Antisolvent Precipitation Process Research Articles

Investigation of the Influence of Anti-Solvent Precipitation Parameters on the Physical Stability of Amorphous Solids.

Amorphous solids exhibit enhanced solubility and dissolution rates relative to their crystalline counterparts. However, attaining optimal bioavailability presents a challenge, primarily due to the need to maintain the physical stability of amorphous solids. Moreover, the precise manner in which precipitation parameters, including the feeding rate of the anti-solvent, agitation speed, and aging time, influence the physical stability of amorphous solids remains incompletely understood. Consequently, this study aimed to investigate these three parameters during the precipitation process of the anticancer drug, nilotinib free base. The physical stability of the resultant samples was evaluated by employing characterization techniques including powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), focused beam reflectance measurement (FBRM), and data analysis methods such as pair distribution function (PDF), reduced crystallization temperature (Rc), and principal component analysis (PCA). This study's findings indicated that amorphous solids exhibited the greatest physical stability under particular conditions, namely a feeding rate of 5 mL/min, an agitation speed of 500 rpm, and an aging time of 10 min. Furthermore, the physical stability of the amorphous solids was primarily influenced by particle size and distribution, molecular interactions, microstructure, surface area, and interfacial energy. Notably, the parameters involved in the anti-solvent precipitation process, including the feeding rate of the anti-solvent, agitation speed, and aging time, exerted a significant impact on these factors. Consequently, they directly affected the physical stability of amorphous solids. Hence, this study comprehensively elucidated the mechanistic influence of these operational parameters on the physical stability of amorphous solids during the anti-solvent precipitation process.

A novel organogel of breviscapine via supramolecular self-assembly in DCM

Supramolecular gels provide great advantages for technological applications. More recently, the natural product gelators (NPGs) has been revealed as an interesting strategy to produce soft materials while combining stimuli-responsiveness and biological activities. However, the discovered NPGs till now was quite rare in spite of the enormous quantity of natural products. Herein, a supramolecular organogel with novel architecture was reported for the first time. Breviscapine (Bre), a natural flavonoid glycoside, was found to be spontaneously forming gels in dichloromethane during the ultrasonication-aided anti-solvent precipitation process. The corresponding xerogel were revealed a spherical network of packed microspheres and maintained a certain crystalline state. Hydrogen bonding and π-π stacking were confirmed as the main driving forces for the self-assembly of the organogel by FTIR, NMR and molecular dynamic simulation analysis. Moreover, the obtained Bre organogel showed excellent solvent-retention property and higher skin penetration rate than the pure drug. These would be of great benefit for future discovery of new NPGs and exploration on novel applications of NPG-based gels.

Scale-up of antisolvent precipitation process with ultrasonic microreactors: Cavitation patterns, mixing characteristics and application in nanoparticle manufacturing

In this study, a seamless scale-up strategy for the antisolvent precipitation process was developed using a series of ultrasonic microreactors (USMRs). The key principle of this scale-up strategy was to maintain a constant mixing time, ensuring consistent nanoparticle (NP) production across different scales. First, lab- and production-scale USMRs were developed, enabling the customization of reactors to varying ultrasound frequencies, channel diameters, and power outputs. Then, the distinct cavitation patterns, including array, slug cluster and cluster, along with their corresponding mixing performances were studied in nine USMRs. By establishing a comprehensive map of cavitation patterns, primary factors affecting the formation of cavitation patterns were identified. Among the three cavitation patterns, the slug cluster pattern demonstrated the best mixing performance, wherein cavitation bubbles effectively occupied the channel and traversed rapidly across the cross-section. To guide the operation of USMRs under the slug cluster pattern, a tailored mixing model was developed. This model, in combination with the relationship between NP size and mixing time, enabled the successful seamless scale-up production of 55 nm PLGA-PEG NPs, with a required mixing time of 27 ms. This USMR-based scale-up strategy facilitated efficient process screening with low sample consumption (2 mL/min, 200 μL/sample) as well as high-throughput production (100 mL/min, 30 g/h).

Cavitation behavior and mixing performance of antisolvent precipitation process in an ultrasonic micromixer

AbstractA facile and robust ultrasonic micromixer was developed to intensify antisolvent precipitation via ultrasonic cavitation. The gas supersaturation created from solvent–antisolvent mixing was found to be a novel driving force which facilitated the generation of cavitation bubbles (CBs). Instead of being attached on the channel wall, numerous CBs translated across the microchannel at a speed up to 1.7 m/s, inducing intense transverse flow over the cross‐section. The unique cavitation behavior enabled rapid mixing (mixing time 15–45 ms at 30 W) of solvent–antisolvent over wide Reynolds number range (70–500) and flow rate ratio (5:1–2:3), providing better operability for antisolvent precipitation. The effects of ultrasonic power, total flow rate, flow rate ratio, and solvent on cavitation behavior and mixing performance were quantitatively studied. Finally, the potential of the ultrasonic micromixer as a new tool for antisolvent precipitation was demonstrated by synthesizing size‐controllable and monodisperse polymeric nanoparticles in a high‐throughput and reproducible manner.

Extraction and purification of curcuminoids from Curcuma longa using microwave assisted deep eutectic solvent based system and cost estimation

Deep eutectic solvents (DESs) are explored to develop sustainable and green processes as an alternative to conventional solvents. Likewise, microwave-assisted extraction (MAE) is a widely studied eco-friendly method owing to enhanced extraction of biomolecules with lower solvent and time requirement. The present work illustrated the combined effect of DES as a green medium under microwave irradiation to enhance curcuminoids extraction from turmeric. Choline chloride-alcohol, -acid, and -amide DESs were screened under the microwave, and choline chloride-citric acid (ChCl-CA) DES was stable and resulted in maximum extraction at a 1:1 molar ratio. The ChCl-CA DES yielded 89.87 mg/g curcuminoids with 30% water addition, 1:20 (g/mL) solid to DES ratio, and 0.150 > 0.212 µm particle size under 60 W microwave power and “HIGH stirring” mode in 8 min soaking time and 6 min of irradiation time. Moreover, 43 ± 1.78% curcuminoids were recovered from MA-DES extract by anti-solvent precipitation process comprising 82.32% purity. In addition, the MA-DES method drastically reduced the solvent requirement and extraction time, thereby minimizing energy consumption and cost compared to conventional extraction processes. FT-IR data confirmed the hydrogen bonding formation in DES. The optimized MA-DES extraction process can be implemented as a green and effective alternative to traditional methods for extracting bioactive compounds.

CFD simulation and experimental study of antisolvent precipitation through impinging jets for synthesis of nanodrug particles

The nucleation and growth kinetics of loratadine, one of the primary antihistamines among drugs, are determined experimentally in confined liquid impinging jet channels, followed by simulating the anti-solvent precipitation process to obtain ultrafine loratadine nanoparticles. The effect of supersaturation is assessed as the essential factor on the nucleation and growth rates. Based on classical nucleation theory, induction time and nucleation rate showed homogeneous and heterogeneous nucleation regions in high and low supersaturations, respectively. The interfacial free energy measured from the induction time is obtained at about 18.99 mJ/m2. The size-dependent particle growth and growth dispersion effects are assessed through the experimental data. The nonlinear curve fitting with the experimental data in log population density plot at residence time of 7.69 s reveals that the four-parameter model has a better fit, with no growth dispersion. The microchannel mixing performance is assessed by analyzing the Damkohler number under different Reynolds numbers. The loratadine particle size distribution (CSD) is obtained by combining the population balance equation with the computational fluid dynamics in following the discretization method with and without turbulence aggregation kernel. The simulated CSD with turbulence aggregation kernel are 7 % more consistent with experimental results. The effects of collision angle, outlet nozzle length, Reynolds number, and solution concentration on the average particle size are assessed. An increase in the collision angle from 60 to 180°decreases the average particle size. The ultrafine loratadine nanoparticles of 49 nm are obtained with a narrow distribution, related to the angle of 180⁰, outlet nozzle length of 0.5 cm, Reynolds number of 4875, and the solution concentration of 35 mg/ml.

Curcumin nanospheres and nanorods: Synthesis, characterization and anticancer activity

Development in nanotechnology and its biological application have progressively contributes to the interaction of nanoparticles with cells which helps in treating/diagnosing cancer like diseases. In order to understand the morphological transformation of drug nanoparticles interaction on cancerous cells, we prepared curcumin nanorods (CNRs) and curcumin nanospheres (CNSs) by antisolvent precipitation process. The size, surface charge and morphology were analyzed by Dynamic Light Scattering (DLS) and High Resolution Transmission Microscope (HRTEM). The size of both the nanoparticles ranges below 50 nm and the zeta potential showed the negative surface charge. Powder X-ray Diffraction (PXRD) and Fourier Transformer Infra-Red spectroscopy (FTIR) studies revealed the crystal systems (monoclinic and orthorhombic forms) of curcumin nanoparticles. The cytotoxicity of these drugs was tested using MTT assay, where CNRs exhibited a little more anticancer activity and apoptosis than CNSs in HepG2 cells. Hence, we suggest that the morphological variation may act as another factor, which influences apoptotic cell death in spite of the surface charge.

Shape-controlled fabrication of zein and peach gum polysaccharide based complex nanoparticles by anti-solvent precipitation for curcumin-loaded Pickering emulsion stabilization

Owing to the high desorption energy of colloidal particles, Pickering emulsions can effectively protect the encapsulated bioactives. In this study, zein and peach gum polysaccharide (PGP) based biopolymeric nanoparticles were fabricated to stabilize the Pickering emulsion and deliver curcumin. Effects of the PGP addition order during and after anti-solvent precipitation process (zein-PGP nanoparticles or zein/PGP nanoparticles) on the properties of nanoparticles were discussed. The zein-PGP nanoparticles were spherical with mean size of 172.8 nm, while zein/PGP nanoparticles were rod-like with mean size of 207.5 nm. Both zein-PGP and zein/PGP nanoparticles were negatively charged with the wettability of 93.5° and 90.3°, respectively. Compared to the zein NPs, the zein-PGP and zein/PGP nanoparticles stabilized emulsions had smaller droplet size, better storage and environmental stabilities. The release rates of curcumin in zein-PGP nanoparticles and zein/PGP nanoparticles stabilized emulsions were 23.4% and 26.7% respectively in simulated gastric fluid. The curcumin release rates in zein-PGP nanoparticles and zein/PGP nanoparticles stabilized emulsions were 32.5% and 24.0% respectively in simulated intestinal fluid. These findings might promote an effective delivery system for bioactive food ingredients using zein and PGP based complex nanoparticles.

Facile encapsulation of thymol within deamidated zein nanoparticles for enhanced stability and antibacterial properties

Thymol is one of the main essential oils derived from oregano with wide-ranging potential applications, such as antioxidation, anti-inflammation, and antibacterial properties. However, its low water solubility and bioavailability, as well as poor stability, have severely restricted its practical applications. Herein, deamidated zein nanoparticles loaded with thymol (DZTNPs) have been successfully prepared using the antisolvent precipitation approach. Particularly, a common alkaline deamidation method is used to pretreat zein as the particle precursor. Scanning electron microscopy, dynamic light scattering, zeta potential measurement, X-ray diffraction and differential scanning calorimeter have been used to characterize the resultant DZTNPs. It is worth noting that after freeze-drying, deamidated zein nanoparticles loaded with thymol have good redispersibility and physical stability stored at 4 °C. Furthermore, the as-prepared DZTNPs have greater antibacterial efficacy against E. coli and S. aureus than unencapsulated thymol for a longer period of time. Therefore, this study provides a viable vehicle for delivering hydrophobic active compounds, which is of significance in the application of food, cosmetics and pharmaceutics. Deamidated zein nanoparticles loaded with thymol are prepared by an antisolvent precipitation process, which have good dispersion stability and re-dispersibility after freeze-drying, as well as a better antibacterial performance than unencapsulated thymol.

Preparation of Aspirin Nanosuspension by Antisolvent Precipitation Method

Preparation of Aspirin Nanosuspension by Antisolvent Precipitation Method

Hydrophilic and Functionalized Nanographene Oxide Incorporated Faster Dissolving Megestrol Acetate.

The aim of this work is to present an approach to enhance the dissolution of progestin medication, megestrol acetate (also known as MEGACE), for improving the dissolution rate and kinetic solubility by incorporating nano graphene oxide (nGO). An antisolvent precipitation process was investigated for nGO-drug composite preparation, where prepared composites showed crystalline properties that were similar to the pure drug but enhanced aqueous dispersibility and colloidal stability. To validate the efficient release profile of composite, in vitro dissolution testing was carried out using United States Pharmacopeia, USP-42 paddle method, with gastric pH (1.4) and intestinal pH (6.5) solutions to mimic in vivo conditions. Pure MA is practically insoluble (2 µg/mL at 37 °C). With the incorporation of nGO, it was possible to dissolve nearly 100% in the assay. With the incorporation of 1.0% of nGO, the time required to dissolve 50% and 80% of drug, namely T50 and T80, decreased from 138.0 min to 27.0 min, and the drug did not dissolve for 97.0 min in gastric media, respectively. Additionally, studies done in intestinal media have revealed T50 did not dissolve for 92.0 min. This work shows promise in incorporating functionalized nanoparticles into the crystal lattice of poorly soluble drugs to improve dissolution rate.

Preparation, stabilisation, isolation and tableting of valsartan nanoparticles using a semi-continuous carrier particle mediated process

This work investigated the technical feasibility of preparing, stabilizing and isolating poorly water-soluble drug nanoparticles via a small-scale antisolvent precipitation process operating in semi-continuous mode. Specifically, a novel semi-continuous process was demonstrated for the carrier particle mediated production, stabilization and isolation of valsartan nanoparticles into a solid form using montmorillonite clay particles as the carrier. The semi-continuous process operated robustly for the full duration of the experiment (~16 min) and steady-state conditions were reached after ~5 min. Nanoparticles of valsartan (51 ± 1 nm) were successfully prepared, stabilized and isolated with the help of montmorillonite (MMT) or protamine functionalized montmorillonite (PA-MMT) into the dried form by this semi-continuous route. The dissolution profile of the isolated valsartan nanocomposite solids was similar to that of valsartan nanocomposite solids produced via the corresponding laboratory scale batch mode process, indicating that the product quality (principally the nanoscale particle size and solid-state form) is retained during the semi-continuous processing of the nanoparticles. Furthermore, tablets produced via direct compression of the isolated valsartan nanocomposite solids displayed a dissolution profile comparable with that of the powdered nanocomposite material. PXRD, DSC, SSNMR and dissolution studies indicate that the valsartan nanoparticles produced via this semi-continuous process were amorphous and exhibited shelf-life stability equivalent to > 10 months.

Empirical Modelling of Hydrodynamic Effects on Starch Nanoparticles Precipitation in a Spinning Disc Reactor.

Empirical correlations have been developed to relate experimentally determined starch nanoparticle size obtained in a solvent–antisolvent precipitation process with key hydrodynamic parameters of a spinning disc reactor (SDR). Three different combinations of dimensionless groups including a conventional Reynolds number (Re), rotational Reynolds number (Reω) and Rossby number (Ro) have been applied in individual models for two disc surfaces (smooth and grooved) to represent operating variables affecting film flow such as liquid flowrate and disc rotational speed, whilst initial supersaturation (S) has been included to represent varying antisolvent concentrations. Model 1 featuring a combination of Re, Reω and S shows good agreement with the experimental data for both the grooved and smooth discs. For the grooved disc, Re has a greater impact on particle size, whereas Reω is more influential on the smooth disc surface, the difference likely being due to the passive mixing induced by the grooves irrespective of the magnitude of the disc speed. Supersaturation has little impact on particle size within the limited initial supersaturation range studied. Model 2 which characterises both flow rate and disc rotational speed through Ro alone and combined with Re was less accurate in predicting particle size due to several inherent limitations.

Enhanced Water Solubility and Oral Bioavailability of Paclitaxel Crystal Powders through an Innovative Antisolvent Precipitation Process: Antisolvent Crystallization Using Ionic Liquids as Solvent.

Paclitaxel (PTX) is a poor water-soluble antineoplastic drug with significant antitumor activity. However, its low bioavailability is a major obstacle for its biomedical applications. Thus, this experiment is designed to prepare PTX crystal powders through an antisolvent precipitation process using 1-hexyl-3-methylimidazolium bromide (HMImBr) as solvent and water as an antisolvent. The factors influencing saturation solubility of PTX crystal powders in water in water were optimized using a single-factor design. The optimum conditions for the antisolvent precipitation process were as follows: 50 mg/mL concentration of the PTX solution, 25 °C temperature, and 1:7 solvent-to-antisolvent ratio. The PTX crystal powders were characterized via scanning electron microscopy, Fourier transform infrared spectroscopy, high-performance liquid chromatography–mass spectrometry, X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Raman spectroscopy, solid-state nuclear magnetic resonance, and dissolution and oral bioavailability studies. Results showed that the chemical structure of PTX crystal powders were unchanged; however, precipitation of the crystalline structure changed. The dissolution test showed that the dissolution rate and solubility of PTX crystal powders were nearly 3.21-folds higher compared to raw PTX in water, and 1.27 times higher in artificial gastric juice. Meanwhile, the bioavailability of PTX crystal increased 10.88 times than raw PTX. These results suggested that PTX crystal powders might have potential value to become a new oral PTX formulation with high bioavailability.

Enhancement of the apparent solubility and bioavailability of Tadalafil nanoparticles via antisolvent precipitation

The ability to increase the bioavailability and dissolution of poorly soluble hydrophobic drugs has been a major challenge for pharmaceutical development. This study shows that the dissolution rate, apparent solubility and oral bioavailability of tadalafil (Td) can be improved by nano-sized amorphous particles prepared by using antisolvent precipitation. Acetone and an acetone-water solution (v:v, 9:1) were selected as solvents, with deionized water as the antisolvent. The antisolvent precipitation process was conducted at a constant drug concentration of 10 mg/ml, at temperatures of 5, 10 and 15 °C and at volume ratios of antisolvent to solvent (AS/S) of 5, 8 and 10. Solid dispersion was achieved by dissolving the polymer in the antisolvent prior to the precipitation and by spray drying the suspension after the antisolvent precipitation process. The selected polymers were HPMC, VA64, and PVPK30 at concentrations of 33, 100 and 300 mg per 100 ml of water (equivalent to weight ratios of drug-to-polymer of 1:3, 1:1 and 3:1, respectively). The solid dispersions were characterized by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and fourier transform infrared spectroscopy (FT-IR). The improvements in the dissolution rate, equilibrium solubility, apparent solubility and bioavailability were tested and compared with unprocessed Td. Td particles in the suspension (before spray drying) were 200 nm, and the obtained Td solid dispersion had a size of approximately 5–10 μm. The XRPD, DSC and FT-IR analyses confirmed that the prepared Td particles in the solid dispersions were amorphous. The solid dispersion obtained using the optimized process conditions exhibited 8.5 times faster dissolution rates in the first minute of dissolution, 22 times greater apparent solubility at 10 min and a 3.67-fold increase in oral bioavailability than the as-received Td. The present work demonstrated that low temperature antisolvent precipitation technique has excellent potential to prepare nano-sized amorphous particles with a faster release and a higher bioavailability.

Impact of molecular rearrangement of amphiphilic stabilizers on physical stability of itraconazole nanoparticles prepared by flash nanoprecipitation

Flash nanoprecipitation (FNP) is a controlled antisolvent precipitation process that has proven effective for consistent production of drug nanoparticles with a defined mean particle size and narrow particle size distribution. However, physical instability of the generated nanoparticles remains a major challenge in the application of this technology in pharmaceutical formulation. Aimed at resolving this problem, the present study has investigated the FNP process and associated stabilization mechanism of itraconazole (ITZ) nanoparticles through in-depth nanoparticle characterization. Results showed that ITZ nanoparticles could be reproducibly produced with a mean particle size <100 nm and a polydispersity index <0.2 in the presence of amphiphilic stabilizers (ASs). Surface analysis of freshly formed nanoparticles by X-ray photoelectron spectroscopy (XPS) revealed initially a disordered packing structure and subsequently a time-dependent molecular rearrangement of incorporated AS towards a micelle-like structure. The faster the molecular rearrangement of AS, the more stable the nanoparticles, as monitored by the change in particle size with time. These findings may have important implications for the selection of effective ASs for formulating stable drug nanoparticles. The present study is the first of its kind to demonstrate the utility of XPS to track the molecular transport of stabilizers in rapidly generated nanoparticles.

A Reduced Graphene Oxide/Disodium Terephthalate Hybrid as a High-Performance Anode for Sodium-Ion Batteries.

As a promising candidate for large-scale energy storage systems, sodium-ion batteries (SIBs) are experiencing a rapid development. Organic conjugated carboxylic acid anodes not only have tailorable electrochemical properties but also are easily accessible. However, the low stability and electrical conductivity hamper their practical applications. In this study, disodium terephthalate (Na2 TP), the most favorable organic conjugated carboxylic acid anode material for SIBs, was proposed to integrate with graphene oxide (GO) by an anti-solvent precipitation process, which ensures the uniform and tight coating of GO on the Na2 TP surface. GO is electrochemically reduced during the first several cycles of the electrochemical measurement, which buffers the volume change and improves the electrical conductivity of Na2 TP, resulting in a better cyclic and rate performance. The incorporation of only 5 wt % GO onto Na2 TP leads to a reversible capability of 235 mA h g-1 after 100 cycles at a current rate of 0.1 C, which is the best among the state of the art organic anodes for SIBs. The one-step synthesis together with the low costs of the raw materials show a promise for the scalable preparation of anode materials for practical SIBs.

Statistical optimization of curcumin nanosuspension through liquid anti-solvent precipitation (LASP) process in a microfluidic platform: Box-Behnken design approach

The paper deals with the development and optimization of curcumin nanosuspension by solvent/anti-solvent precipitation method in a microfluidic platform. A three-level Box-Behnken design was applied as an optimizing technique to investigate the effect of three independent operating variables, namely, volume ratios of anti-solvent to solvent, flow rate of drug solution, and curcumin concentration on the preferred response. In presence of PVP as the stabilizer, a nano-curcumin suspension was obtained in the range of 62–335 nm. Analysis of variance showed that the variables with the highest effect were the linear effects of the anti-solvent to solvent ratio, and its corresponding squared term. Applying response surface methodology, curcumin nanosuspension with average size of 63.12 nm can be obtained under optimum condition As: S=15, solvent flow rate of 1.0 mL/min and curcumin ethanolic concentration of 5.0 mg/mL. The prepared nanoparticles were further characterized by infrared spectroscopy, scanning electron microscopy, and X-ray diffraction tests.

Nanonization of ciprofloxacin using subcritical water-ethanol mixture as the solvent: Solubility and precipitation parameters

Ciprofloxacin (CIP) has been widely used to treat many types of bacterial infections. Herein, we reported a green approach for preparation of CIP nanoparticles via solvent anti-solvent precipitation by using subcritical water-ethanol mixture as the solvent. The solubility of CIP in subcritical water-ethanol mixture (with various ethanol ratio of 0, 5, and 20wt%) at the temperature range from 100°C to 170°C and constant pressure of 4MPa were measured. The chemical structure of CIP was stable after processed in subcritical water-ethanol mixture at up to 170°C, confirmed by Fourier transformed infrared analysis. The obtained solubility data of CIP were correlated using a modified Apelblat model and the results of the predicted solubility show good agreement with the experimental value. The nanonization of CIP via solvent anti-solvent precipitation process that used the tunable solvent power of subcritical water-ethanol mixture was conducted. Two kinds of no-ionic, hydrophilic polymer, including polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG), were introduced as stabilizers in the precipitation process to obtain CIP nanoparticle with improved dissolution rate. These results show that as-synthesized CIP nanoparticles are promising for oral administration of CIP drugs.

Assessment of the liquid mixture density effect on the prediction of supercritical carbon dioxide volume expansion of organic solvents by Peng-Robinson equation of state

Volume expansion and liquid mixture density are key-factors to design particle precipitation processes from expanded organic solvents using supercritical fluids such as carbon dioxide. To predict volume expansion it is necessary to know the volume or the density of the liquid mixture that is in equilibrium with its vapor at a certain temperature, pressure and composition. However, equations of state that fail to accurately describe the liquid mixture density are used to predict the volume expansion and results are considered satisfactory. In this work we investigated why this occurs using vapor-liquid equilibrium data of 13 binary systems containing CO2 and an organic solvent at high pressures with wide spread application in supercritical anti-solvent particle precipitation processes. Peng-Robinson cubic equation of state was applied with quadratic (PR-QMR) and LCVM-UNIFAC mixing rules (PR-LCVM-UNIFAC), and Peneloux’s volume correction was adopted too (PR-QMR-Peneloux). The results show that there is an offset of terms during volume expansion calculation that explains why large deviations in the prediction of liquid mixture density from bubble pressure data can lead to small deviations in prediction of organic solvents volume expansion by carbon dioxide.