Sequential purification of cannabidiol by two-dimensional liquid chromatography combined with modeling and simulation of elution profiles.

Cannabidiol (CBD) has garnered significant attention for its neuroprotective properties, and research on its therapeutic effects has increased dramatically in recent years. However, the systematic purification of CBD through scalable processes has remained bottleneck due to the structural similarities of the cannabinoids. Although preparative chromatography is considered as a potential solution, it is usually time-consuming and expensive. Therefore, the development of scalable strategy via fast and accurate optimization approach is crucial. The present study aimed to develop a sequential process for the scalable purification of CBD through an eco-friendly ethanolic extraction using ultrasonic assisted extraction, decarboxylation of cannabidiolic acid optimized by response surface methodology, followed by the development of off-line two-dimensional semi-preparative chromatography, boosted with stacked injection overloading. In the first dimension, a column packed with macroporous resin allows to enrich the target substance and then, the behavior of resin column for scale-up procedure were predicted and optimized by developed mathematical model. A C18 column was used in the second dimension. The CBD purity and recovery obtained were 94.3 and 82.1 %, respectively. A robust and reliable method was employed for CBD enrichment/purification, which can be generalized to other bioactive compounds in complex matrices.

Computational fluid dynamics simulation of a jet crystallizer for continuous crystallization of lovastatin.

Continuous crystallization of lovastatin from a lovastatin-methanol solution and water as the anti-solvent in an impinging jet crystallizer is investigated using a computational fluid dynamics model. To capture the important phenomena, the model is coupled with micro-mixing, population balance, and related energy balance equations. It is implemented in OpenFOAM and validated against experimental data, where a fairly good agreement is found. The effects of key process parameters on the crystallization performance are also studied using the validated model. The results show that increasing the inlet jet velocity from 1 to 4 m/s yields a much narrower size distribution and 70% reduction in the mean crystal size. The four-fold increase in the inlet jet velocity also reduces the crystal production rate by one order of magnitude. Also, it is found that increasing the inlet supersaturation ratio from 6.8 to 8.8 nearly doubles the mean crystal size. Moreover, it results in a wider size distribution and a six-fold increase in the crystal production rate. The simulations also confirm that lower solution to anti-solvent mass flow ratios yield a wider size distribution, a larger mean crystal size and a higher crystal production rate. Increasing this ratio from 0.5 to 2 reduces the production rate by two orders of magnitude.

Comparison of the Effect of Nifedipine Alone and the Combination of Nifedipine and Sildenafil in Delaying Preterm Labor: A Randomized Clinical Trial.

Objective: Recently, sildenafil as a drug effective in relaxing smooth muscles can be used as an adjunct to delay the onset of uterine contractions and therefore the occurrence of preterm labor. The aim of this study was to evaluate the effect of nifedipine combination with sildenafil on preterm delivery compared with nifedipine alone. Materials and methods: This randomized double-blinded clinical trial was performed on pregnant women with a gestational age of 26-34 weeks with singleton pregnancy and symptoms of preterm delivery. The mothers were randomly assigned into two groups receiving nifedipine plus sildenafil or those receiving nifedipine alone. The time of delivery, maternal and neonatal complications were compared between the two groups. Results: Mothers who received the combination therapy experienced significantly lower preterm delivery within 72 hours of intervention compared to nifedipine alone (4.5% versus 27.3%, p = 0.002). The rate of delivery during the first 7 days after discharge was 7.6% and 31.8% in nifedipine plus sildenafil and nifedipine alone, respectively (P = 0.001). The prevalence of neonatal respiratory distress syndrome (RDS) as well as mean birth weight was higher in the nifedipine group alone. Treatment protocol with nifedipine and sildenafil compared with nifedipine alone was associated with a significant increase in preterm delivery delay (beta =-5.819, p = 0.001). Conclusion: The use of sildenafil in addition to nifedipine causes more delay in delivery in cases of preterm labor, followed by lower risk for RDS, reduces neonatal intensive care unit (NICU) admission, and preserves neonatal birth weight.

Tissue Sampling through Endoscopic Ultrasound-Guided Fine Needle Aspiration versus Endoscopic Retrograde Cholangiopancreatographic Brushing Cytology Technique in Suspicious Malignant Biliary Stricture.

BACKGROUND Differentiation of benign and malignant biliary strictures plays a pivotal role in managing biliary strictures. Brush cytology via endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) are two diagnostic methods. In the present study, we aimed to compare the accuracy of the results of EUS-FNA and ERCP-based sampling of biliary strictures. METHODS In a prospective study, between January 2019 and March 2020, patients with indeterminate biliary strictures who had no history of hepatobiliary surgery, opium usage, cancer of pancratobiliary system, and acute liver disease were selected. They underwent EUS and ERCP in the same session. They were followed up for 6 months, and the sensitivity, specificity, positive and negative predictive values, and accuracy of these imaging modalities were compared. RESULTS A total of 60 patients were enrolled. 28 lesions were located in the distal and 32 lesions in the proximal parts of the biliary tree. 55 malignant and 5 benign lesions were diagnosed. The sensitivity and accuracy of EUS-FNA and ERCP tissue sampling were 78.2% and 80.0% versus 50.9% and 55.0%, respectively (p = 0.024). The combination of both methods improved the sensitivity and accuracy to 85.5% and 86.7%, respectively. Regarding the location, EUS-FNA is superior to ERCP-brush cytology in diagnosing proximal lesions with sensitivity and specificity of 73.3% and 75.0% vs. 50.0% and 53.1%, respectively (p = 0.04). CONCLUSION EUS-FNA is superior to ERCP brushing in the diagnosis of indeterminate biliary strictures, particularly in distal lesions. Combining ERCP brushing and EUS-FNA improves the diagnosis accuracy.

Simulation of pellet coating in Wurster coaters.

A combination of computational fluid dynamics (CFD), discrete element method (DEM), and discrete droplet method (DDM), i.e., a CFD-DEM-DDM model, was developed to simulate coating of pellets in a Wurster coater. The model equations were implemented in parallel using an approach that uses the computational resources of both CPU and GPU. Effects of the gas flow pattern, inlet gas temperature, partition gap, and spray characteristics were studied on the process. Decreasing the peripheral gas velocity, increasing the central jet velocity, and reducing the partition gap caused more uniform distributions of the circulation time and draft tube time, while the inlet gas temperature had negligible effect on them. Very high jet velocity caused a wider distribution of the circulation time. The dynamics of the spray and its interaction with pellets had significant effects on the coating mass distribution. Widening the spray angle while maintaining the droplet size constant caused the most uniform coating mass distribution and the highest deposition rate. Heat and mass transfer conditions as well as the deposition pattern changed the distributions of the solvent content and temperature of the pellets.

Development and modeling of two-dimensional fast protein liquid chromatography for producing nonstructural protein-free food-and-mouth diseases virus vaccine.

Concerns for the use of non-purified or incompletely purified inactivated foot-and-mouth disease (FMD) vaccine, like difficulties for differentiation vaccinated from infected animals, can be a motivation in order to develop methods based on size exclusion chromatography (SEC). In this study, a two dimensional size exclusion chromatography (2D-SEC) system was successfully constructed using two different SEC column media to achieve a high-throughput purification system for the cell culture-derived foot and mouth diseases virus (FMDV). A mathematical model was also utilized to predict and to get a better insight into the separation process. Column and the packing particles characteristics such as column void volume, total column volume, particle porosity and accessible particle porosity was acquired experimentally. Retention times and elution profile of two different molecules, blue dextran and bovine serum albumin, were used for evaluating the capability of SEC media for separating two critical impurities (residual DNA (rDNA) and non-structural protein (NSP)) from active ingredient of vaccine (FMDV particle). Experiments were carried out with two different commercial columns (XK 26/60) and (XK 16/100) and with four different packing media superdex 200 prep grade, sephacryl S-500 HR, Sephacryl S-400 HR and Sephacryl S-300HR. The mathematical model was first validated by experimental chromatographic data of different SEC media and was then used to propose the best 2D-SEC system for downstream processing of the FMDV vaccine. The loading capacity of the constructed 2D-SEC sample was increased to 12.5% of total column volume and the purity of the final product was more than 90%. The entire purification process was performed with 77% FMDV recovery and 79.1% virus yield. Based on the high-performance size exclusion chromatography (HPSEC), the purity of the final NSP-free FMDV was about 90% and over 94.6% of host cell DNA was removed. Analyses of the purified FMDV by HPSEC, transmission electron microscopy (TEM) and dynamic light scattering (DLS) indicated that the final product had spherical shape with mean size about 30 nm and their structure remained intact.