Water-soluble Hydroxypropyl Cellulose Research Articles

Simplification of fused deposition modeling 3D-printing paradigm: Feasibility of 1-step direct powder printing for immediate release dosage form production.

Direct powder three-dimensional (3D)-printing (DPP) of tablets to simplify fused deposition modelling (FDM) was explored. The FDM paradigm involving hot-melt extrusion for making 3D-printable drug-loaded filaments as intermediate products for tablet manufacturing has been gaining attention for the decentralized on-site production of personalized dosage forms. For direct 3D-printing, powder blends were loaded into a cartridge-like head and were successfully printed with honeycomb design following heating of the extrusion cartridge. This 1-step DPP with incorporation of in-built porosity providing higher surface area served as proof of concept for manufacture of rapid release dosage forms. Water soluble hydroxypropylcellulose SSL was chosen as matrix former and caffeine as model drug. The effect of PEG4000 as plasticizer/pore former and Kollidon VA64 as rapidly dissolving polymer on DPP processability and dissolution rate was investigated. Directly 3D-printed tablets with low (30%) infill density showed rapid dissolution independently of the formulation, whereas for high (80%) infill density a combination of PEG4000 and Kollidon VA64 was required to achieve rapid release. The obtained tablets demonstrated good uniformity of percent drug content but had variable weight. Caffeine was present in crystalline state and in the stable polymorph in the tablets. Hence, DPP feasibility for immediate release dosage form manufacture was demonstrated. This technique might create an opportunity to avoid hot-melt extrusion allowing 3D-printing independently of mechanical properties of a filament and potentially prolonging product shelf life by reducing thermal stress.

Polymer Distribution and Mechanism Conversion in Multiple Media of Phase-Separated Controlled-Release Film-Coating.

Phase-separated films of water-insoluble ethyl cellulose (EC) and water-soluble hydroxypropyl cellulose (HPC) can be utilized to tailor drug release from coated pellets. In the present study, the effects of HPC levels and the pH, type, ionic strength and osmolarity of the media on the release profiles of soluble metoprolol succinates from the EC/HPC-coated pellets were investigated, and the differences in drug-release kinetics in multiple media were further elucidated through the HPC leaching and swelling kinetics of the pellets, morphology (SEM) and water uptake of the free films and the interaction between the coating polymers and the media compositions. Interestingly, the drug release rate from the pellets in different media was not in agreement with the drug solubility which have a positive correlation with the drug dissolution rate based on Noyes–Whitney equation law. In particular, the drug release rate in acetate buffer at pH 4.5 was faster than that in other media despite the solubility of drug was relatively lower, regardless of the HPC levels. It may be attributed to the mutual effect between the EC and acetate buffer, which improved the permeability of the film. In contrast, the release of drug in HCl solution was dependent on the HPC levels. Increasing the levels of HPC increased the effects of hydrogen ions on the polymer of HPC, which resulted in a lower viscosity and strength of the gel, forming the larger size of pores in polymer films, thus increasing the drug diffused from the coating film. Further findings in phosphate buffer showed a reduction in the drug release compared to that in other media, which was only sensitive to the osmolarity rather than the HPC level and pH of the buffer. Additionally, a mathematical theory was used to better explain and understand the experimentally measured different drug release patterns. In summary, the study revealed that the effects of the media overcompensated that of the drug solubility to some extent for controlled-release of the coating polymers, and the drug release mechanism in multiple media depend on EC and HPC rather than on HPC alone, which may have a potential to facilitate the optimization of ideally film-coated formulations.

Microstructural characterization of papaverine-loaded HPC/PVA gels, films and nanofibers

Papaverine hydrochloride loaded gels, films and electrospun fibers were prepared for buccal drug delivery with the aim of improving the oral bioavailability of the crystalline drug, which can be achieved by the increased solubility and by the circumvention of the intensive first pass metabolism. The water soluble hydroxypropyl cellulose (HPC) was chosen as a mucoadhesive polymer. In order to improve the electrospinnability of HPC, the similarly mucoadhesive poly(vinyl alcohol) (PVA) was used. Since the drying of gels is of decisive role in either the formation of drug-loaded cast films or electrospun fibers, a real time ortho-positronium (o-Ps) tracking of gels was applied in order to obtain information about the supramolecular changes of the drying-induced gel-film transition. An anomalous increase of o-Ps lifetime value in the gel-film transition region was observed which refers to the remaining intramolecularly bound water in the drug-loaded polymeric gel matrix. The latter could provide information about the characteristics of polymer-water interactions in the phase transition, consequently the storage stability of the formulated solid system.

Preformulation Studies of Furosemide-Loaded Electrospun Nanofibrous Systems for Buccal Administration.

Furosemide loaded electrospun fibers were prepared for buccal administration, with the aim of improving the oral bioavailability of the poorly soluble and permeable crystalline drug, which can be achieved by the increased solubility and by the circumvention of the intensive first pass metabolism. The water soluble hydroxypropyl cellulose (HPC) was chosen as a mucoadhesive polymer. In order to improve the electrospinnability of HPC, poly (vinylpyrrolidone) (PVP) was used. During the experiments, the total polymer concentration was kept constant at 15% (w/w), and only the ratio of the two polymers (HPC-PVP = 5:5, 6:4, 7:3, 8:2, 9:1) was changed. A combination of rheological measurements with scanning electron microscopic morphological images of electrospun samples was applied for the determination of the optimum composition of the gels for fiber formation. The crystalline–amorphous transition of furosemide was tracked by Fourier transform infrared spectroscopy. A correlation was found between the rheological properties of the polymer solutions and their electrospinnability, and the consequent morphology of the resultant samples. With decreasing HPC ratio of the system, a transition from the spray-dried droplets to the randomly oriented fibrous structures was observed. The results enable the determination of the polymer ratio for the formation of applicable quality of electrospun fibers.

Prediction of the hydroxypropyl cellulose—poly(vinyl alcohol) ratio in aqueous solution containing papaverine hydrochloride in terms of drug loaded electrospun fiber formation

Papaverine hydrochloride loaded electrospun fibers were prepared for buccal drug delivery with the aim of improving the oral bioavailability of the crystalline drug, which can be achieved by the increased solubility and by the circumvention of the intensive first pass metabolism. The water soluble hydroxypropyl cellulose (HPC) was chosen as a mucoadhesive polymer. In order to improve the electrospinnability of HPC, the also mucoadhesive poly(vinyl alcohol) (PVA) was used. During the experiments, the total polymer concentration was kept constantly at 15% (w/w), and only the ratio of the two polymers was changed. Five different HPC:PVA ratios (5:5, 6:4, 7:3, 8:2, 9:1) were examined. Combination of rheological measurements and molar reflectance characterization with scanning electron microscopy was applied for the determination of the optimum composition of the gels for fiber formation. The crystalline-amorphous transition of papaverine hydrochloride was also tracked by Fourier transform infrared spectroscopy. A correlation was found between the macrostructural properties of the polymer solutions and their electrospinnability and the consequent morphology of the resultant samples. Along with the changes of the polymer ratio, the corresponding morphology of the electrospun samples also varied. With decreasing HPC ratio of the system, a transition from the spray-dried film-like structure through fibrous film to fibers was observed. Polymer solutions of the lowest elasticity and smallest intermolecular interactions contributed to the best fiber characteristics of the samples. The results enable the determination of the polymer ratio for the formation of applicable quality of electrospun fibers. According to the results 5:5 and 6:4 polymer ratios enabled the best fiber performance.

The influence of the molecular weight of the water-soluble polymer on phase-separated films for controlled release

Hydroxypropyl cellulose (HPC) and ethyl cellulose (EC) can be used for extended release coatings, where the water-soluble HPC may act as a pore former. The aim was to investigate the effect of the molecular weight of HPC on the microstructure and mass transport in phase-separated freestanding EC/HPC films with 30% w/w HPC. Four different HPC grades were used, with weight averaged molecular weights (Mw) of 30.0 (SSL), 55.0 (SL), 83.5 (L) and 365 (M) kg/mol. Results showed that the phase-separated structure changed from HPC-discontinuous to bicontinuous with increasing Mw of HPC. The film with the lowest Mw HPC (SSL) had unconnected oval-shaped HPC-rich domains, leaked almost no HPC and had the lowest water permeability. The remaining higher Mw films had connected complex-shaped pores, which resulted in higher permeabilities. The highest Mw film (M) had the smallest pores and very slow HPC leakage, which led to a slow increase in permeability. Films with grade L and SL released most of their HPC, yet the permeability of the L film was three times higher due to greater pore connectivity. It was concluded that the phase-separated microstructure, the level of pore percolation and the leakage rate of HPC will be affected by the choice of HPC Mw grade used in the film and this will in turn have strong impact on the film permeability.

Novel Method for Visualizing Water Transport Through Phase-Separated Polymer Films

Drug release from oral pharmaceutical formulations can be modified by applying a polymeric coating film with controlled mass transport properties. Interaction of the coating film with water may crucially influence its composition and permeability to both water and drug. Understanding this interaction between film microstructure, wetting, and mass transport is important for the development of new coatings. We present a novel method for controlled wetting of polymer coating films in an environmental scanning electron microscope, providing direct visual information about the processes occurring as the film goes from dry to wet. Free films made of phase-separated blends of water-insoluble ethyl cellulose (EC) and water-soluble hydroxypropyl cellulose (HPC) were used as a model system, and the blend ratio was varied to study the effect on the water transport properties. Local variations in water transport through the EC/HPC films were directly observed, enabling the immediate analysis of the structure-mass transport relationships. The leaching of HPC could be studied by evaporating water from the films in situ. Significant differences were observed between films of varying composition. The method provides a valuable complement to the current approach of making distinct diffusion and microscopy experiments for studying the dynamic interaction of polymer films with water.

Effects of molecular weight on permeability and microstructure of mixed ethyl-hydroxypropyl-cellulose films

Films of ethyl cellulose (EC) and water-soluble hydroxypropyl cellulose (HPC) can be used for extended release coatings in oral formulations. The permeability and microstructure of free EC/HPC films with 30% w/w HPC were studied to investigate effects of EC molecular weight. Phase separation during film spraying and subsequent HPC leaching after immersion in aqueous media cause pore formation in such films. It was found that sprayed films were porous throughout the bulk of the films after water immersion. The molecular weight affected HPC leaching, pore morphology and film permeability; increasing the molecular weight resulted in decreasing permeability. A model to distinguish the major factors contributing to diffusion retardation in porous films showed that the trend in permeability was determined predominantly by factors associated with the geometry and arrangement of pores, independent of the diffusing species. The film with the highest molecular weight did, however, show an additional contribution from pore wall/permeant interactions. In addition, rapid drying and increasing molecular weight resulted in smaller pores, which suggest that phase separation kinetics affects the final microstructure of EC/HPC films. Thus, the molecular weight influences the microstructural features of pores, which are crucial for mass transport in EC/HPC films.

Coated formulations: New insights into the release mechanism and changes in the film properties with a novel release cell

The effect of the blend ratio of water-insoluble ethyl cellulose (EC) and water-soluble hydroxypropyl cellulose (HPC-LF), on the properties of sprayed films and on the drug release mechanism of formulations coated with the material was investigated. When the original HPC-LF content exceeded 22%, both the amount of HPC-LF leached out and the water permeability of the films increased drastically when they were immersed in a phosphate buffer solution. The release mechanism of potassium nitrate through EC/HPC-LF films containing 20, 24 and 30% HPC-LF was elucidated in a new release cell equipped with a manometer to measure the pressure build-up inside the cell. A lag phase in the release accompanied by a pressure build-up was observable in all the experiments showing that all the films were initially semi-permeable to KNO 3. However, pressure data revealed that films with 30% HPC-LF became permeable to KNO 3 during the release process due to HPC-LF leaching. Importantly, the blend ratio influenced not only the release rate (which increased as the amount of HPC-LF increased), and the lag time (which increased as the amount of HPC-LF decreased), but also the release mechanism, which changed from osmotic pumping to diffusion as the amount of HPC-LF increased.

Biodegradable brushlike graft polymers. I. Polymerization of ?-caprolactone onto water-soluble hydroxypropyl cellulose as the backbone by the protection of the trimethylsilyl group

After the protection of partial hydroxyl groups with trimethylsilyl (TMS) groups, hydroxypropyl cellulose becomes soluble in organic solvents, and the number of hydroxyl groups as initiating groups can be controlled. As a result, a new brushlike graft poly(ϵ-caprolactone) can be prepared with hydroxypropyl cellulose as the backbone polymer by homogeneous ring-opening graft polymerization and deprotection. The protection and deprotection of the TMS group during the entire procedure were carefully monitored with Fourier transform infrared (FTIR) and NMR, and the final graft copolymers were characterized with FTIR, 1H NMR, 13C NMR, gel permeation chromatography, and differential scanning calorimetry. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 273–280, 2003

Suppression of agglomeration in fluidized bed coating I. Suppression of agglomeration by adding NaCl

Fluidized bed coating was carried out with aqueous spray solution at various additional amounts of NaCl, using water-soluble hydroxypropyl cellulose (HPC) or hydroxypropylmethyl cellulose (HPMC) as membrane material, and spherical granules made of crystalline cellulose (Celphere™) as core particle. The mean particle diameter, density and surface morphology of the coated particles were studied. The viscosity of the spray solution was studied with a corn-plate viscometer at various additional amounts of NaCl, temperatures and concentrations of the spray solution. Agglomeration of particles was clearly suppressed by adding NaCl to the aqueous spray solution in both cases of HPC and HPMC. The mean particle diameter of the coated particles decreased with the increasing additional amount of NaCl in the spray solution. The viscosity of HPC water solution began to decrease at over 6% (w/v) NaCl concentration at 30°C. The NaCl concentration required to reduce the viscosity of the HPC solution became lower as temperature became higher. When the viscosity of the solution decreased, turbidity and/or precipitate were observed. These results suggest that the suppression of agglomeration was caused by the reduction in the viscosity of the spray solution through salting-out of the polymeric membrane materials.

Controlled release of lidocaine hydrochloride from buccal mucosa-adhesive films with solid dispersion

Solid dispersion films were prepared with a highly water-soluble medicine, lidocaine hydrochloride (LDC), water-insoluble ethylcellulose (EC) and water-soluble hydroxypropylcellulose (HPC). The release profiles of LDC from the solid dispersion films of different composition, and the suppression mechanism of the release in the LDC-EC-HPC system were studied. The release rate of LDC from the solid dispersion film as drug-reservoir was well controlled at EC/HPC composition ratio of 5/5. The mechanism of controlled release was speculated that there was a little release of HPC together with LDC, and the retained HPC was swelled in the film by the permeating fluid. Then, the release of LDC occurred via diffusion into the swelled HPC phase, causing a marked decrease in the release rate. The film for clinical use, which had the 30% LDC solid dispersion film, adhered almost completely to the buccal mucosa. These observations will provide useful information on clinical application of the LDC-EC-HPC solid dispersion film.

Application of the solid dispersion method to the controlled release of medicine. IX. Difference in the release of flurbiprofen from solid dispersions with poly(ethylene oxide) and hydroxypropylcellulose and the interaction between medicine and polymers

Solid dispersions were prepared with a slightly water-soluble flurbiprofen (FP) and water-soluble hydroxypropylcellulose (HPC) or poly(ethylene oxide) (PEO). The release of FP from the FP-HPC and the FP-PEO solid dispersion systems was studied. The state of FP and the interaction between FP and the polymers in the solid dispersions were analyzed by powder X-ray diffractometry, thermal analysis and IR spectrometry. The release rate of FP from the FP-PEO system was significantly larger than that from FP powder and the FP-HPC system that we have previously studied. The dissolution property of the polymer base greatly affected the release of FP from the solid dispersions. In the FP-PEO system, the release rate increased with the increasing percent of PEO. In FT-IR spectra, FP has the carbonyl stretching band at 1703 cm −1 because it is in dimer. The new band was observed at 1736 cm −1 which was attributed to hydrogen bonding between FP and PEO in the FP-PEO system. The peak height ratio (the peak height at 1736 cm −1/the sum of that at 1703 cm −1 and that at 1736 cm −1) was evaluated as the indication of interaction between FP and PEO on the basis of a base-line method. A linear relationship between the peak height ratio and the release rate of FP was observed. These results were probably due to an increase in the ratio of hydrogen bonding of FP with the increasing percent of PEO in the solid dispersion.

Application of the Solid Dispersion Method to the Controlled Release of Medicine. VII. Release Mechanism of a Highly Water-Soluble Medicine from Solid Dispersion with Different Molecular Weights of Polymer.

Solid dispersion films were prepared with a highly water-soluble medicine (oxprenolol hydrochloride (OXP)), four grades of water-insoluble ethylcellulose (EC) having different molecular weights and water-soluble hydroxypropyl cellulose (HPC). The internal structure of the solid dispersion films and the penetration of the dissolution medium into the films were studied to clarify the mechanism of OXP release from the OXP-EC and OXP-EC-HPC solid dispersion systems having various molecular weights of EC.In the OXP-EC system, the release rate of OXP slightly decreased with increasing molecular weight of EC and the mechanism of OXP release was hardly affected by the molecular weight of EC. In the OXP-EC-HPC system, the release rate of OXP markedly decreased with increasing molecular weight of EC. When EC with the lowest molecular weight of the four grades was used, the same mechanism of OXP release was observed as in the OXP-EC system, but it was clear that OXP was released from the films with the two higher-molecular-weight grades of EC through a diffusion-controlled release mechanism. This result can be explained in terms of diffusion of OXP through the quasi-equilibrium swollen gel region formed by rapid hydration of HPC with water penetrating into the solid dispersion film.

Application of the Solid Dispersion Method to the Controlled Release of Medicine. VIII. Medicine Release and Viscosity of the Hydrogel of a Water-Soluble Polymer in a Three-Component Solid Dispersion System.

Solid dispersions were prepared with a highly water-soluble medicine (oxprenolol hydrochloride (OXP)), water-insoluble ethylcellulose (EC) and four grades of water-soluble hydroxypropylcellulose (HPC) having different molecular weights. The effects of the composition ratio within the range of 5% of HPC and of the viscosity of HPC hydrogels on the release of OXP were studied. The bulk viscosity of HPC hydrogels was evaluated from the relationship between shear rate and shear stress. The microscopic viscosity was evaluated by the spin probe method of the electron spin resonance (ESR) technique.The release rate of OXP decreased with increasing HPC composition ratio and became almost constant at the HPC composition ratio of 3% and more. This result suggests that the release of OXP will occur through its diffusion into the swollen HPC gel phase formed in a solid dispersion at the HPC composition ratio of 3% and more. The bulk viscosity of HPC hydrogels markedly increased with increasing molecular weight of HPC, but there was little noticeable change in release rate and activation energy for the diffusion of OXP. This result can be explained by the fact that the microscopic viscosity was hardly affected by the molecular weight of HPC, suggesting that the resistance to diffusion of OXP into the swollen HPC gel phase in the solid dispersion was almost the same regardless of the moleclar weight of HPC.

Application of the Solid Dispersion Method to the Controlled Release of Medicine. V. Suppression Mechanism of the Medicine Release Rate in the Three-Component Solid Dispersion System.

Solid dispersions were prepared with a highly water soluble medicine (oxprenolol hydrochloride (OXP)), water insoluble ethylcellulose (EC) and water soluble hydroxypropyl cellulose (HPC). The release profiles of OXP from the solid dispersion granules at various composition ratios of the components, and the suppression mechanism of the release rate in the OXP-EC-HPC system, were studied.The release rate of OXP reached a minimum level at the HPC composition ratio of 5-10%. It was difficult to control the release rate with more than 10% HPC. It was found that a marked decrease in the release rate at the HPC composition ratio of 5-10% was caused by the formation and retention of the swelled phase of HPC in the EC matrix. At more than 10% HPC, because OXP molecules enclosed by HPC molecules or incorporated in the swelled HPC phase increased and most of the OXP molecules were released together with HPC by erosion, the release rate of OXP increased drastically in the early stages of the release process. At the OXP composition ratio of 30% or more, the diameter and volume of the pores formed by the OXP release markedly increased, since the aggregates of OXP molecules that showed crystallinity began to be formed in the solid dispersion.

Effect of Additives on Agglomeration in Aqueous Coating with Hydroxypropyl Cellulose.

Water-soluble hydroxypropyl cellulose (HPC) was applied to fine lactose powder (53-63 μm) by the Wurster process. The effects of various additives on agglomeration were studied by the binding strength of membrane materials, the droplet size and the surface morphology of coated particles. The agglomeration was also computer-simulated by a previously reported model.Methyl cellulose (MC) and sodium alginate (ALG) increased the mass median diameter of droplets at 10% addition to HPC, while the other additives exhibited no significant effect on the droplet size distribution. The production of coarse droplets induced by MC and ALG led to the agglomeration of 76 and 87% cores, respectively, though they reduced the binding strength of HPC. Polyethyleneglycol (PEG) reduced the agglomeration by weakening the binding strength of HPC in particular. NaCl, which was incompatible with HPC, reduced agglomeration by hindering HPC from forming homogeneous film. The computer simulation indicated that the smalleste sizes of droplets causing the agglomeration were 44-71 μm. With MC and ALG the weight fraction of coarse droplets causing the agglomeration reached 5.7 and 4.4%, respectively; however, it was less than 1% with the other additives. Such a minor quantity of droplets caused the agglomeration of cores of 18% (PEG and NaCl) to 69% (polyvinyl alcohol). It was suggested that the agglomeration enhancing factor, K, migth well reflect the state of fluidization.

Application of the solid dispersion method to the controlled release of medicine. IV. Precise control of the release rate of a water soluble medicine by using the solid dispersion method applying the difference in the molecular weight of a polymer.

Solid dispersions were prepared by the evaporation of ethanol after dissolving into ethanol a water soluble medicine (oxprenolol hydrochloride (OXP)), four grades of water insoluble ethylcellulose (EC) and four grades of water soluble hydroxypropyl cellulose (HPC), both having different molecular weights. The precise control of the release rat of a water soluble medicine by applying the difference in the molecular weight of polymers was attempted. The pore size distribution in solid dispersion granules was measured before and after the dissolution test by mercury intrusion porosimetry to clarify the mechanism of medicine release from the granules when the molecular weights of polymers were different. The state of medicine in the solid dispersions was analyzed by thermal analysis and X-ray diffractometry. Although the difference was slight, the release rate of OXP from the granules of the OXP-HPC system decreased as the molecular weight of HPC increased. The release behavior of OXP in the OXP-EC system was scarcely affected by the molecular weight of EC. However, in the OXP-EC-HPC system, the release rate markedly decreased with a larger molecular weight of EC. It was thought from the results of the pore size distribution that there were two types of release routes for OXP; dissolving directly into the dissolution medium and diffusing in the swelled HPC phase, caused by the addition of HPC. The decrease in the release rate of OXP in the OXP-EC-HPC system was caused by the increase in the ratio of OXP dissolving via the latter route, occurring with a larger molecular weight of EC. These results suggest that it is feasible to precisely control the release of a water soluble medicine by varying the molecular weight of the polymers in the solid dispersion.