tablets)., ((c) 2005 Wiley-Liss, Inc.)

Ranitidine hydrochloride Form 1 produced by the original method (Price et al., 1978 US patent) has poor filtration and drying characteristics, which make it less desirable commercially in comparison with Form 2. This article shows that the operating parameters have significant influence on the final properties of Form 1. In terms of filterability and solid bulk density, it was found that at a higher temperature (approximately 48 degrees C), the viscosity of the slurry decreased and improved product quality as compared with operating at room temperature (approximately 25 degrees C). It was found that the rapid addition of acid to the ranitidine base increased product density but led to higher residual solvent inclusion. The presence of excess ranitidine base in the solution and also the manner of reactant addition had a significant influence on the onset of nucleation and the rate of crystallization. The best results in terms of filterability and bulk solid density were obtained using an initial pH of 5.3 and then increasing it to 6.3-6.4 after the onset of nucleation., (Copyright 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1692-1700, 2004)