Recrystallization and micronization of camptothecin (CPT), a potent anticancer agent, has been performed using the supercritical antisolvent (SAS) process in this study. The effect of different solvents on the morphology, mass median diameter (Dp50), particle size distribution (PSD) and the crystallinity of obtained CPT microparticles was investigated in detail. Five pure solvents, acetic acid, dimethylformamide, chloroform, N-methyl-2-pyrrolidone, dimethyl sulfoxide (DMSO), and a series of solvent mixture of ethanol/DMSO with different volume ratios (R), where R was defined as the ethanol volume to total solvent volume, were selected as solvents. The raw CPT and processed CPT particles were characterized using SEM, laser diffraction particle size analysis, FT-IR spectroscopy, LC–MS, powder XRD, and DSC. The processed CPT microparticles were flake-like and much thinner and more uniform than the lamelliform CPT raw material. The Dp50 of the processed CPT ranged from 0.39 to 2.14 μm, and the PSD of the processed CPT microparticles became much narrower. Solvents with a higher ratio of density and viscosity, lower surface tension, and lower solvation power will form smaller CPT microparticles with lower crystallinity, which helps to improve the solubility of CPT in biological liquids. Furthermore, the addition of ethanol into DMSO improves the properties of DMSO and decreases the CPT solubility, which is beneficial to the acquisition of smaller particles, and the particle size decreased significantly with the increase of R. The chemical structure and crystalline structure of CPT did not change after the SAS process. However, the crystallinity of the obtained CPT microparticles was less than that of raw CPT, and varied for different solvents.

By incorporating Cytochrome c (peroxidase, Cyt c) into a skeleton of its corresponding synthetic MOF analogue (peroxidase mimic, CuBDC), approximately 12-fold catalytic efficiency (kcat/KM) enhancement is observed compared to free Cyt c. Meanwhile, the shield endowed by CuBDC prevents encapsulated enzymes from deactivation by trypsin digestion, thermal treatment and long-term storage in vitro. This concept of combining enzymes and their MOF mimics with enhanced enzymatic activity and stability may provide new insights into the design of highly active, stable enzyme–MOF composite catalysts and holds promise for applications in biocatalysis, biosensing and drug delivery systems.

To develop a safer, more stable and potent formulation of gefitinib (GFB), micro-spheres of GFB encapsulated into poly (l-lactic acid) (PLLA) have been prepared by supercritical anti-solvent (SAS) technology in this study. Operating factors were optimized using a selected OA16 (45) orthogonal array design, and the properties of the raw material and SAS processed samples were characterized by different methods The results show that the GFB-loaded PLLA particles prepared were spherical, having a smaller and narrower particle size compared with raw GFB. The optimal GFB-loaded PLLA sample was prepared with less aggregation, highest GFB loading (15.82%) and smaller size (D50 = 2.48 μm, which meets the size of dry powder inhalers). The results of XRD and DSC indicate that GFB is encapsulated into PLLA matrix in a polymorphic form different from raw GFB. FT-IR results show that the chemical structure of GFB does not change after the SAS process. The results of in vitro release show that the optimal sample release was slower compared with raw GFB particles. Moreover, the results of in vitro anti-cancer trials show that the optimal sample had a higher cytotoxicity than raw GFB. After blending with sieved lactose, the flowability and aerosolization performance of the optimal sample for DPI were improved, with angle of repose, emitted dose and fine particles fractions from 38.4° to 23°, 63.21% to >90%, 23.37% to >30%, respectively.Download high-res image (184KB)Download full-size image

•The particle microstructures of gefitinib were tailored by the SAS process.•Key process variables affecting particle microstructures were investigated.•A novel polymorphic form (Form β) of gefitinib was captured after the SAS process.•The aqueous solubility and dissolution rate of gefitinib was enhanced effectively after the SAS process.Supercritical CO2 anti-solvent (SAS) process is a green and effective method to produce particles with designated microstructures. In this study, the particle microstructures of gefitinib, a potent anticancer agent, are tailored by the SAS process to improve its aqueous solubility. The dichloromethane/ethanol (1:4, v/v) was selected as the suitable solvent from typical solvents used in the SAS process at first. Then, the effects of other SAS operating parameters, i.e., the flow rate of gefitinib solution (F), the concentration of gefitinib in the solution (C), the precipitation pressure (P) and the temperature (T), on the gefitinib particle size were investigated in detail. Lower F, lower C, higher P and suitable T were recommended for the formation of gefitinib particles with small particle size. The properties of the raw material and SAS processed samples of gefitinib were characterized by different methods. The results showed that a new polymorphic form (Form β) of gefitinib, which present different physicochemical properties, i.e., smaller particle size, narrower particle size distribution and higher solubility, with raw gefitinib (Form 1), was captured after the SAS process. The predicted structures of gefitinib crystals, which were consistent with the experiments, were performed from their experimental XRD data by the direct space approach using the Reflex module of Materials Studio. Meanwhile, the SAS processed gefitinib particles showed much higher solubility and faster dissolution rate than that of raw gefitinib, which had the potential to improve its bioavailability and decrease the dose-related adverse effects.Download high-res image (136KB)Download full-size image

Nano-drug delivery systems that integrate inorganic and organic or even bioactive components into a single nanoscale platform are playing a hugely important role in cancer treatment. In this article, the fabrication of a versatile nanocarrier based on self-assembled structures of gold nanoparticles (AuNPs)-zein is reported, which displays high drug-loading efficiency for needle-shaped hydroxycamptothecin (HCPT) nanocrystals. The surface modification with folate-conjugated polydopamine (PFA) renders them stable and also facilitates their selective cellular internalization and enhancement of endocytosis. The release of payloads from nanocomplexes (NCs) was shown to be limited at physiological pH (17.1 ± 2.8%) but significantly elevated at endosomal/lysosomal pH (58.4 ± 3.0%) and at enzymatic environment (81.4 ± 4.2%). Compared to free HCPT and its non-targeting equivalent, HCPT@AuNPs-Zein-PFA exerted a superior tumor suppression capacity as well as low side effects due to its active and passive targeting delivery both in vitro and in vivo. These results suggest that the NCs with well-defined core@shell nanostructures encapsulated with HCPT nanocrystals hold great promise to improve cancer therapy with high efficiency in the clinic.Statement of significanceA novel nanocomplex with HCPT nanocrystals encapsulated was designed to achieve selective cellular uptake by endocytosis, acid responsive release in the tumor microenvironment and excellent tumor suppression without toxicity. This nanocomplex with conjugation of folate was stable in the bloodstream, with minimal drug release in extracellular conditions, leading to prolonged blood circulation and high accumulation in tumor tissues. The entrapment of a nanocrystal drug into nanomaterials might be capable of delivering drugs in a predictable and controllable manner.Download high-res image (139KB)Download full-size image

Nanotechnology associated with a crystal engineering approach was proposed for improving the solubility and efficacy of hydrophobic drugs in this study. 10-hydroxycamptothecin polymorphic nanoparticle dispersions (HCPT-PNDs) were prepared using the supercritical anti-solvent technique coupled with the high-pressure homogenization method. Shape- and polymorph-dependent tumor suppression was observed in both in vitro and in vivo models, where needle-shaped HCPT-PND exhibited dramatic improvement of antitumor efficacy. A benefit of controllable size and a large surface-to-volume ratio of needle-shaped nanoparticles is the improvement of dissolution properties, which facilitates enhancing pharmacokinetic and pharmaco-dynamic properties. The needle-shaped HCPT-PND, which with longer blood retention time and more effective cellular uptake, makes it possible to accumulate drug in tumor tissues and exhibit higher cytotoxicity. No severe systemic toxicity was observed due to sustained-dissolution and the low dose of drug in normal tissues. The results suggest that the needle-shaped HCPT-PND is an interesting nano-formulation of HCPT.From the Clinical EditorNanotechnology has enabled the production of novel therapeutics drugs against cancer. Here, the authors investigated the use of a crystal engineering approach for the modification of camptothecin in order to improve its water solubility. Physicochemical and biological properties were studied. The results would suggest the applicability of this approach for nano-formulation.10-hydroxycamptothecin polymorphic nanoparticle dispersions (HCPT-PNDs) were prepared using the supercritical anti-solvent technique coupled with high-pressure homogenization method. Polymorph-dependent tumor suppression was observed both in vitro and in vivo models. The needle-shaped HCPT-PND exhibits dramatic improvement of antitumor efficacy and non-toxic to normal tissues, which could be a potential optimized polymorphic drug in the field of nanochemotherapeutics.

To find a more efficient solution for chemolysis of urinary calculi, several organic acids were chosen to form solutions by consulting the composition of a classic solution, Suby G. The solutions together with Renacidin, another classic solution, were designed to react with the 4 phosphate components of urinary stone. The processes were real-time measured and analysed by a focused beam reflectance measurement, and the efficiency factors were investigated and discussed in detail. The results show that several organic acids, e.g. hydroxyacetic acid, lactic acid and α-ketoglutaric acid, are more efficient than citric acid in dissolving urinary phosphate calculus. The new solutions containing the organic acids are promising for improving chemolysis treatment.

In this study, 10-hydroxycamptothecin (HCPT) and poly (l-lactic acid) (PLLA) are co-precipitated by the supercritical anti-solvent (SAS) process using a mixture of dichloromethane (DCM)/ethanol (EtOH) as co-solvent, and supercritical carbon dioxide as the anti-solvent. The effect of five operating conditions on particle morphology, mass median diameter (Dp50) and HCPT loading is investigated using the single-factor method. The results indicate that HCPT loading can be greatly increased by using DCM/EtOH co-solvent, and the suitable operating conditions for the experimental system are determined. Under suitable conditions, the HCPT loading is 13.3% and Dp50 is 794.5 nm. The drug loaded microparticles are characterized in detail. The SEM images showed that most of the particles were spherical, and PLLA concentration has a major impact on the particle shape. Results of TEM, DSC and XRD indicate that the micronized HCPT is dispersed into the PLLA matrix. For low HCPT loading, most of HCPT existed in the drug loaded microparticles in an amorphous state, but for high HCPT loading, part of the encapsulated drug existed in crystalline form. FT-IR results show that SAS process does not change the chemical structure of HCPT. The result of in vitro drug release test indicated that the crystallinity of HCPT in microparticles affects the control release performance, and the good encapsulated microparticles with higher HCPT loading and higher crystallinity are better.Graphical abstractHighlights► HCPT and PLLA are co-precipitated by supercritical anti-solvent process using dichloromethane/ethanol co-solvent. ► The co-solvent has great effect on HCPT loading. ► HCPT is dispersed into the PLLA matrix. ► Drug existing in a crystalline form increases with an increase in HCPT loading. ► Good encapsulated microparticles with higher HCPT loading and higher crystallinity are better for control release of HCPT.

Recrystallzation and micronization of 10-hydroxycamptothecin (HCPT) was investigated in a supercritical antisolvent (SAS) process using the mixture of dichloromethane and ethanol as the solvent, with supercritical carbon dioxide (sc-CO2) as the antisolvent. Five factors—i.e., the volume ratio of the mixed solvent, the concentration of HCPT in the solution, the flow rate of HCPT solution, the precipitation pressure, and the temperature—were optimized using a selected OA16 (45) orthogonal array design. The unprocessed and processed HCPT particles were characterized using laser diffraction particle size analysis, Fourier transform infrared (FT-IR) spectroscopy, headspace gas chromatography, scanning electron microscopy (SEM), powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The results indicated that the micronized HCPT exhibited a much smaller particle size under the optimal conditions, and the mass median diameter of the micronized HCPT was found to be 223 ± 19 nm. SEM indicated a change in crystal habit for SAS-processed particles, and the results of powder XRD showed that different polymorphs were found after the SAS processing. Polymorph conversation was further demonstrated by DSC and TGA, and the results indicated that the SAS process modified the form of HCPT from monohydrate to anhydrous.

Solubility of disodium 5′-guanylate in water + ethanol binary solvent mixtures was determined by a gravimetric method in the temperature range from 283.15 K to 323.15 K, pH range from 8 to 10 and at different water/ethanol mole ratios. The effects of pH, temperature and water/ethanol mole ratio on the solubility were investigated in detail. The modified Apelblat model and the combined nearly ideal binary solvent (CNIBS)/Redlich–Kister model were selected to correlate the experimental data. The results showed that the experimental data was satisfactorily correlated by the (CNIBS)/Redlich–Kister model, but for the modified Apelblat model, the correlation was not so satisfactory in some cases.

The supercritical phase behavior of the poly(lactic acid)/poly(ethylene glycol)/poly(lactic acid) (PLA-PEG-PLA) + CO2 + dichloromethane (DCM) system and the PLA-PEG-PLA + CO2 + DCM + C2H5OH system was investigated using a supercritical phase monitor. The phase behavior data were measured at temperatures from (313.1 to 338.1) K and pressures up to 35 MPa. The results show that the systems exhibit the characteristics of lower critical solution temperature phase behaviors. The effects of temperature, the mass fraction of DCM (or DCM + C2H5OH), the PEG mass fraction in PLA-PEG-PLA, and the molar ratio of DCM/C2H5OH on cloud-point pressure were discussed in detail.

The solubility of β-artemether in methanol + water and ethanol + water was measured over the temperature range from (288.85 to 331.95) K under atmospheric pressure using a gravimetric method. The experimental data were satisfactorily correlated with a modified empirical logarithmic equation. The experimental solubility data show good agreement with the calculated values. The relative average deviations (RADs) between the experimental and calculated values are less than 3 %.

Paclitaxel (PTX) is an effective anticancer drug with poor solubility in water. Recently, much effort has been devoted into alternative formulations of PTX for improving its aqueous solubility. In this study, PTX and poly(L-lactic acid) (PLLA) were co-precipitated by a supercritical antisolvent (SAS) process using dichloromethane (DCM) and the mixtures of DCM/ethanol (EtOH) or DCM/dimethyl sulfoxide (DMSO) as the solvent, with supercritical carbon dioxide as the antisolvent. The effects of solvent, solvent ratio, temperature, pressure, polymer concentration and solution flow rate on particle morphology, mass median diameter (Dp50) and PTX loading were investigated using single-factor method. The particle samples were characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), laser diffraction particle size analyzer and high pressure liquid chromatography (HPLC). XRD results indicate that the micronized PTX is dispersed into the PLLA matrix in an amorphous form. SEM indicates that the solvent and the solvent ratio have great effect on the particle morphologies, and particle morphology is good at the volume ratio of DCM/EtOH of 50/50. For the mixed DCM/EtOH solvent, Dp50 increases with the increase of the temperature, pressure, PLLA concentration and solution flow rate, and PTX loading increases with pressure. Suitable operating conditions for the experimental system are as follows: DCM/EtOH = 50/50 (by volume), 35 °C, 10-12 MPa, PLLA concentration of 5 g·L−1 and solution flow rate of 0.5 ml·min−1.

Phase behavior of paclitaxel in solvent mixtures of dichloromethane and supercritical carbon dioxide was investigated using a supercritical phase monitor. Cloud point pressures were determined as a function of temperature, pressure and paclitaxel content from 313.1 to 343.1 K and pressures up to 33.52 MPa. The ternary mixtures exhibit a typical lower critical solution temperature behavior. When paclitaxel content increases, the single-phase region shrinks in size. Three cubic equations of state (Redlich-Kworng, Soave-Redlich-Kwong and Peng-Robinson equation of state) coupled with the van der Waals one-fluid mixing rules were selected to correlate the experimental data. The results indicate that SRK EOS coupled with two binary interaction parameters kij and lij can predict paclitaxel solubility for the best fit of experimental data.

•The effect of tailor-made additives on the crystallization of MP was investigated.•The crystal habit of MP crystals was greatly changed by the additives.•The change of crystal habits was induced by selective adsorption of additives.In this study, methyl paraben (MP) was selected as the model component, and acetaminophen (APAP), p-methyl acetanilide (PMAA) and acetanilide (ACET), which share the similar molecular structure as MP, were selected as the three tailor-made additives to study the effect of tailor-made additives on the crystal growth of MP. HPLC results indicated that the MP crystals induced by the three additives contained MP only. Photographs of the single crystals prepared indicated that the morphology of the MP crystals was greatly changed by the additives, but PXRD and single crystal diffraction results illustrated that the MP crystals were the same polymorph only with different crystal habits, and no new crystal form was found compared with other references. To investigate the effect of the additives on the crystal growth, the interaction between additives and facets was discussed in detail using the DFT methods and MD simulations. The results showed that APAP, PMAA and ACET would be selectively adsorbed on the growth surfaces of the crystal facets, which induced the change in MP crystal habits.Download high-res image (280KB)Download full-size image

Concentration monitoring is essential for quality control of crystallizations. This work establishes the technical feasibility of Ultraviolet (UV) fiber spectroscopy for on-line concentration measurement of anti-solvent crystallization of β-artemether, where ethanol was selected as solvent and water was used as anti-solvent. The orthogonal signal correction (OSC) algorithm was selected to preprocess the UV spectra, and the results showed that the wavelength shift of UV maximum absorbance of β-artemether in ethanol+water solvent mixtures can be effectively eliminated by OSC algorithm. Then models for prediction of β-artemether concentration based on Lambert–Beer law were developed, and the models were verified by comparison between the training set and the validation set, as well as its directly application to the anti-solvent crystallization process of β-artemether. The results show that the model is suitable for on-line concentration measurement of anti-solvent crystallization of β-artemether, with reasonable accuracy and precision.