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Coated formulations: New insights into the release mechanism and changes in the film properties with a novel release cell
Journal of Controlled Release 136 (2009) 206–212
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Journal of Controlled Release j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j c o n r e l
Coated formulations: New insights into the release mechanism and changes in the film properties with a novel release cell Mariagrazia Marucci a, Johan Hjärtstam b, Gert Ragnarsson c, Frida Iselau b, Anders Axelsson a,⁎ a b c
Department of Chemical Engineering, Lund University, P.O. Box 124, SE-221 00 Lund, Sweden AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden Medical Products Agency, P.O. Box 26, SE-751 03 Uppsala, Sweden
a r t i c l e
i n f o
Article history: Received 31 October 2008 Accepted 20 February 2009 Available online 27 February 2009 Keywords: Release mechanism Polymer blend Osmotic pumping Diffusion Coating
a b s t r a c t 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. © 2009 Elsevier B.V. All rights reserved.
1. Introduction Polymer film coating is often used in oral controlled release systems. Polymers suitable for this fall into two groups: those based on natural polymers and those based on synthetic polymers. Cellulose is the most wide spread natural polymer and a variety of different cellulose derivates are used. The cellulosic polymer most often used for controlled release is ethyl cellulose (EC) due to its good film forming properties. EC is a water-insoluble polymer generally regarded as non-toxic and non-allergenic. It is stable under physiological as well as during normal storage conditions. Due to the low permeability of pure EC, polymer blends of EC and water-soluble polymers are often used as coatings. Hydroxypropyl methylcellulose (HPMC) is the hitherto most commonly used water-soluble polymer, and the release mechanism from pellets coated with EC/HPMC films with different polymer ratios has been extensively studied [1–3] Hydroxypropyl cellulose (HPC) is another attractive water-soluble polymer as it has low toxicity, is biodegradable and easily forms films. The structure of films made of EC and HPC has been studied by Sakellariou et al. [4–6]. HPC was shown to be incompatible with EC
⁎ Corresponding author. Tel.: +46 46 2228287; fax: +46 46 2224526. E-mail address: [email protected] (A. Axelsson). 0168-3659/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2009.02.017
and phase separation occurred. The use of EC and HPC as coating has been studied previously, and it has been found that the release rate from coated formulations increased with higher percentages of HPC in the film [7–9]. However, the release mechanism at different ratios has not yet been characterized. It is important to understand the underlying mechanism of release (i.e. diffusion and/or osmotic pumping) from coated formulations in order to optimize the polymer blend of the coating film. The release mechanism depends on the nature of the coating film and is mainly osmotic pumping for a semi-permeable film and mainly diffusion for a porous film. A hydrostatic pressure is built up inside the formulation when the release mechanism is osmotic pumping. The release mechanism after the lag phase is often characterized using release experiments by studying the dependency of the release rate on the osmotic pressure of the release medium [10,11]. Release occurs by osmotic pumping if the release rate decreases significantly upon decreasing the osmotic pressure gradient across the coating. In some studies, release experiments have been combined with NMR experiments [12] to investigate water influx and drug dissolution inside the pellet, or with swelling experiments to study water imbibing inside the pellet and the related hydrostatic pressure build-up inside the pellet [2,13]. Pellets swelling caused by water accumulation indicates that the coating is semi-permeable towards the drug studied. However, during the lag and the zero-order release phase, a series of important
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phenomena, such as leaching of the water-soluble polymer and presence of a tensile stress on the coating due to solvent accumulation inside the pellet, can occur and affect the nature, permeability and mechanical properties of the coating. Thus a full understanding of the release mechanism during the whole release process may be complicated and require several different kinds of experiments. The use of isolated films has been reported as an alternative, convenient way of predicting coating properties, and as a good way to screen different coatings [14]. Several types of diffusion cells have been reported in the literature for the study of drug transport through polymer films. Side-by-side diffusion cells are commonly used to characterize free films and to measure the diffusion coefficient of the drug in the film [15], and in many cases the results obtained from the release profile can also be used to predict the drug release from coated formulations [16]. However, due to their construction, these cells are often only useful in simulating formulations coated with permeable films. The pressure rise that occurs in formulations coated with semipermeable films, occurs in these cells in a completely different way, or may not occur at all. Okimoto et al. used a special osmotic pump device which allowed the hydrostatic pressure to build up inside the cell to study semi-permeable films [17]. In a previous study we used a diffusion cell in a holographic set-up, and the analytical technique employed provided discrimination between permeable and semipermeable films, allowing the total bulk flow (drug plus solvent) through the film to be studied [18]. The cell can be easily adjusted to allow for a pressure build-up in the donor compartment. Hjärtstam et al. used a pressurized cell to study the dependency of the permeability of EC films on the hydrostatic pressure applied in the cell and, consequently, on the tensile stress acting on the film [19]. The purpose of this study was to characterize the mechanism of mass transport through films made of EC and HPC-LF with different polymer blend ratios. A novel release cell was designed and used in the release experiments. The cell resembled the pressurized cell used by Hjärtstam et al. [19], the main difference being that no external hydrostatic pressure was applied. The cell was instead equipped with a manometer to measure the pressure that naturally arose inside the cell. The pressure rise is directly correlated to the net bulk flow through the coating, which in turn depends on water imbibing and drug transport through the film. The cell can be regarded as a large coated pellet. The advantage of collecting release and pressure data simultaneously is that the release mechanism from a coated formulation can readily be simulated and studied.
where Lp is the water permeability of the film, σ the reflection coefficient for the drug, h the film thickness, A the film area, ΔΠ the difference in osmotic pressure across the film and ΔP the difference in pressure across the film. At the beginning of the release experiment ΔP is equal to zero. The reflection coefficient, σ, is zero for a permeable film, and Jv is thus equal to zero, and no hydrostatic pressure is built up inside the coated formulation. For a semi-permeable film (or leaky film) the reflection coefficient has a value between zero and one (0b σ ≤ 1). Consequently, Jv has a value higher than zero, a net flow occurs from the release medium into the coated formulation and a hydrostatic pressure is built up inside the coated formulation. For a completely impermeable film the reflection coefficient is equal to one and also in this case a hydrostatic pressure is built up inside the coated formulation. For a film consisting of two regions with very different reflectivities, for example, a semi-permeable region, (with 0 b σ ≤ 1) and a permeable region, (with σ = 0) , it can be convenient to define two different volumetric flows [20], one for the semi-permeable region, Jv1, and one for the permeable region, Jv2, where:
2. Theory
EC (EC N10CR) was supplied from Dow Chemical Co., USA. HPC grade LF was supplied from Aqualon, USA. Tritium labelled water (Amersham, UK) was used in the water permeability measurements. Potassium nitrate was used in the release experiments and was purchased from Merck (Darmstadt, Germany).
The total mass balance for a coated formulation immersed in an aqueous solution is given by: dM = ρ Jv dt
ð1Þ
where M is the mass inside the coated formulation, Jv is the net volumetric bulk flow through the coating and ρ the density of the bulk. Jv depends on the flow of both water and drug. The change in mass induces a change in volume in the formulation and an increase in hydrostatic pressure inside the formulation and in the pressure gradient ΔP across the coating. The following proportionality can thus be written: dM dV dðΔP Þ ~ ~ ~ρ Jv dt dt dt
ð2Þ
For a homogeneous film, Jv can be written according to the irreversible thermodynamic equation: Jv =
Lp A ðσ ΔΠ − ΔP Þ h
ð3Þ
Jv1 =
Lp1 A1 ðσ 1 ΔΠ − ΔP Þ h
ð4Þ
and Jv2 = −
Lp2 A2 ΔP h
ð5Þ
Jv1 and Jv2 have different directions. Jv2 is the volumetric outflow of the drug solution from the coated formulation into the release medium. Jv2 is the volumetric “osmotic pumping” flow and it occurs if there is a difference in pressure across the film coating. Jv1 is the volumetric inflow of water from the release medium into the coated formulation. The resultant mass balance can be expressed as: dM = ρ1 Jv1 + ρ2 Jv2 dt
ð6Þ
where ρ1 is the density of water and ρ2 is the density of the drug solution. 3. Materials and methods 3.1. Materials
3.2. Preparation of polymer films EC/HPC-LF films were prepared by spraying a solution of 94% w/w ethanol (95%) and 6% w/w polymer onto a rotating drum. The drum was filled with hot water and its temperature was approximately 50 °C at the start and 34 °C at the end of film spraying. After spraying, the films were peeled off the drum and kept in a desiccator. Thin films containing 20, 22, 24, 26, 28 and 30% HPC-LF were prepared. Permeability and leaching experiments were performed for all films, and release experiments on films with 20, 24 and 30% HPC-LF. The thickness of the films was measured using an electronic micrometer. The films with 20%, 24% and 30% HPC-LF were 140, 120 and 100 μm thick, respectively. 3.3. Design of the release cell The cell consists of two circular brass end caps, joined together by two lengths of brass. Rectangular films (6.5 cm × 10 cm) were glued to
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to determine the tritium activity in this compartment. From the tritium activity measurements it was possible to calculate the amount of water that had diffused through the film at different times, and thus the water permeability of the film. Experiments were performed in duplicate. 3.6. Release studies
Fig. 1. Schematic representation of the release cell. (1) film, (2) cylindrical end of the cell, (3) brass piece to connect the ends of the cell. Rectangular films are glued to the ends of the cell. Pipe connections for filling are not shown.
the ends of the cell and to one of the metal pieces. A silicone glue was used (Dana Lim A7S, Denmark) and the glue was allowed to dry for 2 days before the release experiments were performed. The film thus formed the shell of the cell, which was cylindrical in shape. The cell was equipped with pipe connections for filling and was filled with the donor solution. The cell was equipped with a manometer to measure the pressure inside the cell. The accuracy of the manometer was 0.0005 bar. A tensile stress will act causing a strain on the film if the pressure inside the cell increases. If the ends of the film were free to move, the tensile stresses would be uniformly distributed over the film. However, the size of the cell was chosen to minimize the edge effects resulting from the fact that the film was glued to the ends of the cell and the tensile stress could be considered uniformly distributed. Fig. 1 shows a schematic illustration of the cell. This cell has the advantage that release data can be collected at the same time as pressure data. 3.4. Leaching of HPC-LF from polymer films A piece of the film of interest was immersed in 70 ml of a phosphate buffer solution, pH 6.8. The system was agitated and maintained at a temperature of 37 °C. Samples were taken at regular intervals and the HPC-LF concentration in the samples was analysed using size exclusion chromatography. Leaching experiments were performed under well-stirred and gently-stirred conditions for comparison. The experiments were performed in duplicate.
The release cell was filled with 40 ml of a preheated solution of KNO3 (28 g/l, 37 °C), connected to the manometer and immersed in a thermostatted vessel containing 1.5 l distilled water. The system was kept at a temperature of 37 °C. The liquid inside the thermostatted vessel was well stirred. The release of KNO3 through the film into the liquid inside the vessel was determined with a conductivity meter. The manometer of the cell was connected to a computer and pressure data were recorded continuously. Triplicate experiments were performed for each polymer blend. 3.7. Film morphology The morphology of the EC/HPC-LF films before and after the release experiments was studied using a scanning electron microscope (SEM) (JSM-840A, Jeol Ltd, Japan). The polymer films were coated with a thin layer of gold in an ion sputtering device before observation in the SEM. 4. Results and discussion 4.1. Leaching of HPC-LF from polymer films The amount of HPC-LF leached from EC/HPC-LF films, after soaking for 24 h in phosphate buffer at pH 6.8 under well-mixed conditions, is shown in Fig. 2 as a function of the amount of HPC-LF initially present in the films. It can be seen that very low amounts of HPC-LF were leached from the polymer films containing 20 and 22% HPC-LF. However, the dissolution of HPC-LF increased drastically when the percentage of HPC-LF in the film increased from 22 to 24%, revealing a critical concentration for HPC-LF dissolution. The amount of HPC-LF dissolved at higher HPC-LF concentrations was above 90%. An explanation for this may be that, at low amounts of HPC-LF, the hydrophilic polymer is probably incapsulated by EC and the leaching is thereby hindered. Above 22% the HPC-LF starts to create a more continuous phase, the domains rich in HPC-LF are connected to each other and forms channels throughout the film. This favours the leaching of HPC-LF. It was also found that the leaching rate depended strongly on the agitation rate. For example, for the membrane with
3.5. Water permeability measurements of the polymer films Water permeability measurements were performed using a sideby-side diffusion cell according to a procedure described in the literature [1]. The two chambers were separated by the film of interest and the system was thermostatted with a water jacket containing water at 37 °C. The area of the film available for diffusion was 0.48 cm2. The chambers were filled at the same time with 15 ml of a 37 °C phosphate buffer solution at pH 6.8. The water diffusion experiment started when a small amount of tritiated water (10 ml, 400 kBq) was added to the donor compartment. The solutions in the donor and receiver compartments were well stirred with paddles. Samples of 500 μl were removed from the receiver compartment at regular intervals and replaced by the same amount of phosphate buffer solution. The samples were weighed and analysed in a liquid scintillator counter (1414 LSC, Win Spectral, Wallac). A sample of 500 μl was taken from the donor compartment 1 min after the diffusion experiment had been started for concentration to be uniform
Fig. 2. HPC-LF leached from EC/HPC-LF films after 24 h exposure to phosphate buffer solution at pH 6.8 under well-stirred conditions.
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Fig. 4. Water permeability of EC/HPC-LF films with different initial HPC-LF contents.
constant during the observation period. For the membrane with 24% HPC-LF, a lag time of about 45 min was observed, after which the water flow was constant during the time of observation. For the 30% HPC-LF membrane, a lag time of 20 min was observed. For films made of blends of water-soluble and water-insoluble polymers, the lag time is mainly associated with the time required for the water-soluble polymer to dissolve and for pores to be created, and for the final film structure to be obtained. The fact that no lag time was observed for the 20% HPC-LF film suggests that the structure of the film remained constant during the diffusion experiment. The water permeability values of the free films at steady state are shown in Fig. 4. The film with 20% HPC-LF had a very low water permeability, 1.3 · 10− 12 m2/s. The water permeability increased drastically when the percentage of HPC-LF in the film was increased from 22 to 24%, confirming that the transport properties of the film are strongly affected by the polymer blend composition. The water permeability of the film with 30% HPC-LF was 2.2 · 10− 10 m2/s. The drastic increase of the value of the water permeability above the HPCLF critical concentration can be explained by the percolation theory. Below the HPC-LF critical concentration, there are no “percolating” channels inside the film. This obstructs the diffusion of water. The existence of a critical concentration of the water-soluble polymer, above which the permeability of the film increases drastically, has been observed in several cases [21–23].
Fig. 3. Water diffusion in EC/HPC-LF films with 20% (A), 24% (B) and 30% (C) HPC-LF.
30% HPC-LF, 60% of the HPC-LF was leached out after the first 30 min under well-stirred conditions, but 10 h was required to extract the same amount under gently-stirred conditions. 4.2. Water diffusion through films The amount of water permeating the films times the film thickness as a function of time for films with 20, 24 and 30% HPC-LF is shown in Fig. 3 A, B and C respectively. The amount of water permeated was multiplied by the film thickness to compensate for differences in film thickness. The higher the amount of HPC-LF initially present in the film, the higher the amount of water that diffused through the film. This is in agreement with the results of the leaching experiments, and would be expected as a more porous film (as a result of the HPC-LF dissolution process) will have higher water permeability. The water flow times film thickness (the amount of water diffused times film thickness per unit time) through the 20% HPC-LF membrane was
Fig. 5. Release (filled symbols) and pressure (empty symbols) data for films containing 20% HPC-LF. Pressure and release data from each of the three experiments are shown with the same symbol. Two of the experiments are similar but the third experiment shows different pressure and release curves. This is due to inherent film heterogeneities, caused by the presence of regions with higher amount of HPC-LF.
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Fig. 6. Release (filled symbols) and pressure (empty symbols) data for films containing 24% HPC-LF. Pressure and release data from each of the three experiments are shown with the same symbol.
4.3. Release study The results of the release experiments for ethyl cellulose films containing different amounts of HPC-LF comprise simultaneous pressure build-up and release data, and are shown in Figs. 5–7. Pressure data are important as they enable comparisons to be made between the solvent inflow from the release medium into the cell and the drug outflow from the cell into the release medium. The pressure inside the cell increased slightly when it was connected to the manometer due to air compression, and then decreased slightly when the cell was immersed in water due to membrane wetting. The pressure data collected during the first few minutes of the release experiments are thus not representative of the release process, and are not shown in the figures. From Figs. 5–7 it can be seen that the amount of HPC-LF affected the release rate such that it increased with increasing amounts of HPCLF. This is in agreement with what has already been reported in the literature [7,8]. However, importantly, the amount of HPC-LF also affected the shape of the pressure build-up. This suggests that the amount of HPC also affects the transport mechanism through the coating. 4.3.1. EC films with 20% HPC-LF The results of the release experiments performed with the films containing 20% HPC-LF are shown in Fig. 5. The film is clearly not permeable to KNO3, as after several hours only a very small fraction of the salt had been released. The hydrostatic pressure inside the cell rose during the entire period of observation for two of the films. In the third film, it increased for about 40 h and then fell to a constant value. It can thus be concluded that a net bulk flow greater than zero occurred through the films (see Eq. (2)) during the phase in which the pressure increased. This means that the water inflow from the release medium into the cell was larger than the drug outflow from the cell into the release medium and that mass was accumulating inside the cell. This means also that the film is selective to the drug investigated, i.e. σ is greater than zero and that the film is semi-permeable. The rate of increase in pressure (which is equal to the derivative of the pressure curve over time) also increased. Thus, the net inflow increased during the experiment. The increase in flow can be explained as an increase in the film area due to swelling (although this contribution is quite small) and as an increase in water permeability, Lp, (see Eq. (3)). The increase in water permeability could be caused by the dissolution of HPC-LF with time and/or by the tensile stress acting on the film which might create changes in the film structure.
In the third film the release rate increased significantly after a long lag time. Pressure data were collected continuously via computer, while release data were collected manually. It is, therefore, not possible to say at exactly which time the release rate started to increase. However, it is reasonable to assume that the lag time is equal to the time at which the pressure dropped, as the decrease in pressure can be explained by the depletion of mass inside the cell (see Eq. (2)). The abrupt decrease in pressure and increase in release rate are probably due to the opening of microvoids in the film due to the tensile stress acting on the film, or the opening of pores due to HPC-LF leaching. These paths connect the interior part of the cell with the release medium, are permeable and make the film heterogeneous. The drug solution outflow through these pores, driven by the difference in pressure across the film (ΔP), is higher than the water inflow through the intact part of the film, which is driven by the difference in osmotic pressure across the film (ΔΠ) during the phase when the pressure decreases. In other words, ρ2 · Jv2 and ρ1 · Jv1 are operating in opposite directions and the absolute value of ρ2 · Jv2 is higher than that of ρ1 · Jv1 (see Eqs. (2) and (6)). The driving force for the convective outflow (ΔP) decreases with decreasing pressure inside the cell. The fact that pressure, and consequently the difference in pressure, falls to an almost constant value indicates that the system has reached equilibrium, i.e. that the solvent inflow through the non-porous coating and the drug solution outflow through the pores are equal in size. This is normally quoted as the zero order release phase. Drug is
Fig. 7. Release (filled symbols) and pressure (empty symbols) data for films containing 30% HPC-LF over 30 (A) and 4 h (B). Pressure and release data from each of the three experiments are shown with the same symbol.
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released through the pores by osmotic pumping and by diffusion. However, the fact that the difference in pressure during the zero order release phase is different from zero indicates that the release occurs mainly by osmotic pumping and that the major part of the coating is still semi-permeable. The pressure and release profiles were reproducible during the lag phase for the three films containing 20% HPC-LF. Differences are instead observable in the lag time. This is due to inherent film heterogeneities, caused by the presence of regions with higher amount of HPC-LF. The result is not surprising. In an ongoing study, differences in the lag time were observed also between the single-pellet-release profiles for pellets coated with an EC/HPC-LF film containing 20% HPC-LF. Importantly, it is possible to deduce that in pellets or tablets coated with such a film the release is expected to occur mainly by osmotic pumping. In an on-going study on pellets coated with an EC/HPC-LF film containing 20% HPC-LF, release experiments were performed at different osmotic pressures of the release medium, in order to validate the results obtained with the release cell. Interestingly, it was found that the release mechanism was osmotic pumping. The lag time is particularly long for the 20% HPC-LF films, and for 2 of the 3 films studied it is longer than 70 h. It has been shown that the lag time decreases with decreasing coating thickness and decreasing pellet radius [24,25] in systems developing small cracks in the coating due to the increase in pressure. The same is expected when microvoids open due to the tensile stress on the coating. The lag time is also expected to depend on the film thickness in systems that develop pores due to HPC-LF leaching, and is expected to be shorter for thinner films. Thus, for a formulation coated with a thinner film, the lag time is expected to be shorter than that observed. 4.3.2. EC films with 24% HPC-LF The results of the release experiments for the films containing 24% HPC-LF are shown in Fig. 6. A lag phase is observable during which the release rate is very slow and the pressure increases inside the cell. The lag phase is long, between 21/2 h and 4 h. The difference in the lag phase is due to inherent heterogeneities in the films. The film is clearly semi-permeable to the drug studied during the lag phase. Release starts when the pressure drops. The same explanation as that given in Section 4.3.1 for the film for which an increase in the release rate was observed is valid. The lag phase ends when channels are created in the film to allow drug release by convection and diffusion. The pressure drop indicates that the drug solution outflow is higher than the water inflow. The pressure initially falls to a constant value and then decreases slowly. The pressure decrease is due to the decrease in the difference in osmotic pressure across the film, which is the driving force for water uptake, and to the fact that the film becomes more and more porous, and thus a smaller area of the film has a reflection coefficient close to one and a larger area has a reflection coefficient equal to zero. The pressure decrease was thus due to the decrease in Jv1 and to the increase in A2. It can be deduced that the contribution to the drug release by convection decreases with time as the pressure inside the membrane drops. Interestingly, the release rate increases with time in spite of the decrease in pressure inside the cell and in spite of the decrease in salt concentration inside the cell and, thus, a decrease in the force driving drug diffusion. This can be explained by considering the fact that more and more HPC-LF is leached out during the release experiment. HPC-LF leaching leads to an increase in the area of pores which in turns affect Jv2 compensating for a decrease in pressure (see Eq. (5)) and causes an increase in the effective diffusion coefficient of the drug in the film. A lag phase was also observed for this film composition in the water diffusion experiment. The difference in the lag time between the water diffusion experiments and the release experiments is due to the different agitation conditions in the two experiments (HPC-LF leaching depends on the agitation rate), the difference in the molecular size between water and KNO3, and the difference in the
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ionic strength of the solution in contact with the film which may affect the HPC-LF leaching process. By comparing the pressure data of the 24% HPC-LF film with those of the 20% HPC-LF film, it can be deduced that the increase in pressure during the lag phase occurs more rapidly for the 24% HPC-LF film. This can be attributed to the fact that Lp · σ is higher for the 24% HPC-LF film than for the 20% HPC-LF film (see Eq. (3)), as ΔΠ was the same for both films. The reflection coefficient of the 24% HPC-LF film is lower than that of the 20% HPC-LF film, as can be deduced from the fact that during the lag phase, the release rate was higher for the 24% HPC-LF film (not visible in Figs. 5 and 6 due to the difference in the scales). The water permeability of the 24% HPC-LF film during the lag phase must be higher than that of the membrane with 20% HPC-LF for the relationship Lp σ j 24%HPC−LF N Lp σ j 20%HPC−LF to be valid, which is in agreement with the measurements of the water permeability. 4.3.3. EC films with 30% HPC-LF The results of the release experiments for the films containing 30% HPC-LF are shown in Fig. 7. Also in this case a lag time is observable during which the pressure increases inside the cell. This means that at the beginning of the experiment the film is semi-permeable to the drug. The lag time is very short compared with that observed for the 20 and 24% HPC-LF films, being only about 25 min. This is in agreement with the finding that HPC-LF leaches faster from the film with 30% HPC-LF than from the film with 20 and 24% HPC-LF. After 25 min the pressure decreases quickly and release starts. The pressure drops to value corresponding to ΔP = 0. This implies that after the first hours both Jv1 and Jv2 are equal to zero, which is the case if the film is permeable. Thus, apart from the initial period during which ΔP N 0, the release occurs by diffusion only. The release rate is almost constant despite the decrease in the drug concentration inside the cell, and thus the decrease in the force driving the diffusion process. This is due to the increase in the porosity of the film caused by HPC-LF leaching. It can be concluded that for formulations coated with this film the release is expected to occur by diffusion. 4.4. Film morphology before and after the release experiments The morphology of the EC/HPC-LF films before and after the release experiments was studied using scanning electron microscopy,
Fig. 8. SEM images of films initially containing 20 (A), 24 (B) and 30% (C) HPC before (1) and after the release experiments (2).
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and some typical images are shown in Fig. 8. No remarkable differences were observed in the films before the experiments. However, after the release experiments, the films appeared very different. Interestingly, few depressions were observable on the surface of the 20% HPC-LF film. Several depressions were seen in the 24% HPC-LF film. Several deep and large depressions were clearly visible on the surface of the 30% HPC-LF films. It should be pointed out that some depressions are pores. As EC is insoluble in water, the depressions must be produced by the leaching of HPC-LF. These SEM observations are in accordance with the results of the drug release, water permeability and pressure measurements. Films with 24 and 30% HPC-LF showed an increase in porosity and permeability. The porosity of 20% HPC-LF membranes did not change significantly after incubation in water, and the membrane was still semi-permeable even after many hours in water. 5. Conclusions A release cell equipped with a manometer is an easy and efficient means of accurately characterizing the nature of a film, i.e. whether it is permeable or semi-permeable, and the drug release mechanism from coated formulations. Importantly, for formulations coated with blends of water-soluble and water-insoluble polymers, possible changes in the film nature and in the release mechanism during the release process can be investigated. The release cell was used to study the transport of a model compound through EC/HPC-LF films. It was found that EC/HPC-LF films containing 20–30% HPC-LF were semi-permeable to the compound at the beginning of the release experiments. However, films with 30% HPC-LF became permeable during the release due to HPC-LF leaching. The release mechanism depended on the amount of HPC-LF initially present in the film and changed from osmotic pumping to diffusion as the amount of HPC-LF increased. Acknowledgments Liza Lindmark is gratefully acknowledged for her assistance with the measurements of the water permeability of the films. Leif Stanley is gratefully acknowledged for the assistance in the construction of the release cell. This study was partially funded by the Swedish Research Council. References [1] B. Lindstedt, G. Ragnarsson, J. Hjärtstam, Osmotic pumping as a release mechanism for membrane-coated drug formulations, Int. J. Pharm. 56 (1989) 261–268. [2] J. Hjärtstam, T. Hjertberg, Swelling of pellets coated with a composite film containing ethyl cellulose and hydroxypropyl methylcellulose, Int. J. Pharm.161 (1) (1998) 23–28.
[3] Hjärtstam J. Ethyl cellulose membranes used in modified release formulations (PhD thesis), Chalmers University of technology, Göteborg, Sweden, 1998. [4] P. Sakellariou, R.C. Rowe, E.F.T. White, Polymer/polymer interaction in blends of ethyl cellulose with both cellulose derivatives and polyethylene glycol6000, Int. J. Pharm. 34 (1986) 93–103. [5] P. Sakellariou, R.C. Rowe, E.F.T. White, A study of the leaching/retention of watersoluble polymers in blends with ethylcellulose using torsional braid analysis, J. Control. Release 7 (1988) 147–157. [6] P. Sakellariou, R.C. Rowe, Interaction in cellulose derivative films for oral drug delivery, Prog. Polym. Sci. 20 (1995) 889–942. [7] A.G. Thombre, A.R. DeNoto, F.C. Falkner, J.D. Lazar, In vivo/in vitro correlations of sustained-release coated multiparticulate formulations of doxazosin, Int. J. Pharm. 111 (1994) 181–189. [8] K. Umprayn, P. Chitropas, S. Amarekajorn, Development of terbutaline sulfate sustained-release coated pellets, Drug Dev. Ind. Pharm. 25 (1999) 477–491. [9] M. Donbrow, Y. Samuelov, Zero order drug delivery from double-layered porous film: release rate profiles from ethyl cellulose, hydroxypropyl cellulose and polyethylene glycol, J. Pharm. Pharmacol. 32 (1980) 463–470. [10] A.G. Ozturk, S.S. Ozturk, B.O. Palsson, T.A. Wheatley, J.B. Dressman, Mechanism of release from pellets coated with an ethylcellulose-based film, J. Control. Release 14 (3) (1990) 203–213. [11] M. Marucci, G. Ragnarsson, A. Axelsson, Evaluation of osmotic effects on coated pellets using a mechanistic model, Int. J. Pharm. 336 (2) (2007) 67–74. [12] S. Ensslin, K.P. Moll, K. Paulus, K. Mäder, New insight into modified release pelletsinternal structure and drug release mechanism, J. Control. Release 128 (2008) 149–156. [13] P. Schultz, P. Kleinebudde, A new multiparticulate delayed release system. Part I: dissolution properties and release mechanism, J. Control. Release 47 (1997) 181–189. [14] S.C. Porter, The effect of additives on the properties of an aqueous film coating, Pharm. Technol. 4 (1980) 67–75. [15] E.L. Cussler, Diffusion, Mass transfer in fluid systems, 2nd ed, Cambridge university press, Cambridge, 1997. [16] Z. Ye, P. Rombout, J.P. Remon, C. Vervaet, G.V. Mooter, Correlation between the permeability of metropolol tartrate through plasticized isolated ethylcellulose/ hydroxypropyl methylcellulose films and drug release from reservoir pellets, Eur. J. Pharm. Biopharm. 67 (2007) 485–490. [17] K. Okimoto, R. Rajewski, V.J. Stella, Release of testosterone from an osmotic pump tablet utilizing (SBE)7m-b-cyclodestrin as both a solubilizing and an osmotic pump agent, J. Control. Release 58 (1999) 29–38. [18] M. Marucci, G. Ragnarsson, A. Axelsson, ESPI: a novel non-invasive tool for studying drug transport rate and drug permeability through free films, J. Control. Release (114) (2006) 369–380. [19] J. Hjärtstam, K. Borg, B. Lindstedt, The effect of tensile-stress on permeability of free films of ethyl cellulose containing hydroxypropyl methylcellulose, Int. J. Pharm. 61 (1990) 101–107. [20] B. Lindstedt, M. Sjöberg, J. Hjärtstam, Osmotic pumping release from KCl tablets coated with porous and nonporous ethylcellulose, Int. J. Pharm. 67 (1991) 21–27. [21] L. Tang, J.B. Schwartz, S.C. Porter, R.L. Schnaare, R.J. Wigent, Drug release from filmcoated chlorpheniramine maleate nonpareil beads: effect of water-soluble polymer, coating level, and soluble core material, Pharm. Dev. Technol. 5 (2000) 383–390. [22] F. Lecomte, J. Siepmann, M. Walther, R.J. MacRae, R. Bodmeier, pH-sensitive polymer blends used as coating materials to control drug release from spherical beads: elucidation of the underlying mass transport mechanism, Pharm. Res. 22 (2005) 1129–1141. [23] F. Lecomte, J. Siepmann, M. Walther, R.J. MacRae, R. Bodmeier, Blends of enteric and GIT-insoluble polymers used for film coating: physicochemical characterization and drug release patterns, J. Control. Release 89 (3) (2003) 457–471. [24] D.O. Kuethe, D.C. Augenstein, J.D. Gresser, D.L. Wise, Design of capsules that burst at predetermined times by dialysis, J. Control. Release 18 (2) (1992) 159–164. [25] M. Marucci, G. Ragnarsson, U. Nyman, A. Axelsson, Mechanistic model for drug release during the lag phase from pellets coated with a semi-permeable membrane, J. Control. Release 127 (2008) 31–40.
Contents lists available at ScienceDirect
Journal of Controlled Release j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j c o n r e l
Coated formulations: New insights into the release mechanism and changes in the film properties with a novel release cell Mariagrazia Marucci a, Johan Hjärtstam b, Gert Ragnarsson c, Frida Iselau b, Anders Axelsson a,⁎ a b c
Department of Chemical Engineering, Lund University, P.O. Box 124, SE-221 00 Lund, Sweden AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden Medical Products Agency, P.O. Box 26, SE-751 03 Uppsala, Sweden
a r t i c l e
i n f o
Article history: Received 31 October 2008 Accepted 20 February 2009 Available online 27 February 2009 Keywords: Release mechanism Polymer blend Osmotic pumping Diffusion Coating
a b s t r a c t 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. © 2009 Elsevier B.V. All rights reserved.
1. Introduction Polymer film coating is often used in oral controlled release systems. Polymers suitable for this fall into two groups: those based on natural polymers and those based on synthetic polymers. Cellulose is the most wide spread natural polymer and a variety of different cellulose derivates are used. The cellulosic polymer most often used for controlled release is ethyl cellulose (EC) due to its good film forming properties. EC is a water-insoluble polymer generally regarded as non-toxic and non-allergenic. It is stable under physiological as well as during normal storage conditions. Due to the low permeability of pure EC, polymer blends of EC and water-soluble polymers are often used as coatings. Hydroxypropyl methylcellulose (HPMC) is the hitherto most commonly used water-soluble polymer, and the release mechanism from pellets coated with EC/HPMC films with different polymer ratios has been extensively studied [1–3] Hydroxypropyl cellulose (HPC) is another attractive water-soluble polymer as it has low toxicity, is biodegradable and easily forms films. The structure of films made of EC and HPC has been studied by Sakellariou et al. [4–6]. HPC was shown to be incompatible with EC
⁎ Corresponding author. Tel.: +46 46 2228287; fax: +46 46 2224526. E-mail address: [email protected] (A. Axelsson). 0168-3659/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2009.02.017
and phase separation occurred. The use of EC and HPC as coating has been studied previously, and it has been found that the release rate from coated formulations increased with higher percentages of HPC in the film [7–9]. However, the release mechanism at different ratios has not yet been characterized. It is important to understand the underlying mechanism of release (i.e. diffusion and/or osmotic pumping) from coated formulations in order to optimize the polymer blend of the coating film. The release mechanism depends on the nature of the coating film and is mainly osmotic pumping for a semi-permeable film and mainly diffusion for a porous film. A hydrostatic pressure is built up inside the formulation when the release mechanism is osmotic pumping. The release mechanism after the lag phase is often characterized using release experiments by studying the dependency of the release rate on the osmotic pressure of the release medium [10,11]. Release occurs by osmotic pumping if the release rate decreases significantly upon decreasing the osmotic pressure gradient across the coating. In some studies, release experiments have been combined with NMR experiments [12] to investigate water influx and drug dissolution inside the pellet, or with swelling experiments to study water imbibing inside the pellet and the related hydrostatic pressure build-up inside the pellet [2,13]. Pellets swelling caused by water accumulation indicates that the coating is semi-permeable towards the drug studied. However, during the lag and the zero-order release phase, a series of important
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phenomena, such as leaching of the water-soluble polymer and presence of a tensile stress on the coating due to solvent accumulation inside the pellet, can occur and affect the nature, permeability and mechanical properties of the coating. Thus a full understanding of the release mechanism during the whole release process may be complicated and require several different kinds of experiments. The use of isolated films has been reported as an alternative, convenient way of predicting coating properties, and as a good way to screen different coatings [14]. Several types of diffusion cells have been reported in the literature for the study of drug transport through polymer films. Side-by-side diffusion cells are commonly used to characterize free films and to measure the diffusion coefficient of the drug in the film [15], and in many cases the results obtained from the release profile can also be used to predict the drug release from coated formulations [16]. However, due to their construction, these cells are often only useful in simulating formulations coated with permeable films. The pressure rise that occurs in formulations coated with semipermeable films, occurs in these cells in a completely different way, or may not occur at all. Okimoto et al. used a special osmotic pump device which allowed the hydrostatic pressure to build up inside the cell to study semi-permeable films [17]. In a previous study we used a diffusion cell in a holographic set-up, and the analytical technique employed provided discrimination between permeable and semipermeable films, allowing the total bulk flow (drug plus solvent) through the film to be studied [18]. The cell can be easily adjusted to allow for a pressure build-up in the donor compartment. Hjärtstam et al. used a pressurized cell to study the dependency of the permeability of EC films on the hydrostatic pressure applied in the cell and, consequently, on the tensile stress acting on the film [19]. The purpose of this study was to characterize the mechanism of mass transport through films made of EC and HPC-LF with different polymer blend ratios. A novel release cell was designed and used in the release experiments. The cell resembled the pressurized cell used by Hjärtstam et al. [19], the main difference being that no external hydrostatic pressure was applied. The cell was instead equipped with a manometer to measure the pressure that naturally arose inside the cell. The pressure rise is directly correlated to the net bulk flow through the coating, which in turn depends on water imbibing and drug transport through the film. The cell can be regarded as a large coated pellet. The advantage of collecting release and pressure data simultaneously is that the release mechanism from a coated formulation can readily be simulated and studied.
where Lp is the water permeability of the film, σ the reflection coefficient for the drug, h the film thickness, A the film area, ΔΠ the difference in osmotic pressure across the film and ΔP the difference in pressure across the film. At the beginning of the release experiment ΔP is equal to zero. The reflection coefficient, σ, is zero for a permeable film, and Jv is thus equal to zero, and no hydrostatic pressure is built up inside the coated formulation. For a semi-permeable film (or leaky film) the reflection coefficient has a value between zero and one (0b σ ≤ 1). Consequently, Jv has a value higher than zero, a net flow occurs from the release medium into the coated formulation and a hydrostatic pressure is built up inside the coated formulation. For a completely impermeable film the reflection coefficient is equal to one and also in this case a hydrostatic pressure is built up inside the coated formulation. For a film consisting of two regions with very different reflectivities, for example, a semi-permeable region, (with 0 b σ ≤ 1) and a permeable region, (with σ = 0) , it can be convenient to define two different volumetric flows [20], one for the semi-permeable region, Jv1, and one for the permeable region, Jv2, where:
2. Theory
EC (EC N10CR) was supplied from Dow Chemical Co., USA. HPC grade LF was supplied from Aqualon, USA. Tritium labelled water (Amersham, UK) was used in the water permeability measurements. Potassium nitrate was used in the release experiments and was purchased from Merck (Darmstadt, Germany).
The total mass balance for a coated formulation immersed in an aqueous solution is given by: dM = ρ Jv dt
ð1Þ
where M is the mass inside the coated formulation, Jv is the net volumetric bulk flow through the coating and ρ the density of the bulk. Jv depends on the flow of both water and drug. The change in mass induces a change in volume in the formulation and an increase in hydrostatic pressure inside the formulation and in the pressure gradient ΔP across the coating. The following proportionality can thus be written: dM dV dðΔP Þ ~ ~ ~ρ Jv dt dt dt
ð2Þ
For a homogeneous film, Jv can be written according to the irreversible thermodynamic equation: Jv =
Lp A ðσ ΔΠ − ΔP Þ h
ð3Þ
Jv1 =
Lp1 A1 ðσ 1 ΔΠ − ΔP Þ h
ð4Þ
and Jv2 = −
Lp2 A2 ΔP h
ð5Þ
Jv1 and Jv2 have different directions. Jv2 is the volumetric outflow of the drug solution from the coated formulation into the release medium. Jv2 is the volumetric “osmotic pumping” flow and it occurs if there is a difference in pressure across the film coating. Jv1 is the volumetric inflow of water from the release medium into the coated formulation. The resultant mass balance can be expressed as: dM = ρ1 Jv1 + ρ2 Jv2 dt
ð6Þ
where ρ1 is the density of water and ρ2 is the density of the drug solution. 3. Materials and methods 3.1. Materials
3.2. Preparation of polymer films EC/HPC-LF films were prepared by spraying a solution of 94% w/w ethanol (95%) and 6% w/w polymer onto a rotating drum. The drum was filled with hot water and its temperature was approximately 50 °C at the start and 34 °C at the end of film spraying. After spraying, the films were peeled off the drum and kept in a desiccator. Thin films containing 20, 22, 24, 26, 28 and 30% HPC-LF were prepared. Permeability and leaching experiments were performed for all films, and release experiments on films with 20, 24 and 30% HPC-LF. The thickness of the films was measured using an electronic micrometer. The films with 20%, 24% and 30% HPC-LF were 140, 120 and 100 μm thick, respectively. 3.3. Design of the release cell The cell consists of two circular brass end caps, joined together by two lengths of brass. Rectangular films (6.5 cm × 10 cm) were glued to
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to determine the tritium activity in this compartment. From the tritium activity measurements it was possible to calculate the amount of water that had diffused through the film at different times, and thus the water permeability of the film. Experiments were performed in duplicate. 3.6. Release studies
Fig. 1. Schematic representation of the release cell. (1) film, (2) cylindrical end of the cell, (3) brass piece to connect the ends of the cell. Rectangular films are glued to the ends of the cell. Pipe connections for filling are not shown.
the ends of the cell and to one of the metal pieces. A silicone glue was used (Dana Lim A7S, Denmark) and the glue was allowed to dry for 2 days before the release experiments were performed. The film thus formed the shell of the cell, which was cylindrical in shape. The cell was equipped with pipe connections for filling and was filled with the donor solution. The cell was equipped with a manometer to measure the pressure inside the cell. The accuracy of the manometer was 0.0005 bar. A tensile stress will act causing a strain on the film if the pressure inside the cell increases. If the ends of the film were free to move, the tensile stresses would be uniformly distributed over the film. However, the size of the cell was chosen to minimize the edge effects resulting from the fact that the film was glued to the ends of the cell and the tensile stress could be considered uniformly distributed. Fig. 1 shows a schematic illustration of the cell. This cell has the advantage that release data can be collected at the same time as pressure data. 3.4. Leaching of HPC-LF from polymer films A piece of the film of interest was immersed in 70 ml of a phosphate buffer solution, pH 6.8. The system was agitated and maintained at a temperature of 37 °C. Samples were taken at regular intervals and the HPC-LF concentration in the samples was analysed using size exclusion chromatography. Leaching experiments were performed under well-stirred and gently-stirred conditions for comparison. The experiments were performed in duplicate.
The release cell was filled with 40 ml of a preheated solution of KNO3 (28 g/l, 37 °C), connected to the manometer and immersed in a thermostatted vessel containing 1.5 l distilled water. The system was kept at a temperature of 37 °C. The liquid inside the thermostatted vessel was well stirred. The release of KNO3 through the film into the liquid inside the vessel was determined with a conductivity meter. The manometer of the cell was connected to a computer and pressure data were recorded continuously. Triplicate experiments were performed for each polymer blend. 3.7. Film morphology The morphology of the EC/HPC-LF films before and after the release experiments was studied using a scanning electron microscope (SEM) (JSM-840A, Jeol Ltd, Japan). The polymer films were coated with a thin layer of gold in an ion sputtering device before observation in the SEM. 4. Results and discussion 4.1. Leaching of HPC-LF from polymer films The amount of HPC-LF leached from EC/HPC-LF films, after soaking for 24 h in phosphate buffer at pH 6.8 under well-mixed conditions, is shown in Fig. 2 as a function of the amount of HPC-LF initially present in the films. It can be seen that very low amounts of HPC-LF were leached from the polymer films containing 20 and 22% HPC-LF. However, the dissolution of HPC-LF increased drastically when the percentage of HPC-LF in the film increased from 22 to 24%, revealing a critical concentration for HPC-LF dissolution. The amount of HPC-LF dissolved at higher HPC-LF concentrations was above 90%. An explanation for this may be that, at low amounts of HPC-LF, the hydrophilic polymer is probably incapsulated by EC and the leaching is thereby hindered. Above 22% the HPC-LF starts to create a more continuous phase, the domains rich in HPC-LF are connected to each other and forms channels throughout the film. This favours the leaching of HPC-LF. It was also found that the leaching rate depended strongly on the agitation rate. For example, for the membrane with
3.5. Water permeability measurements of the polymer films Water permeability measurements were performed using a sideby-side diffusion cell according to a procedure described in the literature [1]. The two chambers were separated by the film of interest and the system was thermostatted with a water jacket containing water at 37 °C. The area of the film available for diffusion was 0.48 cm2. The chambers were filled at the same time with 15 ml of a 37 °C phosphate buffer solution at pH 6.8. The water diffusion experiment started when a small amount of tritiated water (10 ml, 400 kBq) was added to the donor compartment. The solutions in the donor and receiver compartments were well stirred with paddles. Samples of 500 μl were removed from the receiver compartment at regular intervals and replaced by the same amount of phosphate buffer solution. The samples were weighed and analysed in a liquid scintillator counter (1414 LSC, Win Spectral, Wallac). A sample of 500 μl was taken from the donor compartment 1 min after the diffusion experiment had been started for concentration to be uniform
Fig. 2. HPC-LF leached from EC/HPC-LF films after 24 h exposure to phosphate buffer solution at pH 6.8 under well-stirred conditions.
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Fig. 4. Water permeability of EC/HPC-LF films with different initial HPC-LF contents.
constant during the observation period. For the membrane with 24% HPC-LF, a lag time of about 45 min was observed, after which the water flow was constant during the time of observation. For the 30% HPC-LF membrane, a lag time of 20 min was observed. For films made of blends of water-soluble and water-insoluble polymers, the lag time is mainly associated with the time required for the water-soluble polymer to dissolve and for pores to be created, and for the final film structure to be obtained. The fact that no lag time was observed for the 20% HPC-LF film suggests that the structure of the film remained constant during the diffusion experiment. The water permeability values of the free films at steady state are shown in Fig. 4. The film with 20% HPC-LF had a very low water permeability, 1.3 · 10− 12 m2/s. The water permeability increased drastically when the percentage of HPC-LF in the film was increased from 22 to 24%, confirming that the transport properties of the film are strongly affected by the polymer blend composition. The water permeability of the film with 30% HPC-LF was 2.2 · 10− 10 m2/s. The drastic increase of the value of the water permeability above the HPCLF critical concentration can be explained by the percolation theory. Below the HPC-LF critical concentration, there are no “percolating” channels inside the film. This obstructs the diffusion of water. The existence of a critical concentration of the water-soluble polymer, above which the permeability of the film increases drastically, has been observed in several cases [21–23].
Fig. 3. Water diffusion in EC/HPC-LF films with 20% (A), 24% (B) and 30% (C) HPC-LF.
30% HPC-LF, 60% of the HPC-LF was leached out after the first 30 min under well-stirred conditions, but 10 h was required to extract the same amount under gently-stirred conditions. 4.2. Water diffusion through films The amount of water permeating the films times the film thickness as a function of time for films with 20, 24 and 30% HPC-LF is shown in Fig. 3 A, B and C respectively. The amount of water permeated was multiplied by the film thickness to compensate for differences in film thickness. The higher the amount of HPC-LF initially present in the film, the higher the amount of water that diffused through the film. This is in agreement with the results of the leaching experiments, and would be expected as a more porous film (as a result of the HPC-LF dissolution process) will have higher water permeability. The water flow times film thickness (the amount of water diffused times film thickness per unit time) through the 20% HPC-LF membrane was
Fig. 5. Release (filled symbols) and pressure (empty symbols) data for films containing 20% HPC-LF. Pressure and release data from each of the three experiments are shown with the same symbol. Two of the experiments are similar but the third experiment shows different pressure and release curves. This is due to inherent film heterogeneities, caused by the presence of regions with higher amount of HPC-LF.
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Fig. 6. Release (filled symbols) and pressure (empty symbols) data for films containing 24% HPC-LF. Pressure and release data from each of the three experiments are shown with the same symbol.
4.3. Release study The results of the release experiments for ethyl cellulose films containing different amounts of HPC-LF comprise simultaneous pressure build-up and release data, and are shown in Figs. 5–7. Pressure data are important as they enable comparisons to be made between the solvent inflow from the release medium into the cell and the drug outflow from the cell into the release medium. The pressure inside the cell increased slightly when it was connected to the manometer due to air compression, and then decreased slightly when the cell was immersed in water due to membrane wetting. The pressure data collected during the first few minutes of the release experiments are thus not representative of the release process, and are not shown in the figures. From Figs. 5–7 it can be seen that the amount of HPC-LF affected the release rate such that it increased with increasing amounts of HPCLF. This is in agreement with what has already been reported in the literature [7,8]. However, importantly, the amount of HPC-LF also affected the shape of the pressure build-up. This suggests that the amount of HPC also affects the transport mechanism through the coating. 4.3.1. EC films with 20% HPC-LF The results of the release experiments performed with the films containing 20% HPC-LF are shown in Fig. 5. The film is clearly not permeable to KNO3, as after several hours only a very small fraction of the salt had been released. The hydrostatic pressure inside the cell rose during the entire period of observation for two of the films. In the third film, it increased for about 40 h and then fell to a constant value. It can thus be concluded that a net bulk flow greater than zero occurred through the films (see Eq. (2)) during the phase in which the pressure increased. This means that the water inflow from the release medium into the cell was larger than the drug outflow from the cell into the release medium and that mass was accumulating inside the cell. This means also that the film is selective to the drug investigated, i.e. σ is greater than zero and that the film is semi-permeable. The rate of increase in pressure (which is equal to the derivative of the pressure curve over time) also increased. Thus, the net inflow increased during the experiment. The increase in flow can be explained as an increase in the film area due to swelling (although this contribution is quite small) and as an increase in water permeability, Lp, (see Eq. (3)). The increase in water permeability could be caused by the dissolution of HPC-LF with time and/or by the tensile stress acting on the film which might create changes in the film structure.
In the third film the release rate increased significantly after a long lag time. Pressure data were collected continuously via computer, while release data were collected manually. It is, therefore, not possible to say at exactly which time the release rate started to increase. However, it is reasonable to assume that the lag time is equal to the time at which the pressure dropped, as the decrease in pressure can be explained by the depletion of mass inside the cell (see Eq. (2)). The abrupt decrease in pressure and increase in release rate are probably due to the opening of microvoids in the film due to the tensile stress acting on the film, or the opening of pores due to HPC-LF leaching. These paths connect the interior part of the cell with the release medium, are permeable and make the film heterogeneous. The drug solution outflow through these pores, driven by the difference in pressure across the film (ΔP), is higher than the water inflow through the intact part of the film, which is driven by the difference in osmotic pressure across the film (ΔΠ) during the phase when the pressure decreases. In other words, ρ2 · Jv2 and ρ1 · Jv1 are operating in opposite directions and the absolute value of ρ2 · Jv2 is higher than that of ρ1 · Jv1 (see Eqs. (2) and (6)). The driving force for the convective outflow (ΔP) decreases with decreasing pressure inside the cell. The fact that pressure, and consequently the difference in pressure, falls to an almost constant value indicates that the system has reached equilibrium, i.e. that the solvent inflow through the non-porous coating and the drug solution outflow through the pores are equal in size. This is normally quoted as the zero order release phase. Drug is
Fig. 7. Release (filled symbols) and pressure (empty symbols) data for films containing 30% HPC-LF over 30 (A) and 4 h (B). Pressure and release data from each of the three experiments are shown with the same symbol.
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released through the pores by osmotic pumping and by diffusion. However, the fact that the difference in pressure during the zero order release phase is different from zero indicates that the release occurs mainly by osmotic pumping and that the major part of the coating is still semi-permeable. The pressure and release profiles were reproducible during the lag phase for the three films containing 20% HPC-LF. Differences are instead observable in the lag time. This is due to inherent film heterogeneities, caused by the presence of regions with higher amount of HPC-LF. The result is not surprising. In an ongoing study, differences in the lag time were observed also between the single-pellet-release profiles for pellets coated with an EC/HPC-LF film containing 20% HPC-LF. Importantly, it is possible to deduce that in pellets or tablets coated with such a film the release is expected to occur mainly by osmotic pumping. In an on-going study on pellets coated with an EC/HPC-LF film containing 20% HPC-LF, release experiments were performed at different osmotic pressures of the release medium, in order to validate the results obtained with the release cell. Interestingly, it was found that the release mechanism was osmotic pumping. The lag time is particularly long for the 20% HPC-LF films, and for 2 of the 3 films studied it is longer than 70 h. It has been shown that the lag time decreases with decreasing coating thickness and decreasing pellet radius [24,25] in systems developing small cracks in the coating due to the increase in pressure. The same is expected when microvoids open due to the tensile stress on the coating. The lag time is also expected to depend on the film thickness in systems that develop pores due to HPC-LF leaching, and is expected to be shorter for thinner films. Thus, for a formulation coated with a thinner film, the lag time is expected to be shorter than that observed. 4.3.2. EC films with 24% HPC-LF The results of the release experiments for the films containing 24% HPC-LF are shown in Fig. 6. A lag phase is observable during which the release rate is very slow and the pressure increases inside the cell. The lag phase is long, between 21/2 h and 4 h. The difference in the lag phase is due to inherent heterogeneities in the films. The film is clearly semi-permeable to the drug studied during the lag phase. Release starts when the pressure drops. The same explanation as that given in Section 4.3.1 for the film for which an increase in the release rate was observed is valid. The lag phase ends when channels are created in the film to allow drug release by convection and diffusion. The pressure drop indicates that the drug solution outflow is higher than the water inflow. The pressure initially falls to a constant value and then decreases slowly. The pressure decrease is due to the decrease in the difference in osmotic pressure across the film, which is the driving force for water uptake, and to the fact that the film becomes more and more porous, and thus a smaller area of the film has a reflection coefficient close to one and a larger area has a reflection coefficient equal to zero. The pressure decrease was thus due to the decrease in Jv1 and to the increase in A2. It can be deduced that the contribution to the drug release by convection decreases with time as the pressure inside the membrane drops. Interestingly, the release rate increases with time in spite of the decrease in pressure inside the cell and in spite of the decrease in salt concentration inside the cell and, thus, a decrease in the force driving drug diffusion. This can be explained by considering the fact that more and more HPC-LF is leached out during the release experiment. HPC-LF leaching leads to an increase in the area of pores which in turns affect Jv2 compensating for a decrease in pressure (see Eq. (5)) and causes an increase in the effective diffusion coefficient of the drug in the film. A lag phase was also observed for this film composition in the water diffusion experiment. The difference in the lag time between the water diffusion experiments and the release experiments is due to the different agitation conditions in the two experiments (HPC-LF leaching depends on the agitation rate), the difference in the molecular size between water and KNO3, and the difference in the
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ionic strength of the solution in contact with the film which may affect the HPC-LF leaching process. By comparing the pressure data of the 24% HPC-LF film with those of the 20% HPC-LF film, it can be deduced that the increase in pressure during the lag phase occurs more rapidly for the 24% HPC-LF film. This can be attributed to the fact that Lp · σ is higher for the 24% HPC-LF film than for the 20% HPC-LF film (see Eq. (3)), as ΔΠ was the same for both films. The reflection coefficient of the 24% HPC-LF film is lower than that of the 20% HPC-LF film, as can be deduced from the fact that during the lag phase, the release rate was higher for the 24% HPC-LF film (not visible in Figs. 5 and 6 due to the difference in the scales). The water permeability of the 24% HPC-LF film during the lag phase must be higher than that of the membrane with 20% HPC-LF for the relationship Lp σ j 24%HPC−LF N Lp σ j 20%HPC−LF to be valid, which is in agreement with the measurements of the water permeability. 4.3.3. EC films with 30% HPC-LF The results of the release experiments for the films containing 30% HPC-LF are shown in Fig. 7. Also in this case a lag time is observable during which the pressure increases inside the cell. This means that at the beginning of the experiment the film is semi-permeable to the drug. The lag time is very short compared with that observed for the 20 and 24% HPC-LF films, being only about 25 min. This is in agreement with the finding that HPC-LF leaches faster from the film with 30% HPC-LF than from the film with 20 and 24% HPC-LF. After 25 min the pressure decreases quickly and release starts. The pressure drops to value corresponding to ΔP = 0. This implies that after the first hours both Jv1 and Jv2 are equal to zero, which is the case if the film is permeable. Thus, apart from the initial period during which ΔP N 0, the release occurs by diffusion only. The release rate is almost constant despite the decrease in the drug concentration inside the cell, and thus the decrease in the force driving the diffusion process. This is due to the increase in the porosity of the film caused by HPC-LF leaching. It can be concluded that for formulations coated with this film the release is expected to occur by diffusion. 4.4. Film morphology before and after the release experiments The morphology of the EC/HPC-LF films before and after the release experiments was studied using scanning electron microscopy,
Fig. 8. SEM images of films initially containing 20 (A), 24 (B) and 30% (C) HPC before (1) and after the release experiments (2).
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and some typical images are shown in Fig. 8. No remarkable differences were observed in the films before the experiments. However, after the release experiments, the films appeared very different. Interestingly, few depressions were observable on the surface of the 20% HPC-LF film. Several depressions were seen in the 24% HPC-LF film. Several deep and large depressions were clearly visible on the surface of the 30% HPC-LF films. It should be pointed out that some depressions are pores. As EC is insoluble in water, the depressions must be produced by the leaching of HPC-LF. These SEM observations are in accordance with the results of the drug release, water permeability and pressure measurements. Films with 24 and 30% HPC-LF showed an increase in porosity and permeability. The porosity of 20% HPC-LF membranes did not change significantly after incubation in water, and the membrane was still semi-permeable even after many hours in water. 5. Conclusions A release cell equipped with a manometer is an easy and efficient means of accurately characterizing the nature of a film, i.e. whether it is permeable or semi-permeable, and the drug release mechanism from coated formulations. Importantly, for formulations coated with blends of water-soluble and water-insoluble polymers, possible changes in the film nature and in the release mechanism during the release process can be investigated. The release cell was used to study the transport of a model compound through EC/HPC-LF films. It was found that EC/HPC-LF films containing 20–30% HPC-LF were semi-permeable to the compound at the beginning of the release experiments. However, films with 30% HPC-LF became permeable during the release due to HPC-LF leaching. The release mechanism depended on the amount of HPC-LF initially present in the film and changed from osmotic pumping to diffusion as the amount of HPC-LF increased. Acknowledgments Liza Lindmark is gratefully acknowledged for her assistance with the measurements of the water permeability of the films. Leif Stanley is gratefully acknowledged for the assistance in the construction of the release cell. This study was partially funded by the Swedish Research Council. References [1] B. Lindstedt, G. Ragnarsson, J. Hjärtstam, Osmotic pumping as a release mechanism for membrane-coated drug formulations, Int. J. Pharm. 56 (1989) 261–268. [2] J. Hjärtstam, T. Hjertberg, Swelling of pellets coated with a composite film containing ethyl cellulose and hydroxypropyl methylcellulose, Int. J. Pharm.161 (1) (1998) 23–28.
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