Co-rotating twin screw process for continuous manufacturing of solid crystal suspension: A promising strategy to enhance the solubility, permeation and oral bioavailability of Carvedilol.

Background: In the current work, co-rotating twin-screw processor (TSP) was utilized to formulate solid crystal suspension (SCS) of carvedilol (CAR) for enhancing its solubility, dissolution rate, permeation and bioavailability using mannitol as a hydrophilic carrier. Methods: In-silico molecular dynamics (MD) studies were done to simulate the interaction of CAR with mannitol at different kneading zone temperatures (KZT). Based on these studies, the optimal CAR: mannitol ratios and the kneading zone temperatures for CAR solubility enhancement were assessed. The CAR-SCS was optimized utilizing Design-of-Experiments (DoE) methodology using the Box-Behnken design. Saturation solubility studies and in vitro dissolution studies were performed for all the formulations. Physicochemical characterization was performed using differential scanning calorimetry , Fourier transform infrared spectroscopy, X-ray diffraction studies, and Raman spectroscopy analysis. Ex vivo permeation studies and in vivo pharmacokinetic studies for the CAR-SCS were performed. Stability studies were performed for the DoE-optimized CAR-SCS at accelerated stability conditions at 40 ºC/ 75% RH for three months. Results: Experimentally, the formulation with CAR: mannitol ratio of 20:80, prepared using a KZT of 120 ºC at 100 rpm screw speed showed the highest solubility enhancement accounting for 50-fold compared to the plain CAR. Physicochemical characterization confirmed the crystalline state of DoE-optimized CAR-SCS. In-vitro dissolution studies indicated a 6.03-fold and 3.40-fold enhancement in the dissolution rate of optimized CAR-SCS in pH 1.2 HCl solution and phosphate buffer pH 6.8, respectively, as compared to the pure CAR. The enhanced efficacy of the optimized CAR-SCS was indicated in the ex vivo and in vivo pharmacokinetic studies wherein the apparent permeability was enhanced 1.84-fold and bioavailability enhanced 1.50-folds compared to the plain CAR. The stability studies showed good stability concerning the drug content. Conclusions: TSP technology could be utilized to enhance the solubility, bioavailability and permeation of poor soluble CAR by preparing the SCS.

Drug-Carrier Miscibility in Solid Dispersions of Glibenclamide and a Novel Approach to Enhance Its Solubility Using an Effervescent Agent.

The present research aims to investigate the miscibility, physical stability, solubility, and dissolution rate of a poorly water-soluble glibenclamide (GLB) in solid dispersions (SDs) with hydrophilic carriers like PEG-1500 and PEG-50 hydrogenated palm glycerides (Acconon). Mathematical theories such as Hansen solubility parameters, Flory Huggins theory, Gibbs free energy, and the in silico molecular dynamics simulation study approaches were used to predict the drug-carrier miscibility. To increase the solubility further, the effervescence technique was introduced to the conventional solid dispersions to prepare effervescent solid dispersions (ESD). Solid dispersions (SDs) were prepared by microwave, solvent evaporation, lyophilization, and hot melt extrusion (HME) techniques and tested for different characterization parameters. The theoretical and in silico parameters suggested that GLB would show good miscibility with the selected carriers under certain conditions. Intermolecular hydrogen bonding between the drug and carrier(s) was confirmed by Fourier transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy. Solid-state characterizations like powder X-ray diffraction, differential scanning calorimetry, and microscopy confirm the amorphous nature of SDs. The addition of the effervescent agent improved the amorphous nature, due to which the solubility and drug release rate was increased. In vitro and ex vivo intestinal absorption studies showed improved flux and permeability than the pure drug, suggesting an enhanced drug delivery. The GLB solubility, dissolution, and stability were greatly enhanced by the SD and ESD technology.

Enteric coating of nanostructured lipid carriers (NLCs) and enteric coating of hard gelatin capsules filled with NLCs: Feasibility studies.

Nanostructured lipid carriers (NLCs) of asenapine maleate (ASPM) were enteric coated with polymethacrylate polymers (Eudragit®) for oral delivery. The present study aimed to compare the feasibility of direct enteric coating of NLCs and enteric coating of hard gelatin capsules filled with lyophilized ASPM-NLCs. Organic solution of Eudragit® was prepared using acetone containing 3% v/v water, acetone or ethanol. Aqueous dispersion of Eudragit® was obtained by neutralization with base. Capsules were enteric coated by dip-coating method with 3:2 ratio of Eudragit® L100-55:S100 (7.5-12.5% w/v). ASPM-NLCs showed particle size of 84.91±2.14nm, polydispersity index of 0.222±0.026, entrapment efficiency of 86.9±1.8% and zeta potential of -4.83±0.29 mV. TEM images showed good sphericity of the particles with the size of ≈100nm. Non-aqueous enteric coating was not successful as NLCs were precipitated in organic solvent. Aqueous enteric coated ASPM-NLCs (lipid:coat=1:2) showed an increased size (150.8±16.7nm) and zeta potential (-23.5±2.2 mV) revealing the deposition of Eudragit®. However, aqueous enteric coated ASPM-NLCs and uncoated ASPM-NLCs showed higher drug release (18.3±3.1-22.3±3.2%) in HCl solution (pH 1.2) indicating no resistance offered by direct enteric coating of NLCs; whereas enteric coated capsules showed less drug release (4.7±0.8%) in HCl solution indicating sufficient gastric protection.

Solid lipid nanoparticles of irbesartan: preparation, characterization, optimization and pharmacokinetic studies

ABSTRACT Irbesartan is an antihypertensive with limited bioavailability and solid lipid nanoparticles (SLN) is one of the approaches to improve bioavailability. Solid lipid nanoparticles were prepared using glyceryl monostearate by solvent emulsification method followed by probe sonication. Irbesartan loaded SLNs were characterized and optimized by parameters like particle size, zeta potential, surface morphology entrapment efficiency and in vitro release. The optimized formulation was then further evaluated for the pharmacokinetic studies in Wistar rats. Irbesartan-loaded SLN of particle size 523.7 nm and 73.8% entrapment efficiency showed good bioavailability in Wistar rats and also showed optimum stability in the studies. The SLN prepared using glyceryl monostearate by solvent emulsification method leads to improve bioavailability of the drug.