methylcellulose and ethyl-citrate

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) has been widely used in amorphous solid dispersions and as an enteric coating polymer. Under aqueous coating conditions and at elevated coating temperatures, HPMCAS particles tend to aggregate and clog the spray-nozzle, hence interrupting the coating process. This research focused on how plasticizers and surfactants, excipients used for aqueous coating, affect the properties and stability of HPMCAS. This information would be useful in identifying suitable excipients for developing a stable HPMCAS aqueous enteric coating formulation. Triethyl citrate was found to be the most compatible plasticizer with HPMCAS, and displayed suitable thermal and mechanical properties. PEG 4000, the co-plasticizer, provided dispersion stability by yielding a dispersible sediment without aggregation at the elevated processing temperatures. Zeta potential measurements indicated sodium lauryl sulfate (SLS) could be used as a potential stabilizing agent at concentrations above its critical micelle concentration (CMC). This study facilitated the understanding of the HPMCAS aggregation mechanism, in addition to identifying suitable stabilizing agents. These stabilizing excipients could potentially be used to develop a stable aqueous coating formulation that does not exhibit polymer aggregation and nozzle clogging during the coating process.

Topics: Citrates; Drug Compounding; Excipients; Kinetics; Mechanical Phenomena; Methylcellulose; Plasticizers; Polyethylene Glycols; Sodium Dodecyl Sulfate; Surface-Active Agents; Tablets; Temperature

This work focused on the control of the manufacturing process for a controlled release (CR) pellet product, within a Quality by Design (QbD) framework. The manufacturing process was Wurster coating: firstly layering active pharmaceutical ingredient (API) onto sugar pellet cores and secondly a controlled release (CR) coating. For each of these two steps, development of a Process Analytical Technology (PAT) method is discussed and also a novel application of automated microscopy as the reference method. Ultimately, PAT methods should link to product performance and the two key Critical Quality Attributes (CQAs) for this CR product are assay and release rate, linked to the API and CR coating steps respectively. In this work, the link between near infra-red (NIR) spectra and those attributes was explored by chemometrics over the course of the coating process in a pilot scale industrial environment. Correlations were built between the NIR spectra and coating weight (for API amount), CR coating thickness and dissolution performance. These correlations allow the coating process to be monitored at-line and so better control of the product performance in line with QbD requirements.

Topics: Automation, Laboratory; Cellulose; Citrates; Delayed-Action Preparations; Hypromellose Derivatives; Kinetics; Methylcellulose; Microscopy; Pharmaceutical Preparations; Quality Control; Solubility; Spectroscopy, Near-Infrared; Technology, Pharmaceutical

A recent development of coating technology is dry coating, where polymer powder and liquid plasticizer are layered on the cores without using organic solvents or water. Several studies evaluating the process were introduced in literature, however, little information about the critical process parameters (CPPs) is given.. Aim of the study was the investigation and optimization of CPPs with respect to one of the critical quality attributes (CQAs), the coating efficiency of the dry coating process in a rotary fluid bed.. Theophylline pellets were coated with hydroxypropyl methylcellulose acetate succinate as enteric film former and triethyl citrate and acetylated monoglyceride as plasticizer. A 2(5-1) design of experiments (DOEs) was created investigating five independent process parameters namely coating temperature, curing temperature, feeding/spraying rate, air flow and rotor speed. The results were evaluated by multilinear regression using the software Modde(®) 7.. It is shown, that generally, low feeding/spraying rates and low rotor speeds increase coating efficiency. High coating temperatures enhance coating efficiency, whereas medium curing temperatures have been found to be optimum in terms of coating efficiency.. This study provides a scientific base for the design of efficient dry coating processes with respect to coating efficiency.

Topics: Citrates; Dosage Forms; Drug Compounding; Equipment Design; Excipients; Linear Models; Methylcellulose; Monoglycerides; Plasticizers; Technology, Pharmaceutical; Temperature; Theophylline

The aim of the present investigation was to develop controlled porosity osmotic system for poorly water-soluble drug based on drug in polymer-surfactant layer technology. A poorly water-soluble drug, glipizide (GZ), was selected as the model drug. The technology involved core of the pellets containing osmotic agent coated with drug dispersed in polymer and surfactant layer, finally coated with release-retardant layer with pore former. The optimized drug-layer-coated pellets were evaluated for solubility of GZ at different pH conditions and characterized for amorphous nature of the drug by differential scanning calorimetry and X-ray powder diffractometry. The optimized release-retardant layer pellets were evaluated for in vitro drug release at different pH, hydrodynamic, and osmolality conditions. The optimized drug layer showed improvement in solubility (10 times in pH 1.2, 11 times in pH 4.5, and 21 times in pH 6.8), whereas pellets coated with cellulose acetate (15.0%, w/w, weight gain) with pore former triethyl citrate (10.0%, w/w, of polymer) demonstrated zero-order drug release for 24 h at different pH conditions; moreover, retardation of drug release was observed with increment of osmolality. This system could be a platform technology for controlled delivery of poorly water-soluble drugs.

Topics: 2-Propanol; Calorimetry, Differential Scanning; Cellulose; Chemistry, Pharmaceutical; Citrates; Delayed-Action Preparations; Drug Carriers; Glipizide; Hydrodynamics; Hydrogen-Ion Concentration; Hypoglycemic Agents; Hypromellose Derivatives; Kinetics; Methanol; Methylcellulose; Models, Chemical; Osmosis; Poloxamer; Polymers; Porosity; Powder Diffraction; Solubility; Solvents; Surface-Active Agents; Technology, Pharmaceutical; Temperature; Water; X-Ray Diffraction

The dry coating process was evaluated in terms of storage stability investigating drug release and agglomeration tendency of the different coated oral dosage forms; hydroxypropyl methylcellulose acetate succinate (HPMCAS) was used with triethylcitrate (TEC) as plasticizer and acetylated monoglyceride (Myvacet) as wetting agent. Talc or colloidal silicon dioxide (Aerosil) was used as anti-tacking agents. In contrast to coating formulations consisting of HPMCAS and Myvacet all formulations containing TEC showed enteric resistance and no agglomeration tendency after preparation. After storage at 10% RH +/- 5% enteric resistance is increased slightly. This increase is more pronounced at 60% RH +/- 5%. The formulations without anti-tacking agents showed higher drug releases after 12 and 24 months due to the damage of the film's integrity during sample preparation caused by the high tackiness of the film. Tackiness is not affected by storing if samples are stored at low relative humidity. At high relative humidity tackiness increases upon storage especially for formulations without anti-tacking agents. The sieving results of the agglomeration measurements after storage can be confirmed by ring shear measurements performed immediately after preparation and approved to be a tool, which is able to predict the agglomeration during storage.

Topics: Adhesiveness; Chemistry, Pharmaceutical; Citrates; Dosage Forms; Drug Compounding; Drug Stability; Humidity; Hydrogen-Ion Concentration; Methylcellulose; Monoglycerides; Powders; Rheology; Silicon Dioxide; Tablets, Enteric-Coated; Talc; Temperature; Theophylline

The objective was to investigate the suitable polymeric films for the development of diltiazem hydrochloride (diltiazem HCl) transdermal drug delivery systems. Hydroxypropyl methylcellulose (HPMC) and ethylcellulose (EC) were used as hydrophilic and hydrophobic film formers, respectively. Effects of HPMC/EC ratios and plasticizers on mechanical properties of free films were studied. Effects of HPMC/EC ratios on moisture uptake, in vitro release and permeation through pig ear skin of diltiazem HCl films were evaluated. Influence of enhancers including isopropyl myristate (IPM), isopropyl palmitate (IPP), N-methyl-2-pyrrolidone, oleic acid, polyethylene glycol 400, propylene glycol, and Tween80 on permeation was evaluated. It was found that addition of EC into HPMC film produced lower ultimate tensile strength, percent elongation at break and Young's modulus, however, addition of EC up to 60% resulted in too hard film. Plasticization with dibutyl phthalate (DBP) produced higher strength but lower elongation as compared to triethyl citrate. The moisture uptake and initial release rates (0-1 h) of diltiazem HCl films decreased with increasing the EC ratio. Diltiazem HCl films (10:0, 8:2 and 6:4 HPMC/EC) were studied for permeation because of the higher release rate. The 10:0 and 8:2 HPMC/EC films showed the comparable permeation-time profiles, and had higher flux values and shorter lag time as compared to 6:4 HPMC/EC film. Addition of IPM, IPP or Tween80 could enhance the fluxes for approx. three times while Tween80 also shorten the lag time. In conclusion, the film composed of 8:2 HPMC/EC, 30% DBP and 10% IPM, IPP or Tween80 loaded with 25% diltiazem HCl should be selected for manufacturing transdermal patch by using a suitable adhesive layer and backing membrane. Further in vitro permeation and in vivo performance studies are required.

Topics: Administration, Cutaneous; Animals; Calcium Channel Blockers; Cellulose; Chemistry, Pharmaceutical; Citrates; Delayed-Action Preparations; Dibutyl Phthalate; Diffusion; Diffusion Chambers, Culture; Diltiazem; Dosage Forms; Drug Carriers; Drug Compounding; Hypromellose Derivatives; Kinetics; Methylcellulose; Models, Chemical; Myristates; Palmitates; Permeability; Plasticizers; Polysorbates; Skin; Skin Absorption; Solubility; Swine; Technology, Pharmaceutical; Tensile Strength; Water

A highly efficient dry coating process was developed to obtain an enteric film avoiding completely the use of organic solvents and water. Using hydroxypropyl methylcellulose acetate succinate (HPMCAS) an enteric coat should be obtained without adding talc as anti-tacking agent because of problems arising from microbiological contamination. Further on, a method was developed preparing isolated films in order to determine the glass transition temperature (T(g)) and the required process temperature. The process was conducted in the rotary fluid bed with a gravimetric powder feeder achieving an exact dosage in contrast to volumetric powder feeder. A three way nozzle was aligned tangential to the pellet bed movement feeding simultaneously powder and plasticizer into the rotary fluid bed. The determined coating efficiency of the talc-free formulation was high with 94% and storage stability regarding tacking could be achieved using colloidal silicium dioxide as top powder. The T(g) of the enteric coat could be determined analyzing the T(g) of isolated films obtained by coating celluloid spheres instead of pellets using the dry coating process in rotary fluid bed. The dry coating process has been demonstrated to be a serious alternative to conventional solvent or water based coating processes.

Topics: Adhesiveness; Chemistry, Pharmaceutical; Citrates; Drug Stability; Hydrogen-Ion Concentration; Methylcellulose; Particle Size; Plasticizers; Polymers; Powders; Quality Control; Solubility; Tablets, Enteric-Coated; Theophylline

The mechanical properties of polymer films used in pharmaceutical coatings of pulsatile drug delivery systems were evaluated in the dry and the wet state by a newly developed puncture test, which allowed the time-dependent measurement of the mechanical properties on the same film specimen. Force, puncture strength, energy at break, modulus, and strain were investigated as a function of water exposure time with respect to the type of polymer and the type and concentration of plasticizer and pore former (hydroxypropyl methylcellulose, HPMC). Eudragit RS films were very flexible, had a high strain, and broke upon puncture with only small cracks. In contrast, ethylcellulose films were more brittle with a lower strain and showed complete film rupture. Increased amounts of the hydrophilic pore former, HPMC, resulted in a reduced puncture strength and in an increase in water uptake and weight loss of the films. The puncture strength decreased with increasing plasticizer concentration and was lower with the lipophilic dibutyl sebacate than with the hydrophilic triethyl citrate.

Topics: Acrylic Resins; Cellulose; Citrates; Dicarboxylic Acids; Drug Delivery Systems; Hypromellose Derivatives; Mechanics; Methylcellulose; Pulsatile Flow; Time Factors; Water

The study aimed to investigate the effect of triethyl citrate (TEC) plasticizer level (10, 15, and 20%), curing temperature (40, 50, and 60 degrees C) and time (0 to 168 h) on the release of a highly lipophilic drug bumetanide from pellets coated with methacrylate ester copolymer (Eudragit RS). Bumetanide was layered onto sugar pellets followed by coating with 6% Eudragit RS with and without hydroxypropyl methyl cellulose (HPMC) seal coat using Wurster Fluid Bed equipment. Coated pellets were stored for 3 months at room temperature and the release was tested in USP purified water. At 10% TEC level, increasing curing time and temperature lead to slower drug release. At 15 and 20% TEC levels, curing initially decreased drug release followed by increase in the release at longer curing time and higher temperature. Drug release from coated pellets plasticized with 15% TEC and completely cured followed zero order kinetic models. At plasticizer level of 20%, bumetanide release from the completely cured pellets was better modeled using the Higuchi's equation reflecting possible drug migration during curing. Storage led to an increase in drug release. The use of HPMC seal coat stabilized drug release after storage. It was concluded that bumetanide migration into Eudragit RS film coat was the main cause of the accelerated release after curing and storage. The drug migration during storage at room temperature was prevented by seal coating the pellets with HPMC.

Topics: Acrylic Resins; Biological Availability; Bumetanide; Chemistry, Pharmaceutical; Citrates; Drug Delivery Systems; Drug Storage; Lactose; Methylcellulose; Oxazines; Plasticizers; Solubility; Temperature; Time Factors