Johan Hjärtstam

Osmotic pumping as a release mechanism for membrane-coated drug formulations

Abstract By using osmotic pumping, it is possible to release a drug from a membrane-coated drug formulation although the drug diffusion through the membrane is very limited. Instead, the water permeability of the membrane is the primary release rate-regulating parameter. Free films made by spraying solutions of ethyl cellulose onto a rotating cylinder were shown to be semipermeable, i.e. the permeability includes water but to a large extent excludes the solute. The water permeability was estimated by diffusion experiments with tritiated water and a more conventional osmosis experiment. The permeability of ethyl cellulose was very low, only about one tenth of that of cellulose acetate, but was increased by incorporating hydroxypropyl methylcellulose (HPMC) in the film composition. Cores of potassium chloride (KCl) coated with mixtures of ethyl cellulose and up to 24% HPMC were shown to release their content mainly through osmotic pumping. When the HPMC content exceeded 24%, the permeability of KCl through the films also becomes substantial. Thus, for cores of KCl coated with such films, both drug diffusion and osmotic pumping mechanisms contribute to the drug release.

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 KNO3. However, pressure data revealed that films with 30% HPC-LF became permeable to KNO3 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.

Osmotic pumping release from KCl tablets coated with porous and non-porous ethylcellulose

Abstract A simple model is described for osmotic pumping drug release from membrane-coated formulations. The process requires at least two different areas in parallel in the membrane coat, which exhibit differing reflectivities to solute (drug and/or excipients). The model was used to calculate the reflectivities of membrane coats on potassium chloride tablets. Tablet coats of pure ethylcellulose (EC) had a low reflectivity of less than 0.005, and was not a major release rate regulating parameter. The higher reflectivity of the same membrane was 0.58, significantly lower than for a free relaxed film. The reduction in high reflectivity resulted in a corresponding lower drug release rate. Incorporation of hydroxypropyl methylcellulose (HPMC) in EC reduces the high reflectivity of the tablet coats even further. The reduction is accelerated when the HPMC content exceeds 24%. Since freezing water could be detected in free EC films with HPMC content of 24% and above, the formation of pores in these membrane coats is proposed. The pores are formed by the leaching of the water-soluble polymer HPMC, which is also found in the soaking liquid.

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.

Effect of ethanol on the water permeability of controlled release films composed of ethyl cellulose and hydroxypropyl cellulose

The robustness of controlled release formulations when co-ingested with alcohol is a current concern expressed by regulatory authorities, especially with regard to dose dumping. One such controlled release formulation commonly used is film coating composed of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC). The aim of this study was to investigate how the presence of ethanol in the dissolution medium affects the water permeability of such films. Film samples were prepared in various EC-HPC compositions, and the effect of different ethanol concentrations in the dissolution medium on the permeability was studied using a modified Ussing chamber and tritiated water. It was found that the effect of ethanol on the film permeability varied depending on the composition of the films. The results were interpreted in terms of swelling of the EC in the films, where the swelling increased with increasing ethanol concentration. Thus, for films with low HPC content (non-interconnected pores), the water permeability of the films increased with increasing ethanol concentration as the diffusion through the ethyl cellulose increased due to swelling. However, for films with higher HPC content (having interconnected pores through the films), the permeability decreased, likely due to the swelling of the ethyl cellulose blocking the pores. The interpretation of the results was supported by dynamic mechanic analysis and SEM analysis.

The effect of tensile stress on permeability of free films of ethyl cellulose containing hydroxypropyl methylcellulose

Abstract The effect of tensile stress on potassium chloride permeability in composite films containing ethyl cellulose (EC) and hydroxypropyl methylcellulose (HPMC) has been measured in a novel pressurized cell. Such a tensile stress is expected to develop in a film-coated drug formulation as a result of osmotic water imbibition. Free composite films of EC with HPMC contents ranging from 0 to 30 wt% were prepared by spraying a polymer solution on a rotating cylinder. It was found that films with 24% HPMC or less became permeable to potassium chloride only under the influence of an applied tensile stress. Increasing the film HPMC content lowered the magnitude of the applied tensile stress required to induce permeability. This tensile stress correlated with the breaking stress of the film. Additionally, provided that the tensile stress remained below the breaking stress of the film, the permeability properties were found to be reversible with respect to changes in the applied tensile stress. It is believed that the application of a tensile stress causes small alterations in film structure which affect transport and mechanical properties of the films.

Studies of the water permeability and mechanical properties of a film made of an Ethyl Cellulose–Ethanol–Water ternary mixture

A water permeability study of ethyl cellulose (EC) film made from an EC–ethanol–water ternary mixture is presented. EC films were prepared by pouring the solution onto a polycarbonate plate and by spraying. The results reveal that the permeability of water, estimated by diffusion experiments, increases as the amount of the nonsolvent increases in the liquid–liquid demixing process. In addition, a relative decrease in the evaporation rate of ethanol compared to that of water following an increase in casting temperature or a higher EC concentration produces a membrane with lower permeability. A mechanical evaluation of the films is also presented. Addition of water to the solvent leads to decreases in the modulus of elasticity, stress, and elongation, due to changes in the morphology of the film. The surface of the film was visualized by SEM photomicrography.

New insights on how to adjust the release profile from coated pellets by varying the molecular weight of ethyl cellulose in the coating film

The major aims of this work were to study the effect of the molecular weight (Mw) of ethyl cellulose (EC) on the drug release profile from metoprolol succinate pellets coated with films comprising EC and hydroxypropyl cellulose (HPC) with a weight ratio of 70:30, and to understand the mechanisms behind the different release profiles. A broad range of Mws was used, and the kinetics of drug release and HPC leaching followed. The higher the Mw of EC, the slower the HPC leaching and the drug release processes. Drug release occurred by diffusion through the pores created in the coating by the HPC leaching. A novel method was used to explain the differences in the release profiles: the effective diffusion coefficient (De) of the drug in the coating film was determined using a mechanistic model and compared to the amount of HPC leached. A linear dependence was found between De and the amount of HPC leached and, importantly, the value of the proportionality constant decreased with increasing Mw of EC. This suggests that the Mw of EC affects the drug release profile by affecting the phase separated microstructure of the coating and the hindrance it imparts to drug diffusion.

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.

New insights on the influence of manufacturing conditions and molecular weight on phase-separated films intended for controlled release

The aim of this work was to investigate how manufacturing conditions influence phase-separated films of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC) with different molecular weights of HPC. Two HPC grades, SSL and M, with weight average molecular weights (Mw) of 30×103g/mol and 365×103g/mol, respectively, were combined with EC 10 cps (70:30w/w EC/HPC) and spray-coated from ethanol solutions onto a rotating drum under well-controlled process conditions. Generally, a low spray rate resulted in a more rapid film drying process and, consequently, in smaller HPC-rich domains in the phase-separated film structure. For EC/HPC films with the low Mw HPC (SSL) the most rapid drying process resulted in a shift from a HPC-discontinuous to a partly bicontinuous structure and an increase in the permeability for water. In contrast, films containing the high Mw HPC (M) all showed bicontinuous structures, which resulted in overall higher water permeabilities and polymer release compared to the low Mw films. Interestingly, a maximum in permeability was observed for the high Mw films at intermediate spray rates. Below this spray rate the permeability decreased due to a lower amount of polymer released and at higher spray rates, the permeability decreased due to a loss of pore connectivity (or increased tortuosity). To conclude, this study shows that different Mw systems of EC/HPC can respond differently to variations in manufacturing conditions.