Determination of Regorafenib monohydrate (colorectal anticancer drug) solubility in supercritical CO2: Experimental and thermodynamic modeling.

In this study, the solubilities of Regorafenib monohydrate (REG), a widely used as a colorectal anticancer drug, in supercritical carbon dioxide (ScCO2) were measured under various pressures and temperature conditions, for the first time. The minimum value of REG in mole fraction was determined to be 3.06×10-7, while the maximum value was found to be 6.44×10-6 at 338 K and 27 MPa. The experimental data for REG were correlated through the utilization of two types of models: (1) a set of 25 existing empirical and semi-empirical models that incorporated 3-8 parameters according to functional dependencies, (2) a model that relied on solid-liquid equilibrium (SLE) and the newly improved association models. All of the evaluated models were capable of generating suitable fits to the solubility data of REG, however, the average absolute relative deviation (AARD) of Gordillo et al. model (AARD=13.2%) and Reddy et al. model (AARD=13.5%) indicated their superiority based on AARD%. Furthermore, solvation and sublimation enthalpies of REG drug were estimated for the first time.

Evaluation of a temperature-responsive magnetotocosome as a magnetic targeting drug delivery system for sorafenib tosylate anticancer drug.

In this investigation, a polymeric fusion of chitosan (CS) and thermosensitive poly (N-isopropyl acrylamide) - PNIPAAm - encapsulated a magnetotocosome, biocompatible nanocarrier. This encapsulation strategy demonstrated improved drug entrapment efficiency, achieving up to 98.8 %. Additionally, it exhibited extended stability, optimal particle dimensions, and the potential for industrial scaling, thus facilitating controlled drug delivery of sorafenib tosylate to cancerous tissue. Reversible Addition-Fragmentation Chain Transfer (RAFT) techniques were employed to synthesize PNIPAAm. The effects of polymer molecular weight and polydispersity index on the lower critical solution temperature (LCST) were evaluated. The resulting polymeric amalgamation, involving the thermosensitive PNIPAAm synthesized using RAFT techniques and CS that coated the magnetotocosome (CS-Raft PNIPAAm-magnetotocosome) with an LCST approximately at 45 °C, holds the potential to enhance drug bioavailability and enable applications in hyperthermia treatment, controlled release, and targeted drug delivery.

Studies on solubility measurement of codeine phosphate (pain reliever drug) in supercritical carbon dioxide and modeling.

In this study, the solubilities of codeine phosphate, a widely used pain reliever, in supercritical carbon dioxide (SC-CO2) were measured under various pressures and temperature conditions. The lowest determined mole fraction of codeine phosphate in SC-CO2 was 1.297 × 10-5 at 308 K and 12 MPa, while the highest was 6.502 × 10-5 at 338 K and 27 MPa. These measured solubilities were then modeled using the equation of state model, specifically the Peng-Robinson model. A selection of density models, including the Chrastil model, Mendez-Santiago and Teja model, Bartle et al. model, Sodeifian et al. model, and Reddy-Garlapati model, were also employed. Additionally, three forms of solid-liquid equilibrium models, commonly called expanded liquid models (ELMs), were used. The average solvation enthalpy associated with the solubility of codeine phosphate in SC-CO2 was calculated to be - 16.97 kJ/mol. The three forms of the ELMs provided a satisfactory correlation to the solubility data, with the corresponding average absolute relative deviation percent (AARD%) under 12.63%. The most accurate ELM model recorded AARD% and AICc values of 8.89% and - 589.79, respectively.

A machine learning approach for thermodynamic modeling of the statically measured solubility of nilotinib hydrochloride monohydrate (anti-cancer drug) in supercritical CO2.

Nilotinib hydrochloride monohydrate (NHM) is an anti-cancer drug whose solubility was statically determined in supercritical carbon dioxide (SC-CO2) for the first time at various temperatures (308-338 K) and pressures (120-270 bar). The mole fraction of the drug dissolved in SC-CO2 ranged from 0.1 × 10-5 to 0.59 × 10-5, corresponding to the solubility range of 0.016-0.094 g/L. Four sets of models were employed to evaluate the correlation of experimental data; (1) ten empirical and semi-empirical models with three to six adjustable parameters, such as Chrastil, Bartle, Sparks, Sodeifian, Mendez-Santiago and Teja (MST), Bian, Jouyban, Garlapati-Madras, Gordillo, and Jafari-Nejad; (2) Peng-Robinson equation of state (Van der Waals mixing rule, had an AARD% of 10.73); (3) expanded liquid theory (modified Wilson model, on average, the AARD of this model was 11.28%); and (4) machine learning (ML) algorithms (random forest, decision trees, multilayer perceptron, and deep neural network with respective R2 values of 0.9933, 0.9799, 0.9724 and 0.9701). All the models showed an acceptable agreement with the experimental data, among them, the Bian model exhibited excellent performance with an AARD% of 8.11. Finally, the vaporization (73.49 kJ/mol) and solvation (- 21.14 kJ/mol) enthalpies were also calculated for the first time.

Solubility measurement and modeling of hydroxychloroquine sulfate (antimalarial medication) in supercritical carbon dioxide.

A supercritical fluid, such as supercritical carbon dioxide (scCO2) is increasingly used for the micronization of pharmaceuticals in the recent past. The role of scCO2 as a green solvent in supercritical fluid (SCF) process is decided by the solubility information of the pharmaceutical compound in scCO2. The commonly used SCF processes are the rapid expansion of supercritical solution (RESS) and supercritical antisolvent precipitation (SAS). To implement micronization process, solubility of pharmaceuticals in scCO2 is required. Present study is aimed at both measuring and modeling of solubilities of hydroxychloroquine sulfate (HCQS) in scCO2. Experiments were conducted at various conditions (P = 12 to 27 MPa and T = 308 to 338 K), for the first time. The measured solubilities were found to be ranging between (0.0304 × 10-4 and 0.1459 × 10-4) at 308 K, (0.0627 × 10-4 and 0.3158 × 10-4) at 318 K, (0.0982 × 10-4 and 0.4351 × 10-4) at 328 K, (0.1398 × 10-4 and 0.5515 × 10-4) at 338 K. To expand the usage of the data, various models were tested. For the modelling task existing models (Chrastil, reformulated Chrastil, Méndez-Santiago and Teja (MST), Bartle et al., Reddy-Garlapati, Sodeifian et al., models) and new set of solvate complex models were considered. Among the all models investigated Reddy-Garlapati and new solvate complex models are able to fit the data with the least error. Finally, the total and solvation enthalpies of HCQS in scCO2 were calculated with the help of model constants obtained from Chrastil, reformulated Chrastil and Bartle et al., models.

Solubility measurement and thermodynamic modeling of pantoprazole sodium sesquihydrate in supercritical carbon dioxide.

Knowing the solubility data of pharmaceutical compounds in supercritical carbon dioxide (ScCO2) is essential for nanoparticles formation by using supercritical technology. In this work, solubility of solid pantoprazole sodium sesquihydrate in ScCO2 is determined and reported at 308, 318, 328 and 338 K and at pressures between 12 and 27 MPa. The solubilities are ranged between 0.0301 [Formula: see text] 10-4 and 0.463 [Formula: see text] 10-4 in mole fraction. The determined solubilities are modelled with a new model using solid-liquid equilibrium criteria and the required activity coefficient is developed using regular solution theory. The measured solubilities data are also modelled with three recent and four conventional empirical models. The recent models used are, Alwi-Garlapati (AARD = 13.1%), Sodeifian et al. (14.7%), and Tippana-Garlapati (15.5%) models and the conventional models used are Chrastil (17.54%), reformulated Chrastil (16.30%), Bartle (14.1%) and Mendenz Santiago and Teja (MT) (14.9%) models. The proposed model is correlating the data with less than 14.9% and 16.23% in terms of AARD for temperature dependent and independent cases. Among exiting models, Mendez Santiago and Teja (MT) and Alwi-Garlapati models correlate the data better than other models (corresponding AARD% and AICc are 14.9, 13.1 and -518.89, -504.14, respectively). The correlation effectiveness of the models is evaluated in terms of Corrected Akaike's Information Criterion (AICc). Finally, enthalpy of solvation and vaporization of pantoprazole sodium sesquihydrate are calculated and reported. The new model proposed in this study can be used for the combination of any complex compound with any supercritical fluid.

Experimental solubility and thermodynamic modeling of empagliflozin in supercritical carbon dioxide.

The solubility of empagliflozin in supercritical carbon dioxide was measured at temperatures (308 to 338 K) and pressures (12 to 27 MPa), for the first time. The measured solubility in terms of mole faction ranged from 5.14 × 10-6 to 25.9 × 10-6. The cross over region was observed at 16.5 MPa. A new solubility model was derived to correlate the solubility data using solid-liquid equilibrium criteria combined with Wilson activity coefficient model at infinite dilution for the activity coefficient. The proposed model correlated the data with average absolute relative deviation (AARD) and Akaike's information criterion (AICc), 7.22% and - 637.24, respectively. Further, the measured data was also correlated with 11 existing (three, five and six parameters empirical and semi-empirical) models and also with Redlich-Kwong equation of state (RKEoS) along with Kwak-Mansoori mixing rules (KMmr) model. Among density-based models, Bian et al., model was the best and corresponding AARD% was calculated 5.1. The RKEoS + KMmr was observed to correlate the data with 8.07% (correspond AICc is - 635.79). Finally, total, sublimation and solvation enthalpies of empagliflozin were calculated.

Investigation of Temperature-Responsive Tocosomal Nanocarriers as the Efficient and Robust Drug Delivery System for Sunitinib Malate Anti-Cancer Drug: Effects of MW and Chain Length of PNIPAAm on LCST and Dissolution Rate.

In this study, for the first time, the coated tocosome by blend of chitosan, CS, and poly(N-isopropylacrylamide), PNIPAAm, was developed as the efficient and robust drug delivery system with improved drug encapsulation efficiency, extended stability, proper particle size and industrial upscaling for Sunitinib malate anti-cancer drug. Tocosome was synthesized by using Mozafari method as a scalable and robust method and without the need for organic solvents. The effects of tocosome composition and drug concentration on the stability, particle size of tocosome, zeta potential, encapsulation efficacy and loading of drug into it were investigated by Taguchi method, and optimum composition was selected for combining with the polymeric blend. Homopolymer of PNIPAAm was synthesized by two different polymerization methods, including free radical and reversible addition-fragmentation chain transfer (RAFT). Effects of molecular weight (MW) and chain length of the polymers on lower critical solution temperature (LCST) were examined. The developed nanocarrier in this research, CS-Raft-PNIPAAm-tocosome, indicated LCST value beyond 37°C (about 45°C) and this is suitable for hyperthermia and spatio-temporal release of drug particles.

Measurement and modeling of clemastine fumarate (antihistamine drug) solubility in supercritical carbon dioxide.

The solubilities of clemastine fumarate in supercritical carbon dioxide (ScCO2) were measured for the first time at temperature (308 to 338 K) and pressure (12 to 27 MPa). The measured solubilities were reported in terms of mole faction (mol/mol total) and it had a range from 1.61 × 10-6 to 9.41 × 10-6. Various models were used to correlate the data. The efficacy of the models was quantified with corrected Akaike's information criterion (AICc). A new cluster salvation model was derived to correlate the solubility data. The new model was able to correlate the data and deviation was 10.3% in terms of average absolute relative deviation (AARD). Furthermore, the measured solubilities were also correlated with existing K.-W. Chen et al., model, equation of state model and a few other density models. Among density models, Reddy and Garlapati model was observed to be the best model and corresponding AARD was 7.57% (corresponding AICc was - 678.88). The temperature independent Peng-Robinson equation of state was able to correlate the data and AARD was 8.25% (corresponding AICc was - 674.88). Thermodynamic parameters like heats of reaction, sublimation and solvation of clemastine fumarate were calculated and reported.

Solubility of Ketoconazole (antifungal drug) in SC-CO2 for binary and ternary systems: measurements and empirical correlations.

One of the main steps in choosing the drug nanoparticle production processes by supercritical carbon dioxide (SC-CO2) is determining the solubility of the solid solute. For this purpose, the solubility of Ketoconazole (KTZ) in the SC-CO2, binary system, as well as in the SC-CO2-menthol (cosolvent), ternary system, was measured at 308-338 K and 12-30 MPa using the static analysis method. The KTZ solubility in the SC-CO2 ranged between 0.20 × 10-6 and 8.02 × 10-5, while drug solubility in the SC-CO2 with cosolvent varied from 1.2 × 10-5 to 1.96 × 10-4. This difference indicated the significant effect of menthol cosolvent on KTZ solubility in the SC-CO2. Moreover, KTZ solubilities in the two systems were correlated by several empirical and semiempirical models. Among them, Sodeifian et al., Bian et al., MST, and Bartle et al. models can more accurately correlate experimental data for the binary system than other used models. Also, the Sodeifian and Sajadian model well fitted the solubility data of the ternary system with AARD% = 6.45, Radj = 0.995.

Diffusional interaction behavior of NSAIDs in lipid bilayer membrane using molecular dynamics (MD) simulation: Aspirin and Ibuprofen.

In this research, for the first time, molecular dynamics (MD) method was used to simulate aspirin and ibuprofen at various concentrations and in neutral and charged states. Effects of the concentration (dosage), charge state, and existence of an integral protein in the membrane on the diffusion rate of drug molecules into lipid bilayer membrane were investigated on 11 systems, for which the parameters indicating diffusion rate and those affecting the rate were evaluated. Considering the diffusion rate, a suitable score was assigned to each system, based on which, analysis of variance (ANOVA) was performed. By calculating the effect size of the indicative parameters and total scores, an optimum system with the highest diffusion rate was determined. Consequently, diffusion rate controlling parameters were obtained: the drug-water hydrogen bond in protein-free systems and protein-drug hydrogen bond in the systems containing protein.

Molecular dynamics simulation study of chitosan and gemcitabine as a drug delivery system.

By using molecular dynamics (MD) simulation, biodegradable biopolymer chitosan as a carrier for the drug gemcitabine was investigated and the effect of three initial drug concentrations (10, 40, and 80%) on its loading efficiency was studied. Then water was added to the systems of drug and biopolymer and the effects of water on the interactions of drug and chitosan and on the drug loading efficiency were examined. From the results it was found that the maximum loading of the drug occurred at 40% of the drug concentration. The radial distribution function calculations indicated that in the absence of water molecules, the drug molecules were located at shorter distance from chitosan and the loading efficiency of the drug in these systems was higher.