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In the current investigation, the solubility of fenoprofen as a nonsteroidal anti-inflammatory drug in supercritical CO2 (SC-CO2) is measured by employing a motorized PVT (pressure–volume–temperatu...

Design and development of efficient processes for continuous manufacturing of solid dosage oral formulations is of crucial importance for pharmaceutical industry in order to implement the Quality-by-Design paradigm. Supercritical solvent-based manufacturing can be utilized in pharmaceutical processing owing to its inherent operational advantages. However, in order to evaluate the possibility of supercritical processing for a particular medicine, solubility measurement needs to be carried out prior to process design. The current work reports a systematic solubility analysis on decitabine as an anti-cancer medicine. The solvent is supercritical carbon dioxide at different conditions (temperatures and pressures), while gravimetric technique is used to obtain the solubility data for decitabine. The results indicated that the solubility of decitabine varies between 2.84 × 10–05 and 1.07 × 10–03 mol fraction depending on the temperature and pressure. In the experiments, temperature and pressure varied between 308–338 K and 12–40 MPa, respectively. The solubility of decitabine was plotted against temperature and pressure, and it turned out that the solubility had direct relation with the pressure due to the effect of pressure on solvating power of solvent. The effect of temperature on solubility was shown to be dependent on the cross-over pressure. Below the cross-over pressure, there is a reverse relation between temperature and solubility, while a direct relation was observed above the cross-over pressure (16 MPa). Theoretical study was carried out to correlate the solubility data using several thermodynamic-based models. The fitting and model calibration indicated that the examined models were of linear nature and capable to predict the measured decitabine solubilities with the highest average absolute relative deviation percent (AARD %) of 8.9%.

One of the effective medications for Glioblastoma Multiforme is Temozolomide (TMZ) which is taken as a treatment for some brain cancers. With respect to the importance of this drug in cancer therapy, the solubility of this medicine was analyzed under various ranges of pressure and temperature in supercritical carbon dioxide (SC-CO2) to evaluate the possibility of drug micronization for reducing its undesired side effects. The measurements were conducted using gravimetric method and revealed that the solubility of the drug is between 4.30 × 10−4 to 5.28 × 10−3 based on mole fraction. The results demonstrated the strong dependency of the TMZ solubility to pressure and temperature, while the effect of pressure is more profound at higher temperatures. Besides, the calculated solubility data was correlated employing five popular semi-empirical density-based correlations including Bartle et al., Chrastil, Kumar and Johnston, Mendez-Santiago-Teja, and Garlapati & Madras models. The obtained outcomes illustrated that among the tested models, KJ led to the best correlative ability with average absolute relative deviation percent (AARD %) of 8.39%, while Garlapati and Madras led to the worst modeling results with AARD % of 15.20%.

Particle size and morphology are among the most important parameters which must be precisely controlled in pharmaceutical industries to enhance the effectiveness of the solid dosage oral formulations. One of the most interesting methods for controlling these two quality attributes is supercritical fluid based technologies by which the drug solubility in supercritical (SC) solvent, commonly carbon dioxide, dictates whether the used method is applicable for suitable particle production or not. In this work, solubility of an anti-cancer drug namely tamoxifen in supercritical CO2 was measured under different conditions. The measurements were carried out between 120 and 400 bar pressure, and 308–338 K temperature. The measurements revealed the solubility of about 1.88 × 10−5 to 9.89 × 10−4 (mole fraction basis) for tamoxifen with strong functionality to pressure and complicated functionality to temperature. In details, pressure showed to have a direct effect on solubility, while the effect of temperature depends on existence of cross-over pressure that is about 200 bar for the case of tamoxifen. It was revealed that for the pressures greater than the cross-over point, increasing temperature led to enhancement of the tamoxifen solubility due to sublimation pressure dominanacy, while for pressures lower than cross-over point, density reduction (solvating power reduction) is the dominant mechanism as the temperature enhances. Besides the experimental measurements, the possibility of correlating and extrapolating the measured solubility of tamoxifen as a function of temperature and pressure was investigated using five well-known semi-empirical density-based models including Kumar-Johnston (K-J), Garlapati-Madras, Chrastil, Mendez-Santiago and Teja (MST), and Bartle et al., among which KJ model showed the lowest average absolute relative deviation percent of about 8.26%.

The tunable nature of the solubility of various compounds, including molecules of pharmaceutical and biological interest, in supercritical fluids (SCFs) makes SCF extraction technology attractive for many separation and purification processes. Among the different influencing parameters, the most important one in the supercritical based processes is the knowledge of solubility of model solute. But, experimental measurement of the solubility of all pharmaceuticals in wide ranges of temperature and pressure is not only cost effective but also impossible in some cases. Regarding this fact, during the past decades, several approaches are proposed to model the solubility of the compounds in the supercritical fluids especially carbon dioxide. In this way, in the current investigation, two different approaches including five semi-empirical density based correlations (Mendez-Santiago and Teja (MST), Bartle et al., Chrastil, Kumar and Johnston (KJ) and Hezave et al.) and Peng-Robinson equation of state are used to find if it is possible to correlate the solubility of cetirizine with acceptable deviation as a function of temperature and pressure. The results reveal that among the examined approaches Hezave and Lashkarbolooki model leads to better overall correlative capability with average absolute relative deviation of 5.04% although Peng-Robinson EoS leads to lower AARD % of 3.85 % in 338 K isotherm.

In recent years, using supercritical carbon dioxide for different chemical processes in particular particle micronization has been surprisingly increased. Knowing the substance solubility in supercritical solvent is a critical parameter during the particle size reduction processes. In this direction, solubility of cephalexin was measured in the supercritical carbon dioxide by changing the temperature and pressure between 308.15 K to 338.15 K and 16 Mpa to 40 MPa, respectively. The measured solubility of cephalexin in supercritical carbon dioxide was in the range of 1.13×10-5 to 4.89 ×10-3 based on the mole fraction at the different operational condition. Besides the experimentally measurement of cephalexin solubility, modeling of the results using four commonly used correlations namely Mendez-Santiago and Teja (MST), Bartle, Kumar and Johnston and Chrastil models were performed. The results revealed that the Chrastil model is the most accurate used semi-empirical correlation in the present study with the lowest average absolute relative deviation percent of (AARD %) of 9.43 %.

Solubility of solute in supercritical fluids at different pressures and temperatures is one of the most important parameters necessary for design of any supercritical fluid-based processes. Among different supercritical fluids, carbon dioxide is one of the most widely used solvents due to its useful and green characteristics. In this work, with the assist of supercritical carbon dioxide as the solvent, solubility of cyproheptadine in different temperatures (308–338 K) and pressures (160–400 bar) are measured using static method. The obtained results demonstrated that solubility of cyproheptadine ranged between 3.35 × 10−5 and 3.09 × 10−3 based on mole fraction. A closer examination of measured solubility data show that not only solubility of cyproheptadine increases by increasing pressure but also experiences a cross over pressure about 200 bar. At last, the measured solubility data are correlated using four widely used density based correlations namely Mendez Santiago–Teja (MST), Kumar and Johnston (KJ), Bartle et al., and Chrastil models. The obtained results demonstrated that the best correlative capability was observed for KJ model leads to the average absolute relative deviation percent (AARD %) of 6.3%.

In the pharmaceutical industry where the supercritical fluid-based technologies are utilized it is very important and vital to know the accurate value of the equilibrium solubility of solids required for the engineers to determine the size of the equipments. According to this requirement, the purpose of this study was measuring the solubility of fluoxetine hydrochloride with IUPAC name of 3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine hydrochloride using a static method coupled with gravimetric method. The measured solubility data at the temperature and pressure range of 308.15–338.15 K and 16–40 MPa was ranged between 2.65 × 10 −5 and 8.12 × 10 −4 based on the mole fraction. The results revealed that the solubility was increased when the pressure was increased while the effect of the temperature was more complex. Finally, the measured solubility data were correlated using three different correlations namely Bartle et al., Mendez-Santiago–Teja and Kumar and Johnston. The results of modeling revealed that the Bartle et al. model leads to the lowest average absolute relative deviation (AARD %) of 9.48.

Supercritical extraction (SE) is a separation technique utilizes near or above critical properties of the solvents. In this technique, modeling of yield and solubility of materials are crucial points in supercritical fluid extraction processes. Generally, mathematical modeling of the supercritical oil extraction is a very difficult task since a highly nonlinear relation exists between process variables and solubility. Considering these facts, in the present study, a trainable cascade-forward back-propagation network (CFBPN) was proposed to correlate the yield of spearmint oil extracted by supercritical carbon dioxide. The results revealed the applicability of the proposed model to correlate the yield of spearmint oil extraction with an acceptable level of accuracy. Finally, the obtained results were compared to mathematical models namely Goodarznia & Eikani and Kim & Hong. The comparison between the results of proposed network and mathematical models demonstrated a better predictive capability of the proposed network.

In this study, the rapid expansion of supercritical solution (RESS) process was used to precipitate fine solid particles of amoxiccilin where supercritical carbon dioxide was used as a solvent. The process has been done by changing the RESS parameters, including extraction pressure (150–210 bar), extraction temperature (313–333 K), nozzle length (2–15 mm), effective nozzle diameter (450–1700 µm), and spraying distance (1–10 cm), to investigate the effect of these parameters on the size and morphology of the precipitated amoxicillin particles. The characterization (size and morphology) of the particles was examined using scanning electron microscopy (SEM). Based on the different experimental conditions, the mean particle size of the fabricated particles were between 1.08 and 5.72 µm, while the intact particles of amoxicillin were about 41.46 µm. Also, no regular changes in the morphology of the processed particles were observed.

During the past 20 years, an increase through measuring, correlating, and calculating solid solubilities especially pharmaceuticals in supercritical fluids for processes such as purification, extraction, and size reduction processes have been observed. In this direction, the solubility of amoxicillin with the International Union of Pure and Applied Chemistry (IUPAC) name of (2S,5R,6R)-6-{[(2R)-2-amino-2-(4-hydroxyphenyl)-acetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylic acid in the pressure and temperature ranges of 16 MPa to 40 MPa and 308.15 K to 338.15 K, respectively, has been measured. For this purpose, a simple gravimetric-based method was utilized to obtain the amoxicillin solubility in supercritical carbon dioxide. During the measurements it was found that the amoxicillin solubility was in the range of 1.08·10–5 and 7.23·10–3 based on the mole fraction. Besides, due to a vast number of efforts have been performed on the solubility correlation by several researchers, ...

Solubility measurements of solids in supercritical fluids have been increasingly performed during the past three decades, and semi-empirical models are utilizing as one of the best methods to fit this type of data. For the proper design of supercritical fluid drug process, it is essential to have a sufficient knowledge of the drug solubilities in supercritical fluids particularly carbon dioxide because of its green characterization. In this regards, the solubility of sulindac with IUPAC name of {(1Z)-5-fluoro-2-methyl-1-[4-(methylsulfinyl)benzylidene]-1H-indene-3-yl}acetic acid were examined in the wide ranges of temperature and pressure of 308.15–338.15 K and 160–400 bar, respectively, in supercritical carbon dioxide. The obtained results show the sulindac solubility was in the range of 3.65 × 10−5 to 8.69 × 10−3 mole fraction and additionally was correlated with four density based semi-empirical correlations namely, Mendez-Santiago–Teja, Bartle, Chrastile and Kumar and Johnston methods.

In this study, rapid expansion of supercritical solution with supercritical carbon dioxide as a solvent is used to micronize fenoprofen particles. Effects of different operating parameters were discussed by the method of changing one factor at a time for the extraction temperature (313–333 K), extraction pressure (140–220 bar), collection distance (1–10 cm), nozzle length (2–15 mm), and effective nozzle diameter (450–1700 µm) on the size and morphology of the fenoprofen particles. The conducted experiments revealed that not only the fenoprofen particles were micronized from 24.3 µm to the range of 10.6 µm and 3.3 µm but also the fenoprofen particles experience a modification on their morphologies.

In this study, the rapid expansion of supercritical solutions process was used to micronize the intact particles of piroxicam. Experiments were carried out to investigate the effect of extraction pressure (160–220 bar), extraction temperature (308–333 K), spraying distance (1–10 cm), and nozzle configuration (length and effective diameter) on the size and morphology of the precipitated piroxicam particle. The characterization of the particles was determined by scanning electron microscopy (SEM). The particle size of the original piroxicam particles was (39.2 µm) while depending upon the different experimental conditions, smaller particles of piroxicam (1.52–8.78 µm) were obtained.

The equilibrium solubility of the diclofenac acid in supercritical carbon dioxide was determined with a static method. The measurements were performed at pressures ranging from (120 to 400) bar and temperatures from (308.15 to 338.15) K. The results show that diclofenac acid solubility was increased by increasing pressure. The experimental solubility data were well correlated with enhanced density-based models including the Chrastil model, Mendez-Santiago and Teja model, Kumar and Johnston model, and the Bartle and co-workers model with an average absolute relative deviation (AARD) of 8.7 %, 6.6 %, 7.2 %, and 9.7 %, respectively. In addition, the solubility data satisfied the self-consistency test, proposed by Mendez-Santiago and Teja.

The RESS method was used to manufacture the fine particles of diclofenac. A reduction in particle size increases the dissolution rate of the drugs in the biological fluids and enhances the bioavailability of them in body. CO2 was used as the supercritical fluid because of its mild critical temperature (31.1 °C) and pressure (7.38 MPa). In this study, effect of extraction temperature (313–333 K), extraction pressure (14–220 MPa), spraying distance (1–10 cm), nozzle length (2–15 mm) and effective nozzle diameter (450–1700 μm) were investigated. Based on the different experimental conditions, the average particle size of diclofenac was between 10.92 and 1.33 μm. The size and morphology of the micronized diclofenac particles were monitored by scanning electron microscopy (SEM). The SEM images show a successful size reduction of virgin diclofenac particles. In all the experiments, the parameters had moderate effect on the mean particle size of the diclofenac. Also, the morphology of the processed particles was change to quasi-spherical and irregular while the virgin particles of diclofenac were irregular in shape.

A simple static technique was used to obtain the solubility of cetirizine in supercritical carbon dioxide. The solubility measurements were performed at temperatures and pressures ranging from 308.15 to 338.15 K and 160 to 400 bar, respectively; resulting in mole fractions in the 1.05 × 10 −5 to 4.92 × 10 −3 range. The Chrastil, Bartle, Kumar & Johnston and the Mendez-Santiago and Teja (MST) models were used to correlate the experimental data. The calculated solubilities showed good agreement with the experimental data in the temperature and pressure ranges studied.

The particle size of organic and inorganic materials is vital parameter to determine its final use. Most of the newly developed pharmaceutical materials are poorly soluble or insoluble in the aqueous media such as biological fluids. Particle size reduction of such pharmaceuticals is one of the clues to improve the dissolution rate, adsorption and bioavailability. In this study, the effect of extraction and expansion parameters of the RESS process such as extraction temperature (313–333 K), extraction pressure (140–230 bar), effective nozzle diameter (450–1700 μm), nozzle length (2–15 mm) and spraying distance (1–7 cm) on the size and morphology of the precipitated particles of cephalexin were investigated. The morphology and particle size of the unprocessed and processed (precipitated) particles were examined by the SEM images. The mean particle size of the precipitated particles was between 0.86 and 7.22 μm depending upon the different experimental conditions used. The precipitated cephalexin particles were close to spherical form while the unprocessed particles were irregular or needle in shape.

In pharmaceutical industry, many drugs exhibit poor solubility in biological fluid. Solubility of drugs affects on the rate of dissolution and bioavailability in biological fluids. The bioavailability of drugs can be enhanced by decreasing the drug particle size. In this study, sulindac was micronized via rapid expansion of supercritical solution (RESS) where CO2 was used as a solvent. The experiments were conducted to investigate the effect of the extraction pressure and temperature (140–230 bar and 40–60 °C), collection distance (1–10 cm), effective nozzle diameter (450–1700 μm) and nozzle length (2–15 mm) on the size and morphology of the sulindac particles. The size and morphology of the precipitated particles were monitored by scanning electron microscopy (SEM). The particle size of intact sulindac particles was about 33.03 μm, while the average particle size of the micronized sulindac particles was between 0.76 and 8.02 μm based on different experimental conditions. Additionally, the different morphology of the micronized particles was observed like needle, rectangular, quasi spherical and irregular form while the morphology of the intact particles of sulindac was rectangular and irregular.

In the pharmaceutical industry, an even greater number of products are in the form of particulate solids. In the case of pharmaceutical substances the particle size is quite important since it can limit the bioavailability of poorly water soluble drugs. Since the mid-1980s, a new method of powder generation has appeared involving crystallization with supercritical fluids. In this study, RESS was used to micronize the creatine monohydrate particles. The RESS process consists in solvating the product in the fluid and rapidly depressurizing this solution through an adequate nozzle, causing an extremely rapid nucleation of the product into a highly dispersed material. In addition, the effect of six different RESS parameters including, extraction temperature (313–333 K), extraction pressure (140–220 bar), nozzle length (2–15 mm), effective nozzle diameter (450–1700 μm), spraying distance (1–7 cm) and pre-expansion temperature (353–393 K) were investigated on the size and morphology of the precipitated particles of creatine monohydrate. The characterization (size and morphology) of the precipitated particles of creatine monohydrate was determined by scanning electron microscopy (SEM). The results show great reduction in the size of the precipitated particles of creatine monohydrate (0.36–9.06 μm) compared with the original particles of creatine monohydrate. Moreover, a slight change into spherical form was observed for the precipitated particles of creatine monohydrate while the original particles were irregular in shape.

The particle size of the pharmaceutical substances is important for their bioavailability (the percentage of the drug absorbed compared to its initial dosage). The absorption rate can be increased by reducing particle size of the drug particles. This study was conducted to investigate the effects of the extraction pressure (140–220 bar), extraction temperature (308–338 K), nozzle length (2–15 mm), effective nozzle diameter (450–1700 μm), and collection distance (1–10 cm) on the size and morphology of the precipitated ketoprofen particles. The characterization (size and morphology) of the particles was investigated using scanning electron microscopy (SEM). The average particle size of the original material was 115.42 μm, while the average particle size of the micronized particles is between 0.35 and 7.03 μm near to quisi-spherical, needle and irregular shape depending upon the experimental conditions.

The rapid expansion of a supercritical solution (RESS) process is an attractive technology for the production of small, uniform and solvent-free particles of low vapour pressure solutes. The RESS containing a nonvolatile solute leads to the loss of solvent power by the fast expansion of the supercritical solution through an adequate nozzle, which can cause solute precipitation. The nozzle configuration plays an important role in RESS method and has a great effect on the size and morphology of the precipitated particles. In this study, ibuprofen was used as a simple test. In addition, besides the nozzle configuration, the effect of other parameters including extraction pressure (140–220 bar), extraction temperature (313–333 K), spraying distance (1–10 cm) and pre-expansion temperature (363–423 K) was investigated on the size and morphology of the precipitated particles of mefenamic acid. The SEM images also show that the precipitated particles of ibuprofen and mefenamic acid had a slight modification in morphology.

During the past 20 years, supercritical fluid (SCF) based technologies have been gaining an increasing attention through the academic and industrial communities due to its advantages. One of the most important parameter for any supercritical-based technologies is the knowledge of the solute solubility at different pressures and temperatures. But, due to several concerns e.g. time and expense, measuring the solubility of all compounds in wide ranges of temperature and pressure is not possible. Respect to this, a new empirical correlation with four fitting parameters has been proposed to correlate the solubility of pharmaceuticals in different temperatures and pressures. The obtained results compared with four widely used density based correlations including Mendez-Santiago and Teja (MST), Bartle et al., Chrastil, Kumar and Johnston (KJ) revealed rather good capability of the proposed simple correlation for predicting the solubility of solutes in supercritical carbon dioxide (SC- CO 2). At last, the obtained results compared with the results of three Equations of State (EoS's) with three different mixing rules.