effect of manufacturing conditions and polymer ratio on...
TRANSCRIPT
K09024
Master Thesis 30 hpUppsala University
Sweden 2009
Effect of manufacturing conditions and polymer ratio on the permeability and film morphology of ethyl cellulose and hydroxypropyl cellulose free-films produced by using a novel spray method
Annica Jarke
Teknisk- naturvetenskaplig fakultet UTH-enheten
Besöksadress: Ångströmlaboratoriet Lägerhyddsvägen 1 Hus 4, Plan 0
Postadress: Box 536 751 21 Uppsala
Telefon:018 – 471 30 03
Telefax: 018 – 471 30 00
Hemsida:http://www.teknat.uu.se/student
Abstract
Effect of manufacturing conditions and polymer ratioon the permeability and film
Annica Jarke
This thesis considers the effect of manufacturing conditions and polymer ratio onwater permeability and morphology of free-films. A novel spray method for producingethyl cellulose (EC) and hydroxypropyl cellulose (HPC) free-films was developedwhere several process parameters was controlled. The process was optimised bypre-spraying solvent until the system reached a steady-state temperature. Thisminimised the variation of outlet air temperature to < 2.5 °C. Coating time wasapproximately 4 minutes excluding drying.
Films were produced using 94 wt% solvent (95 %-ethanol) and 6 wt% polymer. Theamount of HPC in the films was varied (wt% HPC defined as HPC/ (HPC+EC)*100).Films with 30-40-50-57 wt% HPC were studied. Phase diagrams were constructed tostudy the phase transformation of polymer mixtures. Results showed that all polymermixtures with HPC content above 30 wt% were phase separated prior to filmmanufacturing. Temperature had an effect on the phase transformation. In the phasediagram, a temperature above 40 °C showed a larger 2-phase area.
The investigated manufacturing conditions were outlet air temperature (°C) and sprayrate (g/min). Out let air temperature was controlled by adjusting the inlet airtemperature. The films were characterized by measuring water permeability (m2/s).Cross section structure of the films was analysed with confocal laser scanningmicroscopy (CLSM). FITC-HPC was added for enhanced contrast between thedomains.
Higher outlet air temperature gave higher water permeability of the film whereashigher spray rate gave lower water permeability. The outlet air temperature had animpact on evaporation rate. The evaporation rate together with spray rate affectedthe solidification and hence the structure of the film. Images show that longersolidification time smeared the domains into larger domains. Lower waterpermeability could be caused by less connectivity between the pores.
In conclusion, experiments show that water permeability of EC/HPC free-films washighly dependent on the manufacturing conditions.
Tryckt av: Xerox Media Center MölndalISSN: 1650-8297, K09024Examinator: Erik BjörkÄmnesgranskare: Per HanssonHandledare: Mariagrazia Marucci & Christian von Corswant
Teknisk- naturvetenskaplig fakultetUTH-enheten
Besöksadress:ÅngströmlaboratorietLägerhyddsvägen 1Hus 4, Plan 0
Postadress:Box 536751 21 Uppsala
Telefon:018 – 471 30 03
Telefax:018 – 471 30 00
Hemsida:http://www.teknat.uu.se/student
AbstractEffect of manufacturing conditions and polymer ratio on the permeability and film morphology of ethyl cellulose and hydroxypropyl cellulose free-films produced by using a novel spray method
Annica Jarke
This thesis considers the effect of manufacturing conditions and polymer ratio on water permeability and morphology of free-films. A novel spray method for producing ethyl cellulose (EC) and hydroxypropyl cellulose (HPC) free-films was developed where several process parameters was controlled. The process was optimised by pre-spraying solvent until the system reached a steady-state temperature. This minimised the variation of outlet air temperature to < 2.5 °C. Coating time was approximately 4 minutes excluding dry-ing.
Films were produced using 94 wt% solvent (95 %-ethanol) and 6 wt% polymer. The amount of HPC in the films was varied (wt% HPC defined as HPC/ (HPC+EC)*100). Films with 30-40-50-57 wt% HPC were studied. Phase diagrams were constructed to study the phase transformation of polymer mixtures. Results showed that all polymer mixtures with HPC content above 30 wt% were phase separated prior to film manufac-turing. Temperature had an effect on the phase transformation. In the phase diagram, a temperature above 40 °C showed a larger 2-phase area.
The investigated manufacturing conditions were outlet air temperature (°C) and spray rate (g/min). Out let air temperature was controlled by adjusting the inlet air tempera-ture. The films were characterized by measuring water permeability (m2/s). Cross sec-tion structure of the films was analysed with confocal laser scanning microscopy (CLSM). FITC-HPC was added for enhanced contrast between the domains.
Higher outlet air temperature gave higher water permeability of the film whereas higher spray rate gave lower water permeability. The outlet air temperature had an impact on evaporation rate. The evaporation rate together with spray rate affected the solidification and hence the structure of the film. Images show that longer solidification time smeared the domains into larger domains. Lower water permeability could be caused by less con-nectivity between the pores.
In conclusion, experiments show that water permeability of EC/HPC free-films was highly dependent on the manufacturing conditions.
Handledare: Mariagrazia Marucci & Christian von CorswantÄmnesgranskare: Per HanssonExaminator: Erik BjörkISSN: 1650-8297, K09024Tryckt av: Xerox Media Center Mölndal
Teknisk- naturvetenskaplig fakultetUTH-enheten
Besöksadress:ÅngströmlaboratorietLägerhyddsvägen 1Hus 4, Plan 0
Postadress:Box 536751 21 Uppsala
Telefon:018 – 471 30 03
Telefax:018 – 471 30 00
Hemsida:http://www.teknat.uu.se/student
AbstractEffect of manufacturing conditions and polymer ratio on the permeability and film morphology of ethyl cellulose and hydroxypropyl cellulose free-films pro-duced by using a novel spray method
Annica Jarke
This thesis considers the effect of manufacturing conditions and polymer ratio on water permeability and morphology of free-films. A novel spray method for producing ethyl cellulose (EC) and hydroxypropyl cellulose (HPC) free-films was developed where several process parameters was con-trolled. The process was optimised by pre-spraying solvent until the system reached a steady-state temperature. This minimised the variation of outlet air temperature to < 2.5 °C. Coating time was approximately 4 minutes exclud-ing drying.
Free-films were produced using 94 wt% solvent (95 %-ethanol) and 6 wt% polymer. The amount of HPC in the films was varied (wt% HPC defined as HPC/(HPC+EC)*100). Films with 30-40-50-57 wt% HPC were studied. Phase diagrams was constructed to study the phase transformation of poly-mer mixtures. Results show that all polymer mixtures with HPC content above 30 wt% were phase separated prior to film manufacturing. Temperature had an effect on the polymer phase transformation. In the phase diagram, the 2-phase area was larger for temperatures above 40 °C.
The investigated manufacturing conditions were outlet air temperature (°C) and spray rate (g/min). Outlet air temperature was controlled by adjust-ing the inlet air temperature. The films were characterized by measuring water permeability (m2/s). Cross section structure of the films was analysed with confocal laser scanning microscopy (CLSM). FITC-HPC was added for enhanced contrast between the domains.
Higher outlet air temperature gave higher water permeability of the film whereas higher spray rate gave lower water permeability. The outlet air temperature had an impact on evaporation rate. The evaporation rate together with spray rate affected the solidification and hence the structure of the film. Images show that longer solidification time smeared the domains into larger domains. Lower water permeability was caused by less connec-tivity between the pores.
In conclusion, experiments show that water permeability of EC/HPC free-films was highly dependent on the manufacturing conditions.
Supervisors: Mariagrazia Marucci & Christian von CorswantSubject examiner: Per HanssonExaminer: Erik BjörkISSN: 1650-8297, K09024
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Table of Contents 1 Introduction ................................................................................................................ 5
1.1 Background ......................................................................................................... 5
1.2 Aim ...................................................................................................................... 6
2 Theory ....................................................................................................................... 7
2.1 Characteristics of film coating polymers .............................................................. 7
2.2 Phase separation mechanism ............................................................................. 7
2.3 Free-film formation .............................................................................................. 9
3 Material and Methods .............................................................................................. 10
3.1 Material ............................................................................................................. 10
3.2 Phase diagram .................................................................................................. 10
3.2.1 Preparation of polymer stock solutions ........................................................ 11
3.2.2 Phase diagram samples .............................................................................. 11
3.2.3 Visual inspection of phase diagram samples ............................................... 12
3.3 Evaluation of phase diagram samples ............................................................... 12
3.3.1 Sample preparation for SEC ....................................................................... 12
3.3.2 Size exclusion chromatography (SEC) ........................................................ 13
3.3.3 Mass balance / Tie line calculation .............................................................. 13
3.4 Free-films of EC/HPC ........................................................................................ 13
3.4.1 New spray method ...................................................................................... 14
3.4.2 Optimization of new spray method .............................................................. 15
3.5 Methods for characterization of free-films .......................................................... 16
3.5.1 Water permeability ...................................................................................... 16
3.5.2 Confocal Laser Scanning Microscopy (CLSM) ............................................ 17
3.5.2.1 Preparation of free-films for CLSM ........................................................... 17
3.5.2.2 Cross section image of free-films ............................................................. 17
4 Results and Discussion ............................................................................................ 18
4.1 Phase diagram EC/HPC/Ethanol ....................................................................... 18
4.2 Mass balance for tie lines .................................................................................. 20
4.3 Results of characterization of free-films ............................................................. 21
4.3.1 70/30-films .................................................................................................. 22
4.3.2 60/40-, 50/50-, 43/57-films .......................................................................... 23
4.3.3 Effect of polymer mixture spray rate ............................................................ 25
4.3.4 Effect of varying the polymer ratio ............................................................... 27
5 Conclusions ............................................................................................................. 30
6 Future work .............................................................................................................. 31
7 Acknowledgement ................................................................................................... 32
8 References .............................................................................................................. 33
9 Appendices 1-6 ........................................................................................................ 36
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Appendix 1: Calculations of tie lines using mass balance .................................... 36
Appendix 2: Calculations of water permeability, P, for free-films .......................... 37
Appendix 3: The parameter settings for CLSM-imaging ....................................... 38
Appendix 4: Data for tie line calculation ............................................................... 38
Appendix 5: Raw data for free-films ..................................................................... 39
Appendix 6: Open spray method .......................................................................... 40
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1 Introduction
1.1 Background
Drug release from solid oral pharmaceutical dosage forms can be modified by coating a
tablet or pellet with a membrane of polymer film (Siepmann, 2008). The objectives for
modifying the drug release are for example to maintain a prolonged therapeutic effect of
the drug, improve patient compliance and minimise side-effects (Aulton, 2007). Other
benefits, in addition to modified drug release, are masking of unpleasant taste and
improvement of formulation stability (Rowe, 2003).
The rate of drug release from coated pellets or tablets depends on several
physicochemical properties such as the chemical nature of active substance and polymer
membrane. The properties of a polymer membrane on a pellet or tablet are difficult to
characterize, therefore free-films have been produced to work as models for membrane
property characterization. Free-films can be produced by either solution-casting or
spray-coating. Casting of free-films has been used frequently (Woodruff, 1972;
Deshpande, 1997; Lecomte, 2004) however free-films produced by spray-coating may
better resemble the coating process of coating pellets in a fluid-bed (Sun, 1998).
The drug release can be modified by producing membranes made of polymer mixtures
containing one water-insoluble polymer and one water-soluble polymer. Ethyl cellulose
(water-insoluble) and water-soluble cellulose derivatives are frequently used for coating
solid pharmaceutical dosage forms (Ozturk, 1990; Sakellariou, 1995). Hjärtstam has
studied free-films of ethyl cellulose and hydroxypropylmethyl cellulose (1998), which
is one of the traditional types of film studied.
Hydroxypropyl cellulose (HPC) is an attractive polymer for modified release
formulations since HPC is biodegradable, easily form films and has low toxicity. The
structure of EC and HPC films has been studied (Sakellariou, 1986) and it has been
found that the release rate from coated formulations increase with increasing HPC
content in the film (Donbrow, 1980). The mechanism of release from formulations with
EC and HPC coated films has been clarified (Marucci, 2009).
6
1.2 Aim
The aim of the thesis was to study the effect of manufacturing conditions and the wt%
of HPC1 on the water permeability of polymer free-films consisting of ethyl cellulose
(EC) and hydroxypropyl cellulose (HPC).
Polymer membrane applied on a pellet or tablets are difficult to characterize and
therefore free-films were produced. A novel spray coating method was developed. Free-
films were produced by spraying a polymer mixture on a rotating drum.
From a statistical point of view, the aim was to get a first indication on the effect of
manufacturing conditions on free-films. The manufacturing conditions studied were
outlet air temperature and polymer mixture spray rate.
The films were characterized by measuring the water permeability. Cross sections of the
films were investigated with confocal laser scanning microscopy (CLSM) in order to
characterize the HPC and EC domains.
Another aim was to study the polymer phase transformation by constructing phase
diagrams consisting of EC, HPC and 95 %-ethanol. The effect of temperature was
studied. The studied temperatures were 25 C, 40 C and 50 C. Traditional pellet
coating temperature is approximately 40-50 C.
1 Wt% HPC defined as (HPC/(HPC+EC))*100.
7
2 Theory
2.1 Characteristics of film coating polymers
According to Aulton the important characteristics of film coating polymers are
solubility, viscosity, mechanical properties and permeability. High solubility of the
polymer in the gastrointestinal tract will increase the release rate of the drug molecule.
Viscous polymer mixtures can be problematic for many reasons: hard to mix the
polymers to a homogenous mixture and hard to spray the mixture. Good film strength,
film flexibility and film adhesion are important mechanical properties in order to resist
mechanical stresses, avoid film cracking under film coating process and to adhere to the
pellet. Permeability of the films is significantly important for the modification of the
release rate of drug molecule. (Aulton, 2007)
2.2 Phase separation mechanism
The chemical properties of polymer mixtures are of major importance for the structure
of the film. Depending on the polymer-polymer-solvent composition, mixtures of EC
and HPC in ethanol can phase separate. Phase separation typically happens when a
system is brought to a thermodynamically unstable region. The morphology of phase
transformation products is closely related to the mechanism of the transformation
(Allen, 1999). Two intrinsically different transformation mechanisms arise depending
on if the system is thermodynamically meta- or unstable (figure 2.1).
Figure 2.1 shows a schematic T-X phase diagram illustrating the stable, metastable and unstable areas. Binodal line
is the boundary line between one phase and two phase area represented by the straight line. (Fennel Evans, 1999)
8
When a system is metastable the transformation is initiated at discrete sites in the
material, a mechanism called nucleation. Nucleation and growth of the nucleation sites
happens when the process time is long. When a system is unstable it can transform by
growth of microscopic fluctuations throughout the system. This mechanism is called
spinodal decomposition. If the system is quenched into the unstable area the structure of
spinodal decomposition will arise (Fennel Evans, 1999).
9
2.3 Free-film formation
When the solvent evaporates from a polymer mixture a film is formed. There are two
methods for producing free-films: polymer casting and spray coating. In this study free-
films were produced by spraying polymer mixture on a rotating drum. Two examples of
basic process requirements for film coating are sufficient energy input i.e. heated
fluidized air to evaporate the solvent and good exhaust facilities to remove dusty air
(Aulton, 2007). Depending on the solidification time different structures will be formed.
The evaporation rate, which is dependent on temperature, affects the solidification time.
Higher temperatures gives higher evaporation rate and films form more rapidly. The
spray rate of the coating solution is another factor that affects the structure by changing
the ratio between added coating solution and evaporated solvent.
10
3 Material and Methods
3.1 Material
Two cellulose derivatives were used in this study: ethyl cellulose (EC, N10CR) supplied
by Dow chemicals, USA and hydroxypropyl cellulose (HPC-LF) supplied by Hercules,
USA. For characterization of free-films labelled FITC-HPC was added. Flourescinated
HPC (0.5 % labelled) was supplied by CarboMer Inc., USA.
EC and HPC were dissolved in a 95 %-ethanol solvent supplied by Kemetyl, Sweden.
3.2 Phase diagram
Ternary phase diagrams consisting of EC, HPC and ethanol were constructed in order to
distinguish at which equilibrated compositions phase separation occurred. The top area
of the phase diagram was studied (figure 3.1), since polymer mixtures with less than 85
wt% solvent were too viscous and difficult to manage during the spray process.
Figure 3.1 The red triangle shows the part of the phase diagram of EC, HPC and ethanol that was studied in this
thesis.
The effect of temperature was investigated i.e. three phase diagrams were constructed.
The temperatures chosen were 25 C, 40 C and 50 C since the process temperatures
for coating pellets are approximately 40-50 C.
11
3.2.1 Preparation of polymer stock solutions
One stock solution of 15 wt% EC in ethanol and one stock solution of 15 wt% HPC in
ethanol were prepared. Stock solutions were prepared by weighing polymer and solvent
into conical flasks. The stock solutions were mixed with a magnetic stirrer for 24 hours
until the solutions became homogenous.
3.2.2 Phase diagram samples
To obtain the phase diagram samples a weighted amount of EC- and HPC-stock
solutions and 95 %-ethanol were poured in a Corning Pyrex disposable culture tube
(16x100mm). The area of interest in the phase diagram was approximately where the
polymer ratio of HPC/HPC+EC was less than 0.5. Figure 3.2 shows the phase diagram
samples prepared in this study. The total mass for the samples was 5 g. For example, to
obtain sample 96:02:02 (Ethanol wt%: EC wt%: HPC wt%) 666 mg EC-stock solution,
666 mg HPC-stock solution and 3666 mg 95 %-ethanol were poured in a test tube. The
samples were mixed by rotating the samples on a vertical rotating wheel for 24 hours
(figure 3.3). Triplet samples were made and they were put in different heated water
baths for a month in order to reach equilibrium (figure 3.3).
Figure 3.2 The grey dots show the samples for the EC/HPC/ethanol phase diagram
12
Figure 3.3 Left picture shows heated water bath. Right picture shows vertical rotating wheel for the EC/HPC/ethanol
phase diagram
3.2.3 Visual inspection of phase diagram samples
The phase diagram samples in the temperature-controlled water baths were continuously
inspected for a month until the final visual inspection was made. The samples were
divided into two main groups (one phase and two phase samples). The one phase
sample group was divided into two subgroups (clear phase and slightly opaque).
3.3 Evaluation of phase diagram samples
Samples from the two phase area were selected from each phase diagram in order to
evaluate the concentration of EC and HPC in both phases. Density and concentration of
the polymers were measured in each phase in order to calculate tie lines by mass
balances. The samples had one clear phase (phase 1) and one sediment phase (phase 2).
A sample from phase 1 was taken. Density of phase 1 was measured with density meter
PAAR DMA 48. The EC and HPC concentrations were analyzed with size exclusion
chromatography (SEC).
3.3.1 Sample preparation for SEC
SEC does not distinguish between EC and HPC and therefore two measurements per
sample were made: one that measured the total EC and HPC concentration and one that
measured HPC concentration in phase 1. For measuring the HPC concentration the
sample was diluted with purified water until the sample had an ethanol concentration of
4 %, i.e. 1365 μL purified water was added to 60 μL sample in an eppendorf tube. The
samples were centrifuged with a Beckmann GS-15R Centrifuge at 14000 rpm for 60
13
minutes. A pellet of EC was formed. The supernatant was poured into chromatography-
vials and were analysed. Sample preparation for total polymer concentration samples
was easier. The samples were diluted 20 times with 95 %-ethanol and poured in
chromatography-vials.
3.3.2 Size exclusion chromatography (SEC)
For total polymer concentration analysis of the phase diagram samples, the mobile
phase was 95 %-ethanol and the sample was analysed by a TSKgel GMPWXL filtration
column (300mm x 7.5mm). For HPC concentration analysis the mobile phase was 10
mM NaCl with 0.02 % NaN3 and analysed by a TSKgel alpha-M filtration column
(300mm x 7.5mm). Both columns supplied by Tosoh Corp., Germany. Standard
samples of 0.1 mg/ml, 0.5 mg/ml and 0.75 mg/ml HPC were made in order to evaluate
the exchange. For total polymer concentration measurement, HPC standards were made
in 95 %-ethanol. For HPC concentration measurement one standard sample of HPC in
10 mM NaCl with 0.02 % NaN3 was made and three other HPC standards were made in
4 %-ethanol in water solution. Two sample injections of each sample were collected.
The injection volume was 100 μL and an injection was made each 40 minute. Mobile
phase flow was 0.5 ml/min. The detectors used were Dawn Eos MALS and Optilab rEX
both manufactured by Whyatt Tech., USA. Software used to evaluate the signals was
ASTRA 4.90, Whyatt Tech., USA.
3.3.3 Mass balance / Tie line calculation
From SEC the concentration of EC and HPC in phase 1 of each sample was known. The
density was measured. The concentration of EC and HPC in phase 2 was obtained by
measuring the volume of each phase. When the concentrations of each component and
volumes of each phase were known the ratio EC/HPC/Ethanol could be calculated, see
appendix 1 for calculations of tie lines.
3.4 Free-films of EC/HPC
Mixtures of 6 wt% polymers and 94 wt% solvent were prepared and stirred for 24 hours
until homogenous mixtures were obtained. The polymer compositions of EC/HPC in the
mixtures were 30 wt%, 40 wt%, 50 wt% and 57 wt% HPC2. In order to distinguish
between EC-rich and HPC-rich domains in the CLSM images 6 wt% of the total HPC
amount was labelled (FITC-HPC). The polymer mixture was sprayed on a rotating drum
2 Wt% defined as (HPC/(HPC+EC))*100.
14
and as solvent evaporated a film of EC and HPC was formed. Free-films were
manufactured out of the four different polymer mixtures and four films for each
polymer mixture were made with varying manufacturing conditions.
3.4.1 New spray method
Previous film formation of EC/HPC has been done in an open system (Lindmark, 2007).
In order to make the film making process more controlled a rotating drum and a spray
nozzle were installed in laboratory fluid-bed equipment (figure 3.4). The distance
between spray nozzle and drum was set to 100 mm.
Figure 3.4 shows the novel spray method set-up inside the fluid bed chamber. The spray nozzle, moving horizontally,
was set below the rotating drum and heated fluidized air was flowing upward.
In order to resemble pellet coating process the fluidized air flow and atomizer pressure
were set to 40 m3/h and 2 bar respectively. The fluidized air flow can be humidified
however in this study the RH% (relative humidity) was set to zero. The spray nozzle
size determined the spreading of the mixture and it was set to give a spray area of 15.2
cm2. Area of drum was 214 cm
2 (Open spray method: A= 1658 cm
2). Drum rotation and
velocity of the spray nozzle raster determined how often the same area of the drum was
sprayed by polymer mixture and these were set to 80 rpm and 1.3 cm/s respectively.
In this thesis, the effect of temperature and polymer mixture spray rate was studied.
Polymer mixture spray rate was varied from 13 to17 g/min. The outlet air temperature
15
was controlled by adjusting the inlet air temperature. The outlet air temperature was
varied from 40 to 55 C. The mass of polymer mixture used for spraying a film was set
to 60 g. Spraying time was approximately 4 minutes. After 60 g mixture had been
sprayed, the atomizer pressure and polymer mixture spray rate were cut off. Thereafter
the films were left inside the vessel until dried. The drying time varied for the films
depending on the solidification time.
3.4.2 Optimization of new spray method
In order to compare films, the temperature must be kept constant during the spray
process. Before optimisation, when a film was sprayed onto the drum without any
preparations, the outlet air temperature dropped about 20-30 C. A constant temperature
with a variation <2.5 C can be achieved by spraying pure solvent i.e. ethanol until the
system reached a steady-state temperature before starting producing free-films. The
spray rate of pure solvent was set to a slower rate than for producing free-films because
the polymer mixtures contain less solvent than the pure solvent. In this study, where the
polymer mixtures contained 94 wt% solvent, the pre-spray rate was set to 94 wt% of the
polymer mixture spray rate.
16
3.5 Methods for characterization of free-films
EC/HPC films were characterized by measuring the water permeability of the films
(m2/s). Cross section images of polymer films were imaged with Confocal Laser
Scanning Microscopy, which show the EC and HPC domains along the coating process.
3.5.1 Water permeability
Water permeability of an EC/HPC free-film was measured by using a diffusion chamber
(figure 3.5). The diffusion chamber had two chambers; a donor and a receiver chamber.
The thickness of the free-film was measured and then placed between the chambers. 10
μL tritiated water (Hydrogen-3) was added to the donor chamber whereas 15 mL 37 ºC
water was added to both chambers. 0.5 ml samples from both chambers were taken after
1 minute in order to get the initial value. Thereafter samples were taken from the
receiver chamber at specified time intervals. For each sample collection from the
receiver chamber 0.5 ml water was added to compensate for the volume loss. The
temperature inside the chambers was held constant at 34 C with heated water
surrounding the chambers. 4 ml scintillation cocktail (“Hi Safe” 3 Optiphase) was added
to each sample and left to rest over night. The degree of radioactivity was counted with
Winspectral 1414 Liquid Scintillation Counter. The amount of tritiated water that
diffused to the other receiver chamber through the polymer film over time gave the
water permeability. Calculations of water permeability are shown in appendix 2. The
water permeability results were based upon two measurements.
Figure 3.5 shows a schematic illustration of a diffusion chamber: (1) where free-film was placed, (2) water jacket, (3)
donor and receiver compartment (Lindmark, 2007).
17
3.5.2 Confocal Laser Scanning Microscopy (CLSM)
A scan of cross-section of EC/HPC film was made with Confocal Laser Scanning
Microscopy at a wavelength of 488 nm. At this wavelength, labelled HPC gave out a
fluorescent signal whereas EC did not and hence HPC domains were elucidated. Before
a CLSM-image could be taken some preparative work had to be done on the film.
3.5.2.1 Preparation of free-films for CLSM
A piece of EC/HPC film was cut and placed inside a plastic tube that contained epoxy
glue. The sample dried for 72 hours. A sharp cut i.e. microtomization of the film was
done with a Leica ultra cut UCY, MZ6. First coarse cutting was done (5m) and then
fine cutting (0.5m).
3.5.2.2 Cross section image of free-films
A 60x oil objective was used to scan the cross section piece of the EC/HPC free-film.
The parameter settings are given in appendix 3. Higher resolution of the image was
gained by scanning the area until a quality of 20 dB was reached. Time length was
approximately 10 minutes per image. Two images were taken for each film. Image data
was imported and edited in ImageJ. A median despeckle filter was used on the images.
18
4 Results and Discussion
4.1 Phase diagram EC/HPC/Ethanol
Visual inspection of the phase diagram samples shows that samples at higher
temperatures reached their equilibrium state much faster than at lower temperatures.
Three representative phase diagram samples are shown in figure 4.1. The figure shows
two one phase samples (clear and slightly opaque) and one phase separated biphasic
sample. Samples containing solvent and EC were blue shimmered like the slightly
opaque samples due to insoluble residues of EC.
Figure 4.1 shows three phase diagram samples (from left): clear one phase, slightly opaque and last phase
separated biphasic sample. The biphasic sample has a top and a bottom phase.
Figure 4.2 shows the ternary phase diagram for EC/HPC/ethanol. The red binodal line
shows the boundary line between one phase area and two phase area at 40 C and 50 C.
The blue binodal line shows the boundary line at 25 C. The two phase area was larger
for the higher temperatures than for 25 C.
19
Figure 4.2 shows a ternary phase diagram. Red line is the binodal line at 40 C and 50 C whereas blue line
represents the binodal line at 25 C. The grey dots represent the phase diagram samples made in this study.
Higher temperature gave more energy input to the system and according to the T-X
phase diagram (figure 2.1) higher temperature should give higher miscibility. In this
case higher temperatures gave less miscibility. No visible temperature effect can be seen
between 40 C and 50 C.
The phase diagram shows that polymer mixtures with more than 30 wt% HPC were
likely to phase separate before coating. This means that either amount solvent has to be
higher than 95 wt% or amount HPC has to be less than 30 wt%. Larger amount of
solvent was not favourable due to higher solvent costs and higher explosion risks.
20
4.2 Mass balance for tie lines
The total polymer concentration and HPC concentration in the top phase of phase
separated samples were measured. The exchange from the standard samples in SEC was
above 85 %. The density of the top phase was measured at 20C. The data are
displayed in appendix 4.
When the volume of the phase diagram samples was measured the temperature dropped
quickly to room temperature. At the moment of measuring the volume, only
consideration to the possible phase transformation was taken and not to density
variations due to temperature drop. The volume of phase diagram samples was
measured at varying sample temperatures. This means that the measured error became
too large to be able to calculate tie lines. Even though tie lines were not constructed in
this thesis, a method for evaluating EC/HPC samples was established.
21
4.3 Results of characterization of free-films
Water permeability, P, (*10-12
m2/s) and cross-section imaging of free-films were
measured. Free-films were produced at different outlet air temperatures (Tout), polymer
mixture spray rates (SR) and polymer ratios (wt% HPC of total polymer amount). The
films produced are named accordingly 70/30, 60/40, 50/50 and 57/43, where the first
number represents the wt% EC and the second the wt% HPC of total polymer amount in
the free-films.
During the manufacturing of free-films some prototype problems were experienced such
as alternations in exhaust facility and spray nozzle raster velocity, see appendix 5 for
free-film data. Hence, only comparisons were made between free-films produced at the
same equipment settings in order to minimise the effect of prototype variations. For
example, 30 wt% HPC free-films produced at different dates differed in water
permeability due to prototype variations. Appendix 5 table 9.2 shows Tout during
spraying and how the temperature rapidly increased when spray rate and atomizer
pressure were cut off. The results were a first indication of the effect manufacturing
conditions had on free-films and can be used as a guideline for future work.
22
4.3.1 70/30-films
Varying outlet air temperature and polymer mixture spray rate changes the water
permeability of 30 wt% HPC free-films. Table 4.1 shows the water permeability data
and figure 4.3 shows the cross-section images of the films.
Table 4.1 shows the water permeability data for three films produced with a polymer mixture of 30 wt% HPC of total
polymer amount. The water permeability data was based on two measurements per film (n=2).
HPC
(wt%)
Tout
(C)
SR
(g/min)
PH20 n=2
(*10-12
m2/s)
30 40 14 110 0.9
30 55 14 200 13
30 55 16 130 11
The results show that higher temperature gave a water permeability that was almost
twice the value of free-films manufactured at low temperature. Increasing the spray rate
compensated for the effects of higher outlet air temperature and the value of water
permeability was almost the same as for manufacturing at low temperature and low
spray rate. The free-film with highest water permeability (image b) was visually
different from the other two films. The other films had larger EC and HPC domains
since these processes were produced under “wetter” conditions and the solidification
time was longer for these films. Evaporation rate was high and spray rate low for image
b so the structure was solidified faster and smaller domains were created. Films with
lower evaporation rate were less permeable because large insoluble EC domains
covered the HPC domains and water could not as easily permeate though the film. In
drier conditions the connectivity between HPC domains seemed higher which gave
higher water permeability.
23
Figure 4.3 shows three cross section images of 30 wt% films (a, b and c) sprayed from the same polymer mixture but
with varying process parameters. (a: Tout= 40 ºC and SR= 14 g/min. b: 55 ºC and SR= 14 g/min. c: 55 ºC and
SR= 16 g/min). The top of the images was the air-side whereas the bottom was the drum side of the film. The white
domains represent the HPC-rich domains and the dark domains represent EC-rich domains. The large white spots can
be insoluble FITC-HPC residues.
4.3.2 60/40-, 50/50-, 43/57-films
Table 4.2 shows the water permeability data for the CLSM-images in figure 4.4. Results
show that the effect of increasing evaporation rate i.e. higher Tout was diminished by
increasing polymer mixture spray rate (SR). The structures were similar for free-films
manufactured at low Tout and low SR as for high Tout and high SR. Free-films containing
57 wt% HPC had high water permeability variations.
24
Table 4.2 shows the water permeability data for films with varying Tout and SR. The water permeability data was
based on two measurements per film (n=2).
CLSM
image
HPC
(wt%)
Tout
(C)
SR
(g/min)
PH20 n=2
(*10-12
m2/s)
40 40 14 370 1.1
a 40 55 16 340 5.8
b 50 40 14 440 14
c 50 55 16 410 44
57 40 14 833 198
57 55 14 539 104
d 57 55 16 406 170
Figure 4.4 shows CLSM-image a, b, c and d. The water permeability data for these images are shown in table 4.2.
25
4.3.3 Effect of polymer mixture spray rate
Polymer mixture spray rate (SR) affected the solidification time and hence the
morphology of the film. Figure 4.5 shows cross-section images of films with increasing
spray rate and table 4.3 shows the water permeability data.
Table 4.3 shows the water permeability data for three films produced with increasing SR. Higher spray
rate gave lower water permeability. The water permeability data was based on two measurements per film
(n=2).
HPC
(wt%)
Tout
(C)
SR
(g/min)
PH20 n=2
(*10-12
m2/s)
30 55 13 140 3.5
30 55 16 127 0.9
30 55 17 58.4 46.3
The results show that film produced at drier conditions gave higher water permeability.
The standard deviation, based on the results of two pieces of the free-film, indicate how
homogenous the free-films were. Results show that free-film produced with high spray
rate had high standard deviation.
26
Figure 4.5 shows cross section images of 30 wt% HPC films with varying polymer mixture spray rate, SR. Increasing
spray rate from a to c (13-16-17 g/min).
27
4.3.4 Effect of varying the polymer ratio
Higher amount of water-soluble polymer gave higher water permeability of the film.
This is shown in figure 4.6 where the water permeability of films produced by using the
novel spray method was compared with a previous study where films were produced by
using an open spray method (Hjärtstam, 2009). Free-films produced by using the open
spray method were made by spraying polymer mixture on a heated cylinder drum inside
a hood (appendix 6). Free-films produced by using the new spray method were made by
spraying on a rotating drum inside a fluid bed. For the open spray method, the cylinder
was heated by filling it with heated water which caused the temperature of the cylinder
surface to decrease during the spray process. A main difference between the two
methods was that several process parameters can be controlled with the new spray
method.
Figure 4.6 shows the effect of spray method on water permeability of free-films with increasing HPC wt%. The spray
methods compared are an open spray method and the novel spray method introduced. For the new spray method the
process parameters were: SR=13-14 g/min and Tout= 40 C, only varying HPC wt%. For the open spray method:
SR=11 g/min at room temperature. The cylinder drum, on which the coating solution was sprayed on, was filled with
heated water (start temperature approx. 50 ºC and end temperature approx. 34 ºC).
The figure shows that the films produced with the new spray method follow the same
trend as the open spray method except for at high wt% of HPC. Films with high ratio of
HPC had high standard variations suggesting large holes on the free-film were created
when HPC was leached out. In comparison of the methods, the water permeability was
lower with the new spray method. A reason for the lower water permeability could be
28
that the films were manufactured at ”wetter” conditions that made the domain size
larger and decreased the pore connectivity. Figure 4.7 shows cross section images of
films with increasing HPC wt%. It can be seen that the 30 wt% HPC image, which was
less permeable had larger domains. The other images had similar structures. More
studies are suggested.
Figure 4.7 shows four free-films with increasing HPC wt% (a:30, b:40, c:50 and d:57 wt% HPC).
The CLSM-images in figure 4.7 shows that the free-films had similar structures
although varying in domain size. In free-film manufacturing processes where the
29
solidification time was long the domains had long time to grow. It is suggested that the
films were phase separated according to spinodal decomposition since HPC domains
were visible throughout the free-film. The white spots on the free-films were probably
insoluble FITC-HPC residues.
30
5 Conclusions
The phase diagram showed the boundary line where phase separation occurred for
EC/HPC/EtOH system. The results indicate that many of the polymer mixtures studied
were phase separated prior to coating. This means that the structure of the free-films
became more heterogeneous. In order to prevent manufacture of inhomogeneous free-
films it was suggested that coating formulations have compositions that lie in the one
phase area of the phase diagram. Temperature had an affect on the polymer phase
transformation close to the binodal line as well as on the viscosity and the kinetics;
equilibrium state was reached faster due to more energy input into the system. The two
phase area in the phase diagram was larger for temperatures above 40 ºC.
The novel spray method was a good prototype and several process parameters were
controlled during manufacturing of free-films. Furthermore, by pre-spraying the outlet
air temperature was held relatively fixed with a variation of less than 2.5ºC.
Manufacturing conditions had an effect on water permeability of films. Higher outlet air
temperature gave higher water permeability. For a 30 wt% HPC-film the water
permeability doubled when the outlet air temperature was increased from 40 ºC to 55 ºC
(all other parameters kept constant). “Wetter” process conditions gave a longer
solidification time and larger domains of EC were produced. Free-films were less
permeable when insoluble EC domains covered domains of HPC. “Drier” process
conditions gave the opposite results i.e. shorter solidification time, smaller domains and
higher water permeability. The free-films were more permeable and the connectivity
between the HPC pores was better since they were not covered by large EC domains.
The spray rate was a factor that affected solidification time. Higher spray rate gave a
“wetter” process and hence films with lower water permeability were produced due to
the same reasons as described above. Higher amounts of HPC in free-films gave more
porous structure and more permeable films.
In conclusion, experiments show that water permeability of EC/HPC free-films was
highly dependent on the manufacturing conditions.
31
6 Future work
In this study films prepared from a polymer mixture containing 94 wt% solvent was
studied. It would be interesting to investigate the effect of solvent ratio since it has an
impact on the viscosity and hence has an impact on the phase separation.
Further on, it would be interesting to measure the diffusion coefficient of several drug
substances that differ in molecular weight and lastly compare structure of free-films
with film sprayed directly on pellets.
32
7 Acknowledgement
I would like to thank my supervisors Mariagrazia Marucci and Christian von Corswant
for all support, guidance and inspiration throughout this master thesis.
I would also like to thank:
Mats O Johansson – for all the inspirational discussions about fluid bed processes.
Håkan Glad – for his technical creativity and support.
Anette Welinder – for the help with the SEC measurements.
Ingela Niklasson-Björn – for discussions about process parameters.
The SUMO group (Johan Hjärtstam, Catherine Boissier, Marigrazia Marucci, Mark
Nicholas, Hanna Matic, Johan Arnehed and Francois Feidt) – for the rewarding
meetings throughout this thesis.
Part of the OCR-group (Lennart Lindfors, Mariagrazia Marucci, Christian von
Corswant, Johan Hjärtstam, Mats O Johansson) – for insightful discussions and shared
experience on oral controlled release formulations.
Hans Carlsson – for teaching me how to use the fluid bed.
Johan Arnehed – for the collaboration with CLSM-measurements.
Per Hansson – subject examiner at Uppsala University.
AstraZeneca R&D Mölndal – for everything.
Last but not least I want to thank my wonderful family and friends – you are the best!
33
8 References
Allen S.M., Thomas E.L., 1999. The structure of materials. MIT series in material
science and engineering. John Wiley & Sons Ltd, 364.
Aulton M.E., 2007. Aulton’s pharmaceutics – the design and manufacture of
medicines. 3rd Edition. Elsevier Ltd, 487, 504.
Deshpande A.A., Shah N.H., Rhodes C.T., Malick W., 1997. Evaluation of films
used in development of a novel controlled-release system for gastric retention. Int.
J. of Pharm. 159, 255-258.
Donbrow M., Samuelov Y., 1980. Zero order drug delivery from double-layered
porous film: release rate profiles from ethyl cellulose, hydroxypropyl cellulose and
polyethylene glycol. J. Pharm. Pharmacol. 32, 463-470.
Fennel Evans D., Wennerström H., 1999. Colloidal Domain. John Wiley & Sons
Ltd, 434.
Hjärtstam J., 1998. Ethyl cellulose membranes used in modified release
formulations. Doctoral thesis, Chalmers University of Technology.
Hjärtstam J., 2009. Verbal reference at AstraZeneca PAR&D Mölndal.
Lecomte F., Siepmann J.M., Walther M., MacRae R.J., Bodmeier R., 2004.
Polymer blends used for the aqueous coating of solid dosage forms. J. of Contr.
Rel. 99, 1-13.
34
Lindmark L., 2007. Chemical and physical properties of polymer membranes
made of ethyl cellulose and hydroxypropyl cellulose. Diploma work, Lund Institute
of Technology.
Marucci M., 2009. Characterization of the mechanisms of drug release from
polymer-coated formulations using experiments and modelling. Doctoral thesis,
Lund University.
Ozturk A.G., Ozturk S.S., Pålsson B.O., Wheatley T.A., Dressman J.B., 1990.
Mechanism of release from pellets coated with an ethyl cellulose film. J. of Contr.
Rel. 14, 203-213.
Rowe R.C., Sheskey P.J., Weller P.J., 2003. Handbook of pharmaceutical
excipients. 4th Edition. Pharmaceutical Press. 237.
Sakellariou P., Rowe R. C., 1995. Interactions in Cellulose Derivative Films for
Oral Drug Delivery. Prog. Polym. Sci. 20, 889-942.
Sakellariou P., Rowe R. C., White E. F. T., 1986. Polymer/polymer interaction in
blends of ethyl cellulose with both cellulose derivatives and polyethylene glycol
6000. Int. J. of Pharm. 34, 93-103.
Siepmann F., Siepmann J., Walther M., MacRae R.J. Bodmeier R., 2008.
Polymer blends form controlled release coatings. Review J. of Contr. Rel. 125, 1-
15.
Sun Y.-M., Huang W.-F., Chang C.-C., 1998. Spray-coated and solution-cast
ethyl cellulose pseudo latex membranes. J. of Membr. Sci. 157, 159-170.
35
Woodruff C.W., Peck G.E., Banker G.S., 1972. Effect of environmental
conditions and polymer ratio on water vapour transmission through free
plasticized cellulose films. J. of Pharm. Sci. 61, 1956-1959.
36
9 Appendices 1-6
Appendix 1: Calculations of tie lines using mass balance
The volume the phases and density of phase 1 was measured.
111 Vm
21 mmmtotal
12 mmm total
where m= mass, 1= phase 1, 2= phase 2, = density and V = volume.
The concentrations of the polymer measured with SEC gave the polymer ratios in
phase 1 & 2.
11
111
,1
,1
1
1
,1
1
)(1)/(
)()/(
)/(
)/()(
HPCECmmEtOH
HPCECHPCmmEC
Dc
mmHPC
Dc
mmECHPC
HPC
HPC
ECHPC
22
2
112
2
112
)(1)/(
)/(
)/(
HPCECmmEtOH
m
mECmmEC
m
mHPCmmHPC
where c= concentration (mg/ml) and D=dilution quotient
The polymer ratios of EC, HPC and EtOH were plotted on the phase diagram giving
a straight line between the one phase and the two phase compositions.
37
Appendix 2: Calculations of water permeability, P, for free-films
The amount tritium water that diffused through a polymer film over time gave the water
permeability. Samples were taken at specific time intervals. DPMsample was measured
with Scintillation Counter. A zero sample was taken from the donor chamber. It was
diluted with 50 ml water.
The radioactivity per volume in the donor chamber:
00
0.
VV
VDPMDPM
diluted
waterdilutedchamberd
[kBq/m
3] (1)
The radioactivity in the receiver chamber:
[kBq] (2)
Where DPM= radioactivity and V= volume.
The amount of water diffused though polymer film:
[m3] (3)
[m3/s] (4)
[m2/s] (5)
Where F= flux, t= time, h=film thickness, A= area of the film and P= permeability.
chamberr
sample
sample
chamberr VV
DPMDPM ..
chamberd
chamberrdiff
V
DPMV
.
.
dt
dVF
diff
A
hFP
38
Appendix 3: The parameter settings for CLSM-imaging
Channel 515/30 (green)
Channel strength ~100
Wavelength 488 nm
Pixel dwell 10 m
Field zoom 3.01x
Size 1024x1300
Pixel size 76.7 nm
Quality 20 dB
Filter Despeckle (median)
Appendix 4: Data for tie line calculation
Global point EC:
HPC: EtOH (wt%)
Ta
(C) C1,tot
b
(mg/ml)
C1,HPCc
(mg/ml) 1,tot
(mg/ml)
at 20C
mtot
(mg)
5:4:91 25 2.42 0.853 830 5083.9
3.33:2.66:94 25 2.025 0.8795 825 5032.2
2.66:3.33:94 25 1.98 1.165 825 5024.3
1:5:94 25 2.06 1.7 826 5043.5
5:4:91 40 2.56 0.8815 830 5026.9
3.33:2.66:94 40 2.075 0.989 825 5029.0
2.66:3.33:94 40 2.08 1.175 825 4977.3
1:5:94 40 2.01 1.7 826 5045.2
5:4:91 50 2.57 0.882 831 5025.0
3.33:2.66:94 50 2.085 0.9625 825 4993.3
2.66:3.33:94 50 1.875 1.18 826 5075.8
1:5:94 50 1.705 1.51 826 5037.9
aTemperature when the sample was in the water bath. bRaw SEC data: the concentration of total polymer in phase 1, mean value of two duplicates. The samples were
diluted 20 times. The exchange of the standard samples for this method was 86 %. cRaw SEC data: the concentration of HPC in phase 1, mean value of two duplicates. The samples were diluted
23.75 times. The exchange of the standard samples for this method was 97 %.
39
Appendix 5: Raw data for free-films
Film no. HPC
(wt%)a
T
(C)b
SR
(g/min)c
SNRV
(cm/s) d
PH20 n=2
(*10-12
m2/s)
e
1 30 40 14 1.31 110 0.9
- 30 40 16 1.31 too wet
2 30 55 14 1.31 200 13
3 30 55 16 1.31 130 11
4 40 40 13 1.31 370 1.1
- 40 40 16 1.31 too wet
- 40 55 13 1.31 too dry
5 40 55 16 1.31 340 5.8
6 50 40 13 1.31 440 14
- 50 40 16 1.31 too wet
- 50 55 13 1.31 too dry
7 50 55 16 1.31 410 44
8 57 40 13 1.31 833 198
- 57 40 16 1.31 too wet
9 57 55 13 1.27 539 104
10 57 55 16 1.31 406 170
a The HPC wt% out of total polymer amount (wt% HPC defined as HPC/(HPC+EC)*100). b The temperature of outlet air during spraying process c The polymer mixture spray rate during spraying process. d SNRV stands for spray nozzle raster velocity. Prototype problems were experienced during film formation which
meant that the velocity had to be changed for some films. e The water permeability of films based on two measurements per film (n=2). The description too dry means grains on
top of the film were formed during process so that the film thickness was too uncertain to measure (figure 9.1a & b).
An uncertain value of film thickness gave an inaccurate water permeability value.
Figure 9.1a &b show the airside surface of two films. Left image (a) a representative image of a film good for
characterization of water permeability. Right image (b) a representative image of a film not good for characterization
of water permeability due to uneven surface i.e. too dry film process.
40
1Collection of raw data for Tout during manufacturing of free-films 18 times a minute.
Figure 9.2 shows the outlet air temperature, Tout, during film manufacturing. The temperature was kept constant during
spraying and increased in the end when spray rate and atomizer pressure were cut off. The temperature was
increased by approximately 10 ºC and thereafter slowly decreased. The legend shows the HPC wt% in the films and
the number represents the free-film number in the table in appendix 5.
Appendix 6: Open spray method
Figure 9.3 shows the drum for casting of free-films with the open spray method.
1. Gas inlet 2. Rotating drum filled with hot water. 3. Spray nozzle 4. Moving arm 5. Solution inlet. (Lindmark,
2007).
35
40
45
50
55
60
65
70
0 50 100
Tou
t [o
C]
time for data collection1
Tout for produced EC/HPC films with Gandalf 2.
30%, 1
30%, 2
30%, 3
40%, 4
40%, 5
50%, 6
50%, 7
57%, 8
57%, 9
57%, 10