SEMMELWEIS UNIVERSITY
DOCTORAL SCHOOL OF PHARMACEUTICAL AND PHARMACOLOGICAL SCIENCES
STUDIES ON MULTICOMPONENT COATING
SYSTEMS IN RELATION TO PELLETS
Ph.D. THESIS
ÁDÁM ORBÁN
Research Tutor: Prof. Dr. István Rácz, Ph.D., D.Sc.
Semmelweis University Department of Pharmaceutic and Gedeon Richter Ltd.
Budapest, 2002.
I
CONTENTS A INTRODUCTION 1 B OBJECTIVES 2 C LITERATURE REVIEW 3 C.1. The pellet 3
C.1.1 Pellet as a pharmaceutical dosage form 3 C.1.2 The possibilities of pellet manufacturing 7 C.1.3 Coating 17
C.2. Coating systems 18 C.2.1 Coating solution formulation 18
C.2.1.1 Polymers 18 C.2.1.1.1 Physicochemical characteristics of latexes 20 C.2.1.1.2 Minimum film-forming temperature (MFT) 20
C.2.1.2 Plasticizers 21 C.2.1.3 Colouring systems 23
C.2.2 Glass Transition Temperature of Polymers (Tg) 25 C.2.3 Enthalpy relaxation of glassy polymers 25 C.2.4 Film coat quality 28 C.2.5 Release mechanisms and control of 31
drug release of coated dosage forms C.2.5.1 Factors influencing drug release 36
D. MATERIALS AND METHODS 38 D.1 Materials 38 D.2 Sample preparation 38
D.2.1 Preparation of free polymer films 38 D.2.2 Preparation of pellets 38
D.2.2.1. Preparation of pellets in Stephan UMC-5 apparatus 38 D.2.2.2. Preparation of pellets in Pharmex 35T-Spheromat 39
extrusion-spheronization equipment D.2.2.3. Preparation of pellets with rotofluidization equipment 39
D.2.3 Granulometric examination of pellets 40 D.2.3.1 Study of flowability of pellets 40 D.2.3.2 Study of the particle size distribution of pellets 40 D.2.3.3. Determination of the tapped and loose density of pellets 40
D.2.4 Coating of the prepared pellets in Kugelcoater HKC-5 40 coating equipment
D.2.5 Coating of the prepared pellets in Aeromatic Strea-1 43 coating equipment
D.2.6 Coating of the prepared pellets in rotofluidization equipment 44 D.3 Examination of the coating dispersions 44
D.3.1 Determination of the Refractive Index of Polymer Dispersions 44 D.3.2 Calculation of the Molar Refraction by the Lorenz-Lorenz Equation 44 D.3.3 Dynamic surface tension measurements 45 D.3.4 Determination of the white point of dispersions 45 D.3.5 Thermoosmometric study of polymer dispersions 46
D.4 Examination of the polymer free films 46 D.4.1 X-Ray Diffraction (XRD) Measurements 46
II
D.4.2 Determination of the Glass Transition Temperature of cast polymer films by Differential Scanning Calorimetry 47
D.4.3 Determination the enthalpy relaxation of polymer films at the glass 47 transition temperature
D.4.4 Microscopic examination of coating with FT-IR microscope 48 D.4.5 Positron lifetime measurements of free films 48 D.5 Examination of the coated pellets 50
D.5.1 Examination of the particle size distribution of coated pellets 50 D.5.2 Friability test of the coated pellets 50 D.5.3 Scanning electron microscopy studies 50 D.5.4 Recording diffuse reflectance spectra 50 D.5.5 In vitro dissolution study 50 D.5.6 Analysis of the results of dissolution studies 51 D.5.7 Determination of dissolution of drugs in vitro by means of the
Sartorius Dissolution Simulator type SM 167 51 51 E. RESULTS AND DISCUSSION 52 E.1 Effect of the Concentration of the Water Soluble Plasticizer on the
Dissolution Characteristics of Eudragit Coated Metoprolol Pellets 52 E.2 Effect of the Concentration of the Water Insoluble Plasticizer on the
Dissolution Characteristics of Eudragit Coated Theophylline Pellets 56 E.3 Polymer-Plasticizer Interactions: Comparison of
Experimental Data with Theoretical Results 57 E.4 Coating Polymer-Plasticizer Interaction in relation to the
Enthalpy Relaxation of Polymer 74 E.5 Comparative Evaluation of Coated Pellets Produced by Different Fluidized
Bed Equipments 83 SUMMARY 90 REFERENCES 92 ACKNOWLEDGEMENT 100 BIBLIOGRAPHY 101
1
A INTRODUCTION
For historical reasons, sugar coating has been the most extensively employed
method but is at present being superseded by film coating techniques. Film coating of
tablets in contrast is a relatively new technology dating back to the 1950s (Abbott
Laboratories). Most newly developed coated products are film coated and water is now
the first choice solvent for new film coated formulations (tablets, microcapsules,
pellets). The major reasons for coating can be summarized as follows:
1. Protection of active ingredients
from the environment, particularly light and moisture.
2. Safety/Identification
Patients may be taking several medications and colour is a useful
identification of the correct compound.
3. Taste/Odour barrier
Many active substances have a bitter taste or an unpleasant odour. By
placing an isolating barrier around the tablet, these factors can be reduced
or eliminated thus improving patient compliance.
4. Improved appearance
The granular nature of some formulations can be covered by an opaque
coating giving a more homogeneous appearance.
5. Brand identity
Many pharmaceutical companies are rightly proud of their reputations
and a company brand appearance enforces this pedigree.
2
6. Improved handling on high speed automatic filling and packaging
equipment
Very often coating confers an added mechanical strength to the
tablet core. Crosscontamination is also reduced in the
manufacturing plant as "dusting" is eliminated by coating.
7. Functional coatings
These methods are used to impart enteric or controlled release
properties to the coated dosage forms [1].
B OBJECTIVES
In the literature review of my thesis I intend to summarize those references which are in
close connection with my experimental research work. I will give an overview of those
methods further developed by myself in the course of the industrial coating of solid
dosage forms.
The purposes of the literature part of my thesis were to study:
�� the different methods applied for pelletization and coating
�� the commonly applied film coating materials, among them with the
two key excipients of coating, with the coating polymer and plasticizer,
�� the physico-chemical characterisation of coating systems,
�� different modified release dosage forms and the methods applied for their
characterisation.
3
The objectives of the experimental part of my thesis were:
�� to formulate pellets for the coating procedure from commonly applied active
ingredients
�� to prepare and characterize differently coated pellets
�� to characterize the coating systems and
�� the free films of coating systems by different physico-chemical methods
�� to evaluate qualitatively and quantitatively the possible interactions between
the two key ingredients of coating systems, those of the polymer and
plasticizer.
C LITERATURE REVIEW
C.1. The pellet
C.1.1 Pellet as a pharmaceutical dosage form
Although the basic meaning of the word 'pellet' is 'a small ball or tube-shaped piece of
any substance', in the different branches of industry and agriculture this term is used to
indicate particles or piles of particles of various shape, size and scale, which are
produced by granulation, extrudation, pelletisation, drop-frosting �2�.
Henceforward - according to pharmaceutical requirements and specialisation - the term
'pellet' is to refer to granuled pharmaceutical dosage form for peroral usage, which is
characterised by 10-3 - 10-4 m in size, near-spherical form, slightly uneven surface and
compactness approximate to that of agglomerated materials (low porosity). Thus the
4
advantages of the pellet as a pharmaceutical dosage form are implied in the above given
definition �2-4�.
Good coating properties: The minimum scale of surface/capacity (volume) relatively
even surface and small degree of porosity from the point of view of coating - especially
filmcoating - is optimal both technologically (low powder formation, quick drying,
reduced proneness to agglutination) and because of the relative quantity of the coating
material; e.g. fluidisation - granules produced by spraying process - the structure of
which can be compared to that of breadcrumbs' - are practically impossible to abrupt
with reasonable quantity of coating material. In connection with good coating properties
fraction toughness and abrasion hardness derived from the shape and form of the
granules, and the almost identical specific surface of the particles from successive
batches can also be mentioned.
Adjustable active ingredient transmission: The definite specific surface derived from the
near-spherical shape (form) which can reliably influenced by modifying the size of the
particles, and the good coating properties ensure almost infinitely adjustable active
ingredient transmission and planable active ingredient transmission profile.
Regarding the latter we should think - for example - that the 'small balls' can be covered
by coating different in quality and thickness, and these can be arbitrarily blended
together before filling capsules or compression. In this way the ingestion of the initial
and the maintaining dose can happen simultaneously and safely, alongside with the
5
elimination of the side-effects caused by top concentration and the continuous assurance
of the plasma concentration.
Low toxicological risk: If the coating of a retard capsule or a pellet is
incomplete/imperfect or damaged a toxic dose may enter the patient's organism.
However, in the capsule fillings or tablets a few (among several hundred or thousand)
pellets with damaged coating do not cause significant rise of drug concentration
measured in blood. Here it can be mentioned that during further production,
transportation and dosing of the pellet - especially in the case of coated granules - the
danger of dust formation is minimal, because the pile is practically free from powder
and the particles have no sharp ends which, if fractured, could lead to powder formation
(their friability is low).
Good flowing properties: The relatively big volume of the particles, the shape and the
surface mean good flowing properties, and quick dosing ability. The significance of this
is well known in the case of high-speed rotary machines, but filling machines for hard
gelatine capsule have also reached the same speed and so glidant have to be used to
improve the usual flowing properties of the granules.
Stable unit density: In the case of the usual granules - especially that of produced by
fluidisation atomisation- the variable and heterogeneous distribution of the size of the
particles, the fluctuating porosity of the particles, the irregular particle form cause the
change of the unit density within a relatively large domain.
6
The fluctuation of the unit density in the case of pellets is much lower, which is a great
advantage at filling/charging by volume (e.g. in the matrices of tablet machines or
during the process of charging into hard gelatine capsules).
Easy taking in: If necessary, taking/swallowing the medicine can be made easier by
having the spansule decomposable, and the scattered pellets can be swallowed very
easily.
Aesthetic appearance: The pellets of various sizes and their mixtures are quite aesthetic
(this is why they are filled into transparent capsules). This factor is not negligible
neither from the viewpoint of market aspects, nor in the case of the psychological effect
made on the patient.
Adjustable distribution of retention time: In the case of oral dosage form the
pharmaceutical form basically influences the distribution time both in the gastro-
intestinal systems, and the time during which the given product in which part of the
system stays longer (e.g. tablets usually in the stomach, pellets in the bowels).
To avoid being predisposed in the favour of the subject it is necessary to list
contradictions in connection with pellets.
The scientific literature mention disadvantages as well. However, in the field of the
subject the technical and technological development is so fast that those 'yesterday's'
7
counter arguments (e.g. the procedure is rather time and energy consuming) 'today' do
not hold their grounds.
Sometimes natural things are mentioned as disadvantageous, for instance 'in order to
produce pellets new equipment are needed to be obtained, which is costly'. This is true,
of course, although not specifically for pellet manufacturing, but nearly in all when the
aim is to improve formulation.
Besides it is always hard to compare things by quantity measures that differ in quality.
The contradiction can be stated shortly and simply: pellets are not to be produced when
there are no advantages whatsoever compared to the simpler formulation or, if the
expenses incurred are not in scale with the emerging advantages and cannot be realised
in the price.
C.1.2 The possibilities of pellet manufacturing
The ways of pellet manufacturing according to the definitions given in Chapter 1.1
varies largely in: equipment designed for drop frosting (prilling), suspension
polymerisation �5�, spherical crystallisation, liquid-phase spherical agglomeration �6�,
granulation and/or size-increasing layering �7�, rotation �8�, fluidisation �9� and roto-
fluidisation �10-14�, and with multi-step technology usually called 'extrusion-
spheronisation.
8
The above listing is far from being complete �5-25�, because the developments of pellet
manufacturing in the pharmaceutical industry is fairly rapid. As a matter of interest it is
worth mentioning that - for example - pelleting, drying and layering green pellets are
performable in a sufficiently converted rotary granulator �26�.
The schemes of pelleting and the further processing of pellets are shown on the
following diagram:
Diagram 1 — Flowsheet of constructive pellet manufacturing
Approximately spherical granules of good quality, and if it is necessary with layered
structure, may be processed by the gradual surface layering onto any 'core' (practically
with size increasing layering, gelatine coating) �27�.
Preparation of cores �� granulation, milling,
dispergation �� crystallization �� spray drying
Cores
Powder mixing
Powder
Layering
Liquid
Drying
PELLET
9
Diagram 2 —Elementary growth mechanism of pellets
The core of the pellet in the pharmaceutical industry usually can be some sort of sugar,
or even granules, sugar-starch based placebo, salt, etc., that are sieved within narrowly
sized bounds.
The simplest device of formulation is the rotary pan commonly employed in the
pharmaceutical industry. The essence of the method is to get the sufficiently prepared
cores into voluble motion, then have their surface evenly moistened by spraying fluid on
it (if necessary by fluid containing binding material) until agglutinating effect is
reached. Following this, coating powder is evenly added onto the rolling layer (e.g.
through vibratory sieve) until the particles are able to bind the powder strongly on their
surface. The moistening/humidification and powdering are cyclically repeated until the
wished size and form is reached.
Naturally, the combination and the quality of the powder and the fluid can be altered
during the procedure, thus the already mentioned product with layered structure is
produced. The big disadvantage of this simple and flexible method is the low
productivity and the high live force demand, therefore the common technique of rolling
layering is rarely applied in large scale production.
Nucleation Coalescence Layering and abrasion transfer
10
It is well known, that the rotary speed of the rolling layering (rotary-pan) - bowl) - dish)
has a theoretical upper limit, which is called critical rotary speed [82].
Atomiser
Air
Diagram 3
The build-up of the rotor
If the main function of the airflow shown on the diagram is to prevent the clogging of
the slit between the rotor and the bowl, than we speak about rotary machines, and in the
case of bigger airflow we speak about rotary-fluidisation equipment.
This sectioning, however, is fairly free-hearted because the very same equipment is used
for both working methods (e.g. during the size increasing phase in the rotary, during
drying and filmcoating in the rotary-fluidisation working method, see diagram 4.).
There are, of course, separate equipment specially designed for both methods.
11
1 - inlet air, 2 - air filter, 3 - calorifer, 4 - rotor, 5 - product output, 6 - atomiser,
7 - fluidized-bed coloumn, 8 - expansion space, 9 - filter, 10 - shaking instrument,
11 - ventilator, 12 - outlet air
Diagram 4. - Rotary - WSG (Glatt, Benzen)
In the pharmaceutical industry the so called 'extruder-spheronisation' method is
currently the most commonly employed process for pellet producing, the flowsheet of
which can be seen on diagram 4. The most commonly used excipient to aid aqueous
extrusion-spheronization is microcrystalline cellulose, particularly the commercial
grade, Avicel PH-101. This material when dry mixed in adequate concentration with a
drug acts as a molecular sponge for added water, usually forming a plastic mass which
may extrude well prior to forming well-rounded pellets in a spheronizer [78, 83, 84,
117].
12
Diagram 5. - Pellet manufacturing by extrusion-spheronisation
The quality of pellets - in the case of properly prepared wet mass - are basically
influenced by the parameters of the extrusion and the spheronisation. In the most
frequently used screw extruders (see diagram 6-7) the filled wet material is to be
agglomerated by the properly formed screw (or screws) and under high pressure it is
forced to make an axial motion. In some machines the screw can be changed according
to the characteristics of the material, their pitch and profiles are variable [113].
Homogenization Kneeding Extrusion Spheronization
Drying
PELLETS
Powders Liquid
13
Diagram 6. The build-up of an extruder [4]
14
Diagram 7. Continuous pellet manufacturing by extrusion [4]
In order to increase agglomerating power so called breaker plates (intermediary
perforated disk) and blades are frequently used inside the extruders. The material leaves
the extruder via perforated cylindrical shell or circular plate that are situated in the rear
part of the extruder.
15
The diameter of the produced 'string/thread' is usually about 1 mm. (It is very important
that these 'threads' have adequate degree of humidity, so that pellets of right spherocity
are formed during rolling. In some ways these can be chopped into near identical sized
pieces (e.g. rotary knife), although for some interesting reason this is usually needless.
The row hardness of the extruded material, the parameters of the operation/application
and the characteristics of the spheronisation power well indicate the dimensional
domain of the formed pellets.
There is a very important requirement that the extruder has to meet, namely the feeding
rate should be variable within wide limits (infinitely variable gear), and it should have
to be cleaned quickly and safely (GMP). These aspects, of course, are fundamental
regarding other units as well. Stable operation (qualifiability - validation) as well as the
need of instruments that measure and register these parameters, and occasionally the
ability of both heating and cooling, etc. can also be mentioned here. An efficient
extruder is half-way to success.
The process of 'rolling' is performed in an apparatus - without a diffuser/sprayer -
similar to that of shown in diagram 3., which is called spheronizer or marumizer in the
foreign literature. The role of the input airflow into the space under the rotor here is
only to prevent clogging the 0,1 mm slit between the rotary disc and the fixed bowl.
16
The surface or the rotor is corrugated in squarely onto one another, thus beading with
different size and shape can be formed (a spheronizer has several disks that are
changeable) �22, 28�.
Beyond surface finish revolutions (speed) is a basic parameter of 'rolling' process, which
is infinitely variable within broad spectrum. A dust-removal chunk is usually built into
the transparent and lockable cap of the equipment. Requirements that have meet GMP
provisions could also be mentioned here. To dry raw/wet pellets fluid bed dryers and/or
pan dryers are employed. When choosing the type of the dryer the initial and end
density - beyond the usual aspects - are determinant. (The latter is also conditioned by
the speed of drying.)
In the flow-sheet the classifier is not drawn, because its positioning may vary.
In some places the process of sieving succeeds drying, while elsewhere classifying raw
pellets by sizing is favoured. Although the latter is technologically greater a task,
regarding the 're-production' of those pellets that are outlying the size fraction, is more
advantageous.
17
C.1.3 Coating
The produced so called 'bare' pellet is rarely intermedier or finished product, pellets are
usually provided with filmcoating [100].
The further production of pellets, and its theoretical flow-sheet are shown in diagram 8.
Diagram 8. The flow-sheet of the further production of pellets
Most of the above mentioned equipments applied for the production of pellets are
suitable for pellet coating, as well. Such equipments are the fluidization and
rotofluidization systems.
Pellet Coating
Compression Coating Powder
Liquid Filling into capsules
Packaging
18
C.2. Coating systems
C.2.1 Coating solution formulation
A typical film coating system consists of three main ingredients:
— polymer
— plasticiser
— colorants (pigments/opacifiers).
C.2.1.1 Polymers
The fundamental ingredient in the formulation. Most commonly used are the derivatives
of cellulose such as hydroxypropylmethylcellulose, methylcellulose and ethylcellulose
[116] (Figure 1). These have the advantages of forming clear, non-tacky, mechanically
strong films from a wide variety of suitable solvents. Many of these polymers have had
a long history of safe use in the food industry and therefore have a wide regulatory
acceptance.
Acrylate-based polymers are also used in plain film coatings. However other types are
available in modifications designed to give gastric-insoluble films or controlled release
properties (Figure 2) [118].
Other more elderly film coating systems are occasionally encountered such as cellulose
acetate phthalate in combination with PEG.
The film is formed by the combined action of plasticizer and drying heat on the
individual polymer particles thus causing them to coalesce into a film.
19
Figure 1 - Structure of ethylcellulose
Figure 2 - Stucture of Polyacrilates [75]
Eudragit E:
R1, R3=CH3, R2=CH2CH2N(CH3)2, R4=CH3, C4H9
Eudragit L and S:
R1, R3=CH3, R2=H, R4=CH3
Eudragit RL and RS:
R1=H, CH3; R2=CH3, C2H5; R3=CH3; R4=CH2CH2N(CH3)3+Cl-
Eudragit NE 30 D:
R1, R3=H, CH3; R2=H; R4=CH3, C2H5
20
The commonly applied polymeric coating systems are aqueous dispersions [99, 119,
120].
Aqueous dispersions are dispersed substances in the dispersing agent water and can be
gas in water (foam), fluid in water (emulsion), or solid in water (suspension). When the
dispersed phase is built up by polymers, they are called polymeric dispersions, and the
dispersed phase can be solid, fluid, or in any intermediate condition.
C.2.1.1.1 Physicochemical characteristics of latexes
The term latex is used for colloidal polymer dispersions [29]. It comes from the
caoutchouc latex, which is called natural latex. The particle size is the most important
specification of a latex and is between 10 and 1000 nm. The upper limit is imposed by
thermal convention and the Brownian movement of the particles. Both together must be
so high that the sedimentation velocity of the particles is overcompensated and no
sedimentation occurs over a long period of time. The lower limit is defined such that the
latex will give just some light-scattering effect resulting in a milky appearance.
Latexes are characterized by low viscosity even when they have a high solid
content .
Pseudolatex dispersions are also known. The polymer could be ethylcellulose in these
dispersions which is dissolved in organic solvent and the obtained solution is emulgated
in water by cetyl alcohol or sodium laurylsulphate [30, 31].
C.2.1.1.2 Minimum film-forming temperature (MFT)
The term MFT is used for that temperature in degrees Celcius above which a continous
film is formed under distinct drying conditions of the dispersion. According to the ISO
21
determination the MFT is the temperature limit above which a continuous homogeneous
film without cracks is observed [32]. It is largely dependent on the glass transition
temperature (Tg) of the polymer, an attribute which is capable of several definitions but
can be considered as that temperature at which the hard glassy form of an amorphous or
largely amorphous polymer changes to a softer, more rubbery consistency. The concept
of MFT includes the plasticizing effect of water on the film-forming process [33]. With
aqueous dispersions Lehmann recommends to keep the coating temperature 10-20 0C
above the MFT to ensure that optimal conditions for film formation achieved [29, 33].
With aqueous colloidal polymer dispersions, the addition of plasticizers is required for
polymer dispersions having a MFT above the coating temperature. During
plasticization, the plasticizer will diffuse into and soften the polymeric particles thus
promoting particle deformation and coalecence into a homogeneous film. The
effectiveness of a plasticizer for a particular polymer or polymer dispersion will depend
on the plasticizer-polymer compatibility and the permanence of the plasticizer in the
film during coating, storage, and during contact with artifitial or biological fluids.
The white point (WP) is defined as the temperature below which no film and only a
white powdery mass is formed. According to the ISO definition the WP is the
temperature limit below which an opaque mass, and above which a transparent film, is
formed. The WP is normally some degrees below the MFT, between these temperatures
film formation is more or less questionable.
C.2.1.2 Plasticizers
Plasticizers are generally added to film coating formulae to modify the physical
properties of the polymer to make it more usable in film coating. One important
22
property is their ability to decrease film brittleness. According to solubility property of
plasticizers water-soluble and water-insoluble types can be distinguished. With aqueous
polymer dispersions, water-soluble plasticizers dissolve whereas water-insoluble
plasticizers have to be emulsified in the aqueous phase of the dispersion. During
plasticization, the plasticizer will diffuse into the colloidal polymer particles with the
rate and extent of diffusion being dependent on its water solubility and affinity for the
polymer phase. With insoluble plasticizers, the plasticized polymer dispersion can be
visualized as a three-phase system composed of the water phase, polymer particles, and
emulsified droplets [34]. Plasticizers interact with polymers by solvation and separation
of adjacent polymer chains. This allows rigid polymer molecules to slide over each
other imparting flexibility to the film and relieving internal stresses generated as the
film dries on a tablet surface. Examples of common plasticizers include:
�� Polyethylene glycols
�� Propylene glycols
�� Triacetin
�� Glycerol
�� Dibutyl sebacate
�� Pthalate esters
�� Citrate esters
�� Acetylated monoglycerides
The most remarkable effect of plasticizers is their common glass transition temperature
(Tg) decreasing effect. The glass transition temperature is a fundamental property of any
polymeric system. At the glass transition temperature, a polymer undergoes a significant
change in mechanical properties which may have implication in coating performance.
23
The Tg influences many physical properties of coating polymers including: elasticity,
adhesion, viscosity, solvent release and permeability [35-37].
One theory of what happens at the glass transition temperature is the so-called
"Free Volume Theory". At the molecular level the total volume occupied by a given
number of molecules (VT) can be pictured as the sum of the "free volume" (VF) (the
voids) and the "occupied volume" (VO) (the volume of the molecules themselves):
VT = VF + VO (1)
It is assumed that as the temperature increases there is an increase in VF as thus VT will
increase. This will allow more movement of molecular groups and side chains. As Tg is
approached, VF increases with such magnitude as to bring about changes in measurable
mechanical properties.
The two generally applied methods for the determination of Tg are the
Differential Scanning Calorimetry (DSC) and the Thermomechanical Analysis (TMA).
Detailed description of these methods can be found in several comprehensive literature
[36, 38-41, 85-90].
C.2.1.3 Colouring systems
The third part of a film coat system are the pigments and opacifier.
Selection of pigments is often more difficult than would initially appear to be the case.
The pigments selected must be compliant in not just the country of manufacture but also
in every country of sale and consumption. Each European country has its own colour
list and these are constantly changing.
24
Examples of common colorants used in film coating
�� Soluble dyes
�� Aluminium lakes
�� Iron oxides
�� Riboflavine
�� Carotenoids
�� Anthocyanins
�� Carmine
Opacifiers
�� Titanium dioxide
�� Magnesium carbonate
�� Calcium carbonate
Factors affecting opacity are the followings:
�� The quantity of light reflected at the polymer/pigment interface
�� Light absorbed by the pigment
�� Light scattering
�� Light refraction
The quantity of light reflected at the polymer/pigment interface is dependant on the
difference between the refractive indices of the two materials. The greater the difference
between these refractive indices, the greater the opacity of the film. To achieve good
opacity, a formula should contain the maximum quantity of opacifiers such as titanium
dioxide. The inclusion of pigments has effects on the mechanical properties of films.
These effects can be quite complex as particle size, shape and surface characteristics are
all variables. Pigments will reduce tensile strength and increase elastic modulus. This is
25
an undesirable effect but inclusion is a necessity. It is important to maximise the colour
and opacity of a film coating to minimise these negative factors.
C.2.2 Glass Transition Temperature of Polymers (Tg)
The three-dimensional long-range order that normally exists in a crystalline material
does not exist in the amorphous state, and the position of molecules relative to one
another is more random as in the liquid state. Typically amorphous solids exhibit short-
range order over a few molecular dimensions and have physical properties quite
different from those of their corresponding crystalline states [109]. The glass transition
is ixhibited by amorphous polymers or the amorphous regions of partially crystalline
polymers when a viscous or rubbery state is transformed into a hard, brittle, glass-like
state. The glass transition is neither a first- nor a second-order thermodynamic phase
transition since neither the glassy state nor the viscous state is an equilibrium state.
Relaxation phenomena are observed above and below the glass transition temperature
(Tg). The glass transition of polymers is observed by DSC as stepped increase in the
heat capacity of the sample during heating due to an enhancement of molecular motion
in the polymer [114].
C.2.3 Enthalpy relaxation of glassy polymers
Physical ageing is usually manifested even in volume and enthalpy relaxation
indicating serious structural changes in the material. Sometimes common gases (as CO2)
or the natural humidity of air ignite these processes and the plasticization effects of
these everyday materials are enough to change the crystallinity or the Tg of the polymer
significantly. It has been repeatedly proven that the ageing of amorphous polymers is
26
controlled by the type and the rate of their characteristic molecular motion. The
enhanced molecular mobility, caused by plasticization effect of absorbed water, has
been proposed to be the major underlying factor in chemical and physical instability of
amorphous pharmaceutical materials [104-112].
In some practical applications, including operational lifetime prediction,
characterization of enthalpy relaxation by DSC has proved useful. These measurements
are often referred to as “aging experiments”. It can be readily appreciated that whilst
these molecular motions in the glassy region below Tg are relatively slow in normal
experimental terms they can still have a profound influence over the life-time of a
typical pharmaceutical product which is usually of the order of a few years. The failure
to recognise the effects of these time-scale differences on the behaviour of amorphous
systems may explain why many accelerated stability tests performed in the laboratory
provide unrealistic predictions of the stability of pharmaceutical dosage forms stored
under ambient conditions for much longer periods of time [42].
Precise analysis of enthalpy relaxation is not possible owing to the non-equilibrium
nature of glassy polymers above and below the glass transition. Enthalpy relaxation can
be characterized under certain limiting assumption. If the viscous or rubbery state of
polymer above Tg is assumed to be an equilibrium state then the enthalpy of the
supercooled state, formed by slow cooling, can be estimated by extrapolating the heat
capacity in the viscous state to Tg-50 K. The excess enthalpy, �H0, can be calculated
using
(2)
27
where Cpv and Cpg are the heat capacity in the viscous state and in the glassy state
immediately after quenching, respectively, Ta is annealing temperature, Ta=Tg – a.
The enthalpy change for the annealed glassy polymer is given by
(3)
where Cpa is the heat capacity of the annealed polymer. The total excess enthalpy, �Ht, is
calculated from
�Ht = �H0 - �Ha (4)
�Ha increases with annealing time, decreasing �Ht and suggesting that the glassy state
of the sample approaches equilibrium. The rate of change from the quenched state to the
ideal equilibrium state can be characterized by a relaxation time, �, expressed as
∆Ht = -∆H0exp(-t/τ) (5)
where t is the annealing time. Physically � corresponds to a characteristic time for
rearrangement of amorphous chains into more stable configurations. From the gradient
of the plot of ln(∆Ht /∆H0) againts t, � can be estimated. ∆Ht can be estimated even if the
gradients of Cpv and Cpg are not equal using the following equation instead of Eq. 2.
�H0 = a �Cp (6)
28
where �Cp is the Cp difference between the glassy state and the viscous state of the
sample at Tg. In practice, Tg and �Cp are measured for the quenched sample. The sample
is then annealed from Tg – 10K to Tg – 20K for various periods. The DSC heating curves
of the annealed samples are recorded under the same conditions as quenched samples.
The area of the curves from Tg + a to Tg – a of the quenched and annealed samples are
measured and the difference are calculated. The difference area corresponds to the ∆Ht.
These procedures for characterizing enthalpy relaxation in glassy polymers are not
thermodynamically rigorous, particularly the assumption that the viscous state above Tg
is an equilibrium state [89].
C.2.4 Film coat quality
The required properties of a film coat are numerous with respect to their end use. The
coating may be added to a dosage form for cosmetic, processing or functional drug
delivery reasons. Figure 3 summarizes the factors influencing the film coat quality and
the possible interactions between the components of the coated particle. From the
physical properties of film coats deformation properties are of particular interest. The
measurement of the elastic (i.e. they return to their original dimensions on removal of
the deforming stress) and the plastic (i.e. their deformation is permanent) properties can
be applied for their characterization. In the evaluation of film coat quality the gloss and
roughness are of decive impact �43�. The following four techniques are recommended
for assessing film coat quality.
1. Visual examination by naked eye or with a low-power magnifying glass
2. Light-section microscopy
29
3. Surface profilimetry
4. Scanning elctron microscopy (SEM)
Ad 1. Coating defects such as picking, edge splitting, orange peel, bridging of
intagliations can be recognized by visual examination.
Ad 2. The thickness of polymer films applied to tablets or pellets is often determined
either by using a micrometer to measure the film thickness after its removal from the
substrate, or by extrapolation from knowledge of the amount of polymer applied.
Ad 3. Surface roughness can be assessed more accurately by surface profilimetry.
Surface roughness measurements can be made by use of a profilimeter. This instrument
assesses surface roughness from the vertical movement of styles traversing the surface
of a tablet. The vertical movement is converted into an electrical signal which is
amplified and processed to give an Ra. Values of the arithmetic mean surface roughness
(Ra) have been calculated for a wide range of formulation and process condition by
several authors [33].
Ad 4. Examination of a film coat surface or section by SEM gives a very clear
visualisation of coat quality [101-103]. The spreading and coalescence of individual
droplets can be clearly seen. This observations can be correlated with solution viscosity,
droplet size and process conditions in order to help explain measured roughness values.
30
Figure 3
Factors influencing the film coat quality and the possible interactions between the
components of the coated particle [93]
core
coating
pHwater
solventHea
t Hea
t humidityhumidity
Oxi
gen
Oxi
gen
mechanical
mechanical
lightlight
microbiological
microbiological
drug
excipient
excipient
POLIMER
31
C.2.5 Release mechanisms and control of drug release of coated dosage forms
Rowe [43] has classified potential mechanisms for modified release using film
coating into three groups:
�� Diffusion
�� Polymer erosion
�� Osmotic effect
Diffusion
In this mechanism the applied film permits the entry of aqueous fluids from the
gastrointestinal tract. Once dissolution of the drug has taken place it then diffuses
through the polymeric membrane at a rate which is determined by the physico-chemical
properties of the drug and the membrane itself, the latter catl, of course, be altered to
take into account the desired release profile. Suitable formulation techniques such as
optimizing choice of polymer, use of correct plasticizer and concentration of plasticizer
will be considered subsequently, as will the use of dissolution rate modifiers. By using
these techniques, the structure of the film can be altered so that for instance [33, 94�,
instead of diffusing through the polymer , the drug can be made to diffuse through a
network of pores and channels within the membrane, thus facilitating the release
process [121]. In the diffusion process, the membrane is intended to stay intact during
the passage of the coated particle down the gastrointestinal tract.
Polymer erosion
This technique has been used in some rather elderly technology where multiparti- culate
systems were coated with a simple wax or fatty material such as beeswax or glyceryl
32
monostearate, the intention being that during passage down the gastroin- testinal tract, at
some point the characteristics of the coating would permit the complete erosion of the
coating by a softening mechanism. This would, in turn, pernit the complete breakup of
the drug particle. While this in itself is not modified release, a functioning system can
be made by blending together subbatches of particles coated with varying quantities of
retarding material.
Another variant with a different application is that of enteric release where the
controlling membrane is designed to dissolve at a predetennined pH and make available
the entire drug substance with no delay.
Osmotic effects
This effect is utilized in a group of well-known delivery systems using coated
tablets, e.g. 'Oros' from the Alza Corporation. Here a polymer with semi-permeable film
characteristics is used to coat the tablet. Upon immersion in aqueous fluids the
hydrostatic pressure inside the tablet will build up due to the selective ingress of water
across the semi-permeable membrane [115]. Very often these systems are formulated
with a tablet core containing additional osmotically active materials as the drug
substance may not always be soluble in water to the extent of being able to exert
adequate osmotic pressure to drive the device. The sequence is completed by the
internal osmotic pressure rising sufficiently to expel drug solution at a predetermined
rate through a precision laser-drilled hole in the tablet coating.
These systems are capable of delivering drug solution in a zero-order fashion at a rate
determined by the formulation of the core constituents, the nature of the coating and the
diameter of the drilled orifice. Osmotic effects also have a general part to play in release
33
of active materials from many coated particulate systems. This is because pressure will
be built up inside the coated particle as a result of the entry of water, which can be
relieved by drug solution being forced through pores, channels or other imperfections in
the particle coat. It can, of course, be appreciated that, while formulation design has one
prede- termined release mechanism, a mixture of all three will be functioning to a
certain extent in any modified release coated system.
The slow rate of diffusion through this barrier determines the rate of release and,
conseqently, the rate of adsorption [121].
Basically, release follows the pattern described below (Figure 4):
Figure 4
Release from coated dosage forms [44]
— Water/gastric or intestinal juice permeates the coating.
— The drug dissolves; if the core has a sufficient content of drug, solubility Cs is
obtained.
34
— The drug diffuses through the coating.
— As long as Cs is maintained in the core, the rate of release remains constant. If Cs is
no longer given, the release rate decreases exponentially.
The constant release rate Q/t is described as:
Q/t = P*A*Cs/d (7)
where Q = drug released into the sink
t = time
P = permeability of the coating
A = area
d = thickness of the coating
Except for the simple osmotic pump, the mechanism of drug release usually cannot be
defined unequivocally. Numerical fits and microscopical examinations are often used to
assign mechanisms of drug release. The following mathematical models were often
chosen to describe the release pattern on the basis of the known physical geometry of
the particles.
1. First-order Model
Mt/M� = 1 – exp(-kt) (8)
2. Higuchi square root of time Model
Mt/M� = kt1/2 (9)
3. Baker and Lonsdale Model
3/2[1-(1-Mt/M�)2/3]- Mt/M� = kt (10)
35
4. Hixon and Crowell cube-root equation
(1- Mt/M�)1/2 = 1 – kt (11)
where Mt = the amount of drug released at time "t" (min),
M� = the amount of drug released at infinite time,
k = the rate constant of drug release.
A more general function which may be applied successfully to all common types of
distribution curves, was described by Weibull [61] . Langenbucher (1972) showed that
the Weibull equation can be used to describe the 'in-vitro' dissolution process of many
dosage forms [62, 95, 123].
5. ��
�
�
���
���
�
� �
�
�d
tt 0t exp1M=M (12)
where
Mt = the amount of drug released at time "t" (min),
M� = the amount of drug released at infinite time,
t0 = the lag-time (min) of the release,
� = shape parameter of the curve,
�d = time (min) when 63,2% of M� has been released.
The following equation (13) successfully applied by Rácz [45] to compare the
dissolution rate of 40 active ingredients with different chemical structures and physical
propertiesis is identical to Weibull equation. The differentiated form of the equation is:
36
(13)
For direct calculation and for the determination of the K and � values Eq.13 may be
written in logarithmic form:
(14)
The half-life of the process is given as
(15)
C.2.5.1 Factors influencing drug release
The following steps can be taken to increase the release rate when using coatings of
restriced permeability:
Addition of Plasticizers The positive effect of plasticizers is due to various mechanisms. First, they lower the Tg
of the polymers at temperatures below 37 0C [46]. Thus the polymers are more elastic
and more easily penetrated. Second, they promote a much greater uptake of water in the
coating [47, 94]. Both processes result in an increase in the diffusion coefficient and
consequently in an increase in the rate of release [48, 98]. Depending on the solubility
of the plasticizer in water, it either remains in the coating or is eluted and then forms
micro- or macropores [96].
� �CCt
KdtdC
s ����
�
1
tKCC
C
s
s lnlnlnln ���
�
�/1
2/1693.0
��
���
��
Kt
37
Addition of Pore Formers Water-soluble additives such as NaCl [49], sucrose, cellulose derivates, polyethylene
glycols, PEG,[50], additives of this kind produce their own dispersed phase in the
coating, either straight away or in the course of film formation (during the removal of
the solvent or dispersing agent. They dissolve on contact with water and form pores;
e.g. pigments which are released from the coating at the start of the release process after
contact with water [49].
In general, the release characteristics are such the coatings exhibiting relatively good
permeability are not distribution membranes [47, 48]. Indeed, they are permeated by
lipophilic and hydrophilic substances and even by ions. Depending on the additives
used, the dosage form might incorporate micropores (also known as molecular pores) or
macropores, that is to say, homogeneous or hetergeneous membranes. Thus, the type of
additives (plasticizers, pore formers) is of great importance when deciding how to
control the rate of release [51, 97]. This is not only true of diffusion pellets (fluid bed
microcapsules) and similar products but also of coacervate microcapsules.
Microcapsules are typical multiple units dosage forms with the advantage of a fairly
food and fasting condition independent GI-transit. Thus, the variability of the typical
bioavailability characteristics is low [52].
38
D. MATERIALS AND METHODS D.1 Materials Anhydrous Caffeine (Ph. Hg. VII., Hungaropharma), Metoprolol tartarate (Helm
AG, Germany), Theophylline (Ph.Hg. VII.), Avicel PH101 (Ph. Eur., FMC),
Lactose EF (De Melkindustrie Veghel bv, Holland, Batch No. 640937/5),
Eudragit L100-55, Eudragit RL 30 D (Röhm Pharma, Germany), triacetin
(Sigma), sebacic acid dibutyl ester (dibutyl sebacate (DBS), Sigma), sebacic acid
dimethyl ester (dimethyl sebacate (DMS), Macrogolum 400, 1540, 4000 (PEG
400, 1540, 4000, Ph. Hg. VII.), Macrogol 6000 (Ph. Eur.).
D.2 Sample preparation D.2.1 Preparation of free polymer films
Approximately 10 g Eudragit RL30D dispersions containing dibutyl sebacate of
different concentrations were poured on a glass plate and dried in a sealed
container above copper sulphate and stored at room temperature for 1 week. The
obtained casted films were used for DSC and X-ray analysis.
D.2.2 Preparation of pellets
D.2.2.1. Preparation of pellets in Stephan UMC-5 apparatus
The pellets were prepared in Stephan UMC-5 temperature-controlled electronic
apparatus of variable rotating speed. Inlet air temperature: 25°C; rotating speed of
the equipment during the preparation of pellets: 900 rpm. For the formulation of
pellets the following composition was applied: Avicel PH101 380 g, Theophylline
39
or Metoprolol tartarate 20 g, aqua demineralisata 440 g. After the formulation, the
pellets were dried at 40°C.
D.2.2.2. Preparation of pellets in Pharmex 35T-Spheromat extrusion-
spheronization equipment
Parameters of the screw-extruder:
Rotation number of spheronization plate: 1000 rpm, Spheronization time: 2 min
Rotation number of the screw: 75-80 1/min. Diameter of the sieve: 800 m.
D.2.2.3. Preparation of pellets with rotofluidization equipment
The parameters of the preparation of pellets with rotofluidization are summarized
below.
Parameters Revolution number of rotor: 1200 1/min Active ingredient: 50%m/m Avicel PH101: 25%m/m
Composition of the inner phase
Lacose monohydrate: 25%m/m Composition of the granulation liquid
Distilled water: 100%m/m
Feeding rate of the granulation liquid
25 cm3/min
Process
time [min]
Air flow rate
[m3/h]
Inlet air temperature
[oC]
Granulation liquid [ml]
Atomising air rate [dm3/h]
Atomising air pressure
[bar] 0 10 25.4 100 340 0.7
1.5 30 25.4 65 340 0.7 4.0 40 25.6 23 340 0.7 5.5 40 25.8 50 340 0.7 8.5 40 25.9 50 340 0.7 12.5 40 26.2 25 340 0.7 18.0 30 50.5 - 340 0.7 34.0 30 49.8 - 340 0.7
40
D.2.3 Granulometric examination of pellets
D.2.3.1 Study of flowability of pellets
ASTM funnel was applied to measure the outflow time of 100 g pellets. The pellets
were flowed into a volumetric cylinder. The distance between the funnel and the
cylinder was 4 cm. The ourflow time was measured by a stop-watch in seconds.
D.2.3.2 Study of the particle size distribution of pellets
The prepared pellets were fractionated using a vibrating sieve (Retsch AS 200 control,
Retsch Verder GmbH, Germany) for 5 min with 2.5 mm aplitudes without intervals and
sieving aids. The sieve fractions were 1200-1600m, 1000-1200m, 800-1000m, 630-
800m, 500-630m and 0-500m.
D.2.3.3. Determination of the tapped and loose density of pellets
The average tapped and loose density values were determined according to the
Ph.Hg.VII. in g/100 cm3.
D.2.4 Coating of the prepared pellets in Kugelcoater HKC-5 coating
equipment
The pellets were coated in Kugelcoater HKC-5 coating instruments. Figure 5a is
the photo of Kugelcoater HKC-5 equipment and Figure 5b illustrates its cross-
section. The weight of the pellets: 500-1000 g. The selected coating materials
were aqueous Eudragit and HPMC dispersions. The plasticizer concentration was
5, 10, 20% w/w in each samples. Way of atomisation: angle of atomisation: 45,
41
number of nozzles: 4. Inlet air temperature: 60 0C, the end temperature of the
material: 40 0C. Feeding rate of the coating liquid: 600 cm3/h.
Figure 5a Kugelcoater HKC-5
42
Figure 5b
The cross-section of Kugelcoater HKC-5 [53, 100]
pneumatic motor powder transport system
nozzles and pneumatic air tubes
powder injector
apron
powder suspending injector
flexible filter
inlet air
sampling place
atomising air atomising material (coating liquid) nozzle
flow fence
43
D.2.5 Coating of the prepared pellets in Aeromatic Strea-1 coating equipment The fractions of 400-1000 m particle size was coated in Aeromatic STREA-1
(Aeromatic, Switzerland) fluidized bed equipments. Figure 6 illustrates the
characteristic part of Aeromatic Strea-1 Wurster-type equipment. Inlet air
temperature: 40 0C, outlet air temperature: 25 0C. Feeding rate of the coating
liquid: 150 cm3/h. Quantity of the pellets: 200-300 g, coating material: 100 g
6.3 %w/w Eudragit L100-55 aqueous dispersion. Way of atomisation: bottom
spray.
Figure 6
Aeromatic Strea-1 Wurster-type equipment [54]
1 - plastic column, 2 - perforated plate, 3 - metal tube, 4 - nozzle
Coloumn
Tube
Perforated plate
Nozzle
44
D.2.6 Coating of the prepared pellets in rotofluidization equipment The parameters of the coating procedure are summarized below.
Process time [min]
Air flow rate
[m3/h]
Inlet air temperature
[oC]
Feeding rate of coating
liquid [cm3/min]
Outlet air temperature
[oC]
Core temperature
[oC]
0 20 70.0 7 63.3 56.8 3.0 20 70.9 7 57.1 56.9 6.0 25 75.0 7 55.1 57.8 8.5 25 73.5 7 54.5 54.7 12.0 25 73.8 8.5 50.7 50.9 13.0 25 73.8 8.5 49.5 52.5 17.0 25 74.1 8.5 53.7 56.2 21.5 25 74.1 8.5 51.6 54.8 22.0 25 74.3 10.4 50.7 51.7 24.75 25 74.2 10.4 47.9 47.1 27.5 25 74.2 43.5 45.9
D.3 Examination of the coating dispersions
D.3.1 Determination of the Refractive Index of polymer dispersions
The refractive indexes of various polymer dispersions without and in the presence
of plasticizer were determined at 24 � 1C applying Abbe Refractometer.
Preceding the measurements each sample was thoroughly stirred. In spite of the
fact that the examined samples were polymer latex dispersions, the sample
preparation and the determination of the refractive index were reproducible
without any problem.
D.3.2 Calculation of the Molar Refraction by the Lorenz-Lorenz Equation
The following equation was used for the determination of molar refraction values
(R):
45
R Md
n
n�
�
�
2 12 2
(16)
where n is the determined refractive index, M is the molecular weight and d is
the density of the examined material [55]. The molar refraction is an additive
property. Due to the additive characteristic of molar refraction, the molar
refraction of Eudragit dispersions containing dibutyl sebacate can be calculated by
adding up the molar refraction values of each component of the system. The
difference between the measured and the calculated molar refraction values of the
examined polymer-plasticizer systems could refer to the nature and extent of
polymer-plasticizer interaction.
D.3.3 Dynamic surface tension measurements
The dynamic surface tension of different polymer dispersions was determined by
the Du Nouy ring method using a computer-controlled and programmable
tensiometer (KSV Sigma 70, RBM-R. Braumann GmbH, Germany) after
equilibration at 25-40°C for 1 hour. The temperature was continuously increased
in the course of measurements to determine the white point temperature and
consequently the minimum film formation temperature (MFT) of polymer
dispersions. Measuring parameters were the followings: Minimum number of
cycles: 5; Minimum measuring time: 10 min; Speed up: 1 mm/min.
D.3.4 Determination of the white point of dispersions
According to the ISO definition [56] the WP is the temperature limit below which
an opaque mass, and above which a transparent film, is formed. The WP is
46
normally some degrees below the minimum film-forming temperature (MFT),
between these temperatures film formation is more or less questionable.
In the present work the appearance of an exceptionally high standard deviation of
the surface tension is referred to as the white point. For explanatory details see the
discussion section below.
D.3.5 Thermoosmometric study of polymer dispersions
The intermolecular processes in the solutions were investigated by a digital
thermoosmometer which was developed by the Pharmaceutical Institute of the
Semmelweis University [79-81].
Difference between the temperatures of the hanging drop of solvent and that of the
examined dispersion in isotherm saturated gas atmosphere, was determined on the basis
of changes of bridge balance. This difference in temperature is a quantity, which is
proportional with the virtual concentration of the solutions.
When molality is concerned, a calibration diagram is drawn, which is based upon
data, received from the values of 5-6 series of examinations with standard
aqueous solutions of sodium cloride between 0.01-1.00 M. Mol-concentration of
the unknown dispersion can be determined on the basis of calibrating diagram.
D.4 Examination of the polymer free films
D.4.1 X-Ray Diffraction (XRD) Measurements
XRD patters of casted Eudragit films were taken with a computer-controlled
Diffractometer (Philips Analytical X-Ray, type: PW1840). The measuring
47
parameters were the followings: Tube anode: Cu, Generator tension: 30 kV,
Generator current: 30 mA, Wavelength Alpha1: 1.54056, Wavelength Alpha2:
1.54439, Intensity ratio (alpha2/alpha1): 0.500.
D.4.2 Determination of the Glass Transition Temperature of Cast Polymer Films
by Differential Scanning Calorimetry
Approximately 2-5 mg polymer samples were sealed in closed aluminium pans
and transferred to the DSC-cell of Perkin-Elmer DSC 4 instrument. After a
primary cooling to -30C, the samples were heated to 150C and the glass
transition temperature was determined using peak-analysis from the first
derivative of the measured heat flow. The heating and cooling rates were always
20C/min.
D.4.3 Determination the enthalpy relaxation of polymer films at the glass
transition temperature
The enthalpy relaxation of the films was determined using a differential scanning
calorimeter (DSC 2920, TA Instruments, New Castle, DE, USA) equipped with a
liquid nitrogen cooling accessory. Prior to the analysis, the aluminium pans were
weighed, sealed and transferred to the DSC-cell.
In all experiments, the heating and cooling rate was set at 20°C/min. An
‘expanded cooling/heating’ procedure was used to determine the glass transition
temperature and the enthalpy relaxation. The samples were subjected to a thermal
history including an isothermal stage at a temperature of Tg-15 (ageing
temperature) for 30 minutes (ageing time). The temperature profile of this
48
procedure enabled to quantify the molecular mobility of the polymer during the
isothermal phase. The enthalpy relaxation (�H (mJ/g)) was characterised by the
area under the endothermic peak, associated with the glass transition phenomenon
observed during this final cycle [57].
D.4.4 Microscopic examination of coating with FT-IR microscope
For phase-separated multicomponent polymeric systems, characterization
of the interface between the components is particularly challenging. This method
yields images of the interfaces based on the interfaces showing apparent
absorption arising from changes in refractive index at frequencies far from the
specific frequencies associated with the components of the mixture. This method
has been applied to multicomponent samples or polymer-dispersed liquid crystals
where the nature of the interface can be specifically altered by the application of
an electric potential across the sample [76, 77].
The free film samples of Eudragit polymers containing different
plasticizers (DMS, DBS) were prepared for the FT-IR shots. The samples were
put onto the slide of the microscope and they were broken into small pieces to
achieve pictures of good quality. The samples were examined by Spectratech FT-
IR microscope
D.4.5 Positron lifetime measurements of free films
Positron lifetime measurements were performed with a conventional fast-fast
coincidence system [58]. The system was constructed from standard ORTEC
electronic units and the detectors from BaF2 scintillation crystals and XP2020Q
49
photomultiplier tubes. The time resolution of the system was about 200
picoseconds. The spectrum evaluation was done by the RESOLUTION computer
code [59].
Three lifetime components were found in every spectrum but among these
lifetimes the most important was the longest one. This lifetime component is
associated with the annihilation of ortho-positronium atoms and it is proportional
with the free volume size [60]:
�
�
�
� ��
��
�
��
�
�
��
��
�
12
1 12
21
RR R
RR R� �
sin (17)
where � is the positronium lifetime, R is the radius of the free volume hole, and
�R is a constant. Note that the shapes of free volumes are supposed to be spherical
in this approximation.
Although the connection between the lifetime and the size of free volume holes is
not obvious from Eq. (17), a larger lifetime always means larger free volume
holes in the material.
The medium long lifetime component of lifetime spectra is associated with
positrons that are not able to form positronium atoms in the polymer but, instead,
annihilate directly with the electrons of the polymeric chains. The lifetime of
these positrons is determined, rughly speaking, by the average electron density in
the material. Consequently, in a material without serious chemical reactions
taking place, the changes of this liftime indicate the changes of free volume, as
well, as ortho-positronium lifetimes.
50
D.5 Examination of the coated pellets
D.5.1 Examination of the particle size distribution of coated pellets
The prepared and dried pellets were fractionated using vibrating sieve (Retsch AS
200 control, Retsch Verder GmbH, Germany) for 5 minutes without intervals and
sieving aid. The sieve fractions were the following: 1000-800 m; 800-630 m;
630-400 m; 400-250 m.
D.5.2 Friability test of the coated pellets
The friability of the coated pellets were tested using a friabilator which is official
in the Ph. Hg. VII.
D.5.3 Scanning electron microscopy studies
The surface morphology of the differently coated pellets was studied by scanning
electron microscope (Jeol JSM-25, Jeol, Japan) after gold vacuum coating.
D.5.4 Recording diffuse reflectance spectra
The diffuse reflectance spectra of coated pellets of 500-1200 m particle size was
measured by Hitachi U-2501 UV/VIS/NIR spectrophotometer (Hitachi, Japan).
The reflectance of the samples was detected in the 210-2000 nm wavelength range
using 5 mm layered cell.
D.5.5 In vitro dissolution study
The metoprolol release from the coated particles was studied using rotating paddle
method of USP 23, in Pharmatest PTW2 dissolution-tester (Pharmatest
Apparatebau GmbH, Hainburg, Germany).
51
D.5.6 Analysis of the results of dissolution studies
For the characterization of the dissolution profile of various samples, the Weibull
distribution [61] function was applied in the following form:
Mt/M� = 1-exp{-[(t-t0)/ �d]�} (18)
where Mt is the dissolution (%) at time 't', M� is the dissolution (%) at infinite
time, t0 is the lag time of the dissolution, �d is the time at which 63.2% of M� has
been dissolved, � is the shape parameter of the curve [62].
D.5.7 Determination of dissolution of drugs in vitro by means of the
Sartorius Dissolution Simulator type SM 167 51
This model is suitable for the follow-up of the release of the active ingredients
from solid pharmaceutical preparations intended for oral use. This is the first
apparatus that provides the closest possible simulation of the physiological
conditions. Modification of the pH at determined intervals enables us to simulate
conditions corresponding to those of the physiological conditions of the
gastrointestinal tract [122].
Amount of active ingredient released (M G(t)) in time t:
M G(t) = VS x Cn x MF(t) (19)
Cn = concentration of sample "n" (g/ml)
MF(t) = amount collected in the tubes in time t (g)
52
F. RESULTS AND DISCUSSION
E.1 Effect of the Concentration of the Water Soluble Plasticizer on the Dissolution
Characteristics of Eudragit Coated Metoprolol Pellets
The indicated interactions determine the required drug release process and
consequently the bioavailability of coated dosage form.
The aim of the present chapter is to evaluate the effect of the applied plasticizer
content on the dissolution kinetic parameters of Eudragit L100-55 coated Metoprolol
pellets. Figure 7 and 8 illustrate the release profiles of metoprolol at different pH values.
In order to indicate the influence of the water soluble plasticizer on the dissolution
kinetics, the �d and the shape factor (�) of the Weibull distribution were selected. No
lag-time (t0 = 0) values were detected in the case of the samples examined. Table 1
summarizes the estimated dissolution kinetic parameters. With increasing triacetin
content, the �d values decreased. This tendency is less dominant in the case of
dissolution medium of pH = 6.5, because the polymer dissolves together with the
plasticizer. The plasticizer modified the structure of the polymer. The differences in the
values of the shape factors refer to this effect. Figure 9 represents the diffuse reflectance
spectra of the coated pellets of different plasticizer content. With increasing plasticizer
content, the intensity of the reflected light decreased. The possible explanation for the
decreasing reflectance values could be that the porosity of the coating layer increased,
causing a reduction in the effective thickness of the polymer [63, 64]. To sum up, the
application of plasticizers could be remarkable effect on the drug release from coated
particles even if the particles were coated with small amount of coating polymer.
53
Table 1
Dissolution characteristics of Eudragit L100-55 coated pellets containing various
amounts of triacetin (mean values, n = 6)
pH=1.2 5% w/w 10% w/w 20% w/w � 1.57 1.31 0.66 �d (min) 255.42 157.78 32.08 pH = 6.5 � 0.83 0.52 0.49 �d (min) 98.91 47.15 46.81
0
10
20
30
40
50
60
70
80
0 50 100 150 200 250 300 350 400time (min)
Dru
g re
leas
ed (%
)
Figure 7
Effect of the triacetin content (w/w%) on the drug release profile of coated pellets,
pH value of the dissolution medium: 1.2
Surface concentration of the coating: 3.5 mg/cm2
Triacetin concentration: —�— 5%w/w ; – --�– -- 10%w/w ; ---�--- 20%w/w
54
0
10
20
30
40
50
60
70
80
0 50 100 150 200 250 300 350 400time (min)
Dru
g re
leas
ed (%
)
Figure 8
Effect of the plasticizer content (w/w%) on the drug release from coated pellets,
pH value of the dissolution medium: 6.5
Surface concentration of the coating: 3.5 mg/cm2 triacetin concentration:
—�— 5% ; – --�– -- 10% ; ---�--- 20%
55
Figure 9
Diffuse reflectance spectra of Eudragit L100-55 powder (a) and coated pellets of
different triacetin content (5% w/w - b; 20% w/w - c; coating level: 5% w/w)
56
E.2 Effect of the Concentration of the Water Insoluble Plasticizer on the
Dissolution Characteristics of Eudragit Coated Theophylline Pellets
Figure 10
Effect of the dibutyl sebacate concentration (w/w%) on the drug release from Eudragit
coated pellets
-1000
0
1000
2000
3000
4000
5000
6000
7000
0 10 20 30 40 50 60 70 80 90 100
Time (min)
Con
cent
ratio
n ( �
g/m
l)
Coated pellets without plasticizer Coated pellet + 10%DBSCoated pellet + 20%DBSUncoated pellet
57
Figure 10 illustrates that the water insoluble plasticizer decreased the extent of drug
release. In the presence of 20%w/w DBS concentration the amount of released drug
remarkably increased compare to the coated pellets without plasticizer and 10%w/w
DBS. The plasticizer possibily altered the permeability of the coating layer thus
influenced the release process.
E.3 Polymer-Plasticizer Interactions: Comparison of Experimental Data with
Theoretical Results
In the course of formulation of coated dosage forms, selection of the suitable
composition of the coating system is essential as regards dosage form. Since the
systems applied for coating are multicomponent, it is highly important to quantitatively
evaluate the possible interactions between the components. These interactions
determine the physico-chemical stability of the formulated dosage form, the drug
release process and the formulation parameters, as well. In the present study molar
refraction values of polymer dispersions were determined for the quantitative estimation
of polymer-plasticizer interactions. Dynamic surface tension measurements, differential
scanning calorimetry and X-ray diffraction studies were applied to analyse the possible
interactions between the polymer and the selected plasticizer.
The aim of the present chapter was to quantify the extent of interaction between
the selected polymer and plasticizer and to confirm the obtained results with other
physico-chemical — dynamic surface tension, differential scanning calorimetry, X-ray
diffraction, positron lifetime spectroscopy — methods. The selected methods
characterize the film-forming properties of polymer systems which are of importance
from the point of coating process.
58
Table 2 summarizes the measured (Rm) and the calculated (Rc) molar refraction values
of Eudragit RL 30D dispersions containing dibutyl sebacate of different concentrations.
Since the molar refraction is an additive property, the molar refraction of Eudragit RL
30D coating dispersions were obtained by adding the molar refraction values of
Eudragit RL 30D and those of the various plasticizers. The obtained results show (Table
2-4) that along with the increase of plasticizer concentrations, differences between the
measured and calculated molar refraction values also increased. In the case of 20%w/w
DBS concentration the calcaluted molar refraction difference is higher with a magnitude
than that of the difference calculated at 10%w/w plasticizer concentration. The reason
of this phenomena could be the immiscibility of dibutyl sebacate with Eudragit RL 30D
at higher than 10%w/w concentrations.
Additionally, positron lifetime spectroscopy measurements indicated the parallel
increase of the average size of free volume holes in the prepared free films. Figures 11
and 12 illustrate that, along with the increase of DBS concentrations, both positron and
ortho-positronium lifetimes increase. Both curves show saturation at around 10%w/w
DBS concentration and above this concentration the free volume does not change
significantly. The observed free volume increase might as well explain the decrease of
the white point temperature. As the dibutyl sebacate concentration increases, its
plasticization effect changes the originally compact structure of polymer molecules in
the dispersion. The new structure implies larger free volume holes, as shown by the
observed positron lifetemes. These larger holes allow more space for molecular
movements and, thus, molecular groups and side chains possess larger mobility. It is
assumed that this latter phenomenon leads to the decrease of the white point
temperature and, moreover, enables film formation at a lower temperature.
59
A further similarity between free volume and surface tension measurements is
provided by the saturation behaviour of the respective observables. Above 10%w/w
platicizer concentration no significant changes were observed in any case. Neither the
white point temperature, nor the free volume changed above 10%w/w DBS. The
saturation is, most probably, due to the immiscibility of the plasticizer with the polymer
at higher concentrations.
The results indicate that the increasing plasticizer concentration decreased the
minimum film formation temperature, but above 10%w/w dibutyl sebacate
concentration no significant MFT changes were seen. The obtained MFT values leveled
out to constant value with the increasing DBS concentration which also refers to the
immiscibility of the selected plasticizer in the polymer dispersion above 10%w/w
plasticizer concentration. The latter is in good compliance with the molar refraction
results calculated by the Lorenz-Lorenz relationship. The results indicate that not only
the MFT values did not significantly change above 10%w/w plasticizer concentration
but the glass transition values of casted polymer films, as well [65].
The X-ray diffraction pattern of casted Eudragit RL 30D films (Figure 13a)
shows that in the presence of 10 and 20 %w/w dibutyl sebacate concentration a peak
appears indicating the separated plasticizer but the film remained amorphous. The
presence of plasticizer (PEG 400) did not alter the morphology of HPMC (Pharmacoat
606) films (Figure 13b).
The latter can be further confirmed by FT-IR microscopic examination (Figure
14-16). Comparison of the shots of KBr pastilles with that of microscopical ones seems
to prove that the separated dibutyl sebacate is present in small islands. Similar results
can be obtained in the case of dimethyl sebacate at 10%w/w concentration. In the case
60
of DBS the drop acutely appears in Eudragit at 1018 cm-1 is absent, while the vibration
is a great deal more intense at 1736 cm-1 than in the case of Eudragit coating without
plasticizer. At 1171 cm-1 around one peak such streak appear that is also absent in the
case of Eudragit coating without plasticizer, and at 2860 and 2640 cm-1 the CH2
vibrations are more intense. All of these facts prove that plasticizer is present in the
drop.
In contrary, in the presence of water-soluble plasticizers e.g. different types of
PEGs, neither the molecular weight nor the concentration of plasticizer changed the FT-
IR spectra of Eudragit polymer films (Figure 17, 18).
Figure 19 illustrates the effect of molecular weight and concentration of water-
soluble PEGs on the molality of Eudragit dispersions. The results indicate that along
with the increase of the concentration PEGs, the molality of Eudragit dispersions also
increased. In the case of PEG 400, the molality increased linearly with good correlation
as a function of plasticizer concentration, while in the case of PEGs of higher molecular
weights the molality values more differed from the linear with increasing concentration.
The latter refers to the possible interaction between the polymer and the plasticizer in
dispersion.
Information can be obtained from the calculation of molar refraction values of
Eudragit dispersions containing plasticizer concerning the extent of interaction between
the polymer and the plasticizer. The theoretical results based on the calculation of molar
refraction values of the selected polymer-plasticizer system were in good complience
with the results of applied physico-chemical methods that characterize the film-forming
behaviour of polymers.
61
Table 2
Measured (Rm) and calculated (Rc) molar refraction values of different Eudragit RL30D
- dibutyl sebacate systems (average values, n=6, RSD � 5%)
Dibutyl sebacate R m Rc (Rm-Rc)/Rm concentration (%w/w) (%)
0 6547.87
5 6554.61 6551.09 0.01
10 6599.05 6560.43 0.60
20 6860.70 6568.23 4.30
Table 3.
The (Rm-Rc)/Rm values (%) of free films of Eudragit RL 30D polymers containing
different plasticizers
Plasticizer PEG 6000 PEG 400 DBS concentration (%w/w) 5 0.34 0.99 0.01
10 1.26 0.85 0.59
20 2.34 4.45 4.30
62
Table 4.
The (Rm-Rc)/Rm values (%) of free films of Pharmacoat 606 containing different
plasticizers
Plasticizer PEG 400 DBS concentration (%w/w) 5 0.63 11.70
10 0.20 12.48
20 1.09 12.74
63
Figure 11
The lifetime of positrons in free Eudragit films as a function of DBS concentration.
Note that this lifetime component is proportional with the average electron density of
the material and, consequently, also with the average free volume size.
0 5 10 15 20
430
440
450
DBS concentration /%
posi
tron
lifet
ime
/ps
64
Figure 12
The lifetime of ortho-positronium atoms vs. DBS concentration. The connection
between this lifetime and the size of free volume holes is given by Eq. (17).
0 5 10 15 20
1850
1900
1950
2000
2050
posit
roni
um li
fetim
e /
ps
DBS concentration /%
65
Tables 5 and 6 summarize the dynamic surface tension values for the different
Eudragit L 30 D and Eudragit RL 30 D dispersions measured at several temperatures. In
general, the applied plasticizer decreased the surface tension value of the dispersions
compare to the distilled water, due to its interfacial structure modifying effect. The
white point, which could be observed visually, was also appeared in every dispersion,
regardless to the presence of the plasticizer. The plasticizer, however, decreased the
white point temperature significantly. The most remarkable feature of the tables is the
surprisingly high standard deviation of tension data (Table 5, 6) at the white point. In
every case, this high standard deviation occured consequently at the temperature where
the dispersion formed a discontinuous opaque white mass, i.e., at the white point. The
explanation for this coincidence is hidden in the combined effects of the measuring
method and the discontinuity of the material. The Du Nouy ring method involves a
repeated sinking of the ring in the dispersion and, as expected on the basis of statistical
thermodynamics, not always the same molecules contact with the ring in the repeated
measurements. This is exactly the cause of repetition, i.e., the resulted “averaging”
eliminates most of the effects of random fluctuations. In discontinuous materials these
fluctuations are naturally larger, so, the standard deviation of the measured surface
tension have to be definitely higher than in “homogeneaous” dispersions. The most
important consequence of the discussed coincidence is that, in the future, surface
tension measurements might replace the dubious observation with the naked-eye
method in the determination of the white point temperature. The presence of DBS in
Eudragit dispersions caused a decrese in the white point temperature.
66
Table 5
Dynamic Surface Tension Values (mN/m � SD) of Eudragit L 30 D Dispersions
Containing Dibutyl Sebacate Measured at Different Temperatures
Temperature Dibutyl sebacate concentration 5w/w% 10%w/w 20%w/w [0C] � (mN/m) � SD � (mN/m) � SD � (mN/m) � SD 25.0 42.26 � 0.31 38.56 � 0.76 34.23 � 0.72
27.5 41.81 � 0.43 37.67 � 0.90 33.19 � 0.69
30.0 40.94 � 0.96 35.57 � 0.97 33.15 � 0.68
32.5 40.54 � 0.87 31.95 � 8.13 29.42 � 12.27
34.5 38.81 � 2.15 - -
Table 6
Dynamic Surface Tension Values (mN/m � SD) of Eudragit RL 30 D Dispersions
Containing Dibutyl Sebacate Measured at Different Temperatures
Temperature Dibutyl sebacate concentration 5w/w% 10%w/w 20%w/w [0C] � (mN/m) � SD � (mN/m) � SD � (mN/m) � SD 25.0 41.86 � 0.31 38.73 � 0.87 37.95 � 0.72
27.5 40.81 � 0.43 37.67 � 0.90 36.34 � 0.59
30.0 39.94 � 0.96 35.57 � 0.97 33.15 � 0.58
32.5 39.54 � 0.87 31.95 � 2.99 29.42 � 2.36
34.5 37.93 � 2.34 - -
67
Figure 13a
X-ray Diffraction pattern of Eudragit RL 30D casted films containing dibutyl sebacate
of different concentrations
68
Figure 13b
X-ray Diffraction pattern of HPMC cast films containing PEG 400
Black:
Red: HPMC
2�
69
Figure 14
FT-IR microscopic examination of Eudragit L100-55 free film without plasticizer
Figure 15
FT-IR microscopic examination of Eudragit L100-55 free film containing
10%w/w DBS
70
Figure 16
FT-IR microscopic examination of Eudragit L100-55 free film containing
10%w/w DMS
71
Figure 17
FT-IR microscopic examination of Eudragit RL 30D free film containing
10%w/w PEGs of different molecular weigths
72
Figure 18
FT-IR microscopic examination of Eudragit RL 30D free film containing
20%w/w PEGs of different molecular weigths
73
Figure 19
The effect molecular weight of PEGs on the molality of Eudragit RL 30D
dispersions
R2 = 0,9979
00,20,40,60,8
11,21,41,61,8
2
0 5 10 15 20 25
PEG concentration ( m/m% )
Sign
( n
A )
PEG 400PEG 2000PEG 6000Eudragit RL 30D + PEG 400Eudragit RL 30D + PEG 2000Eudragit RL 30D + PEG 6000
74
E.4 Coating Polymer-Plasticizer Interaction in relation to the Enthalpy Relaxation
of Polymer
In the previous chapter the molar refraction values of polymer dispersions
containing plasticizer were determined to quantitatively characterize the possible
polymer-plasticizer interaction and to determine the optimum concentration of the
selected plasticizer.
The purpose of the present part of the work was to study the influence of dibutyl
sebacate on the enthalpy relaxation of casted Eudragit films and to get information from
the thermal history of the sample for the extent of polymer-plasticizer interaction.
Among the additives that are incorporated into aqueous polymeric dispersions, the
plasticizer is the most critical component that dictates proper film formation and quality
of the resulting film [66]. For a plasticizer to be effective, it must be able to diffuse into
and interact with the polymer and have minimal or no tendency for migration or
exudation from the polymer. If a plasticizer does not remain in the film, then changes in
the chemical and/or physical-mechanical properties of the polymeric material could
result. In vitro dissolution studies with cast films of Eudragits have demonstrated that
water-soluble plasticizers were leached more readily from the film when the level of
hydrophilic polymer in the film was increased [67]. Therefore the selection of a
plasticizer by the pharmaceutical scientist for a film-coating formulation is a very
important decision in order to develop and optimize the stability and drug release
properties of a pharmaceutical dosage form. The plasticizers can affect the long term
performance of amorphous polymers in pharmaceutical dosage forms due to a reduction
of glass transition temperature (Tg) [68, 69]. The Tg influences many physical properties
of coating polymers including: elasticity, adhesion, viscosity, solvent release and
75
permeability [70]. It has been repeatedly proven that the ageing of amorphous polymers
is controlled by the type and the rate of their characteristic molecular motion. The
presence of free volume results from a need for space caused by chain segment
mobility, which develops above the Tg. This free volume remains when there is rapid
cooling below the Tg. Since this state is thermodynamically unstable, the more stable
state is reached in the course of time in different ways depending on the ambient
temperature. The macromolecules are arranged in a more space saving manner. This
temporal decrease of the enthalpy at a temperature below the Tg is called enthalpy
relaxation. The nearer the curing or storage temperature lies to the Tg, the faster does
enthalpy relaxation takes place [42]. Volume and enthalpy relaxation are two
phenomena of the physical ageing process, which describe the time dependent changes
of an amorphous polymer held at temperatures below its Tg. By use of differential
scanning calorimetry (DSC) the structural relaxation in amorphous polymers can be
investigated with a high reproducibility. During a DSC experiment a polymer sample is
subjected to a thermal history, starting at a temperature above the glass transition
temperature, involving periods of heating and cooling at constant rates as well as
isothermal stages and finishing at a temperature in the glassy state. Then the specific
heat is measured during a heating scan at constant rate, the heat capacity (Cp) versus
temperature (T) curve thus obtained depends on the thermal history of the sample and
contains information about structural relaxation, which occurred both in the process
prior to the thermal analysis and during the measuring scan itself [71].
Figure 20-23 illustrate the measured heat flow during the final heating run after the
samples were kept in isotherm conditions at Tg – 15 0C for 30 min and Table 7
76
summarizes the characteristics values of glass transition of different Eudragit samples.
The results indicate that the presence of dibutyl sebacate did not remarkably alter the
glass transition temperature of cast Eudragit L 30D polymer films. In the case of
20%w/w plasticizer content relaxation endotherm was observed, under the given
experimental conditions, at the glass transition (Table 7 and Figure 23) which refers to
the improved molecular mobility. It is assumed that as the dibutyl sebacate
concentration increases there is an increase in the free volume of the polymer as thus the
total volume occupied by a given number of molecules will increase. This will allow
more movement of molecular groups and side chains. Table 8 summarizes the
characteristic values of crystallization and melting of dibutyl sebacate. The obtained
endotherm peaks (Figure 21-23) refer to the melting of the crystallized DBS in the
course of the heating phase of the program. The melting peak of DBS measured at
–5.6 (�1.50C) and the calculated melting enthalpy were proportional to the plasticizer
concentration in the polymer dispersion up to 10%w/w concentration
(Table 8), but above this value (20%w/w concentration) it was not proportionally
increased (Figure 23, Table 8). The reason of this phenomenon could be the
immiscibility of dibutyl sebacate with Eudragit L 30D at 20%w/w concentration. The
latter is in good compliance with the previous results calculated by the molar refraction
values on the basis of the Lorenz-Lorenz relationship.
Interaction was observed between Eudragit L 30D and dibutyl sebacate and it
was confirmed by the enthalpy relaxation values measured by differential scanning
calorimetry at the glass transition temperature of cast Eudragit films commonly applied
for film coating procedures. The enhanced molecular mobility of the coating polymer
along with the immiscibility of the plasticizer at 20%w/w dibutyl sebacate
77
concentration, confirmed by DSC, could be an underlying factor in chemical and
physical instability of the examined Eudragit film coatings.
78
Table 7 Characteristic values of glass transition of different Eudragit L 30D samples (average of
two parallels)
Sample Onset (0C) Inflection (0C) Endpoint (0C) �cp (J/gK) �H (J/g)
Eudragit L 30D 68.7 75.5 82.6 0.31 -
without plasticizer
Eudragit L 30D 67.7 76.9 88.4 0.45 - + 5%w/w DBS Eudragit L 30D 69.8 77.0 82.1 0.41 - + 10%w/w DBS Eudragit L 30D 67.2 74.2 77.9 0.44 0.50 + 20%w/w DBS
Table 8 Characteristic values of the crystallisation and the melting of dibutyl sebacate (average
of two parallels)
Sample Crystallisation �H Melting �H
peak (0C) (J/g) peak (0C) (J/g)
Eudragit L 30D - 20.4 1.8 - 7.0 2.2 + 5%w/w DBS Eudragit L 30D -19.7 3.7 - 5.6 3.5 + 10%w/w DBS Eudragit L 30D - 21.1 0.7 - 5.6 1.0 + 20%w/w DBS
79
Figure 20
The heat flow recorded after the isothermal stage versus temperature curves of
Eudragit L 30D films
80
Figure 21
The heat flow recorded after the isothermal stage versus temperature curves of
Eudragit L 30D films containing 5%w/w dibutyl sebacate
81
Figure 22
The heat flow recorded after the isothermal stage versus temperature curves of
Eudragit L 30D films containing 10%w/w dibutyl sebacate
82
Figure 23
The heat flow recorded after the isothermal stage versus temperature curves of
Eudragit L 30D films containing 20%w/w dibutyl sebacate
83
E.5 Comparative Evaluation of Coated Pellets Produced by Different Fluidized
Bed Equipments
Not only the coating polymer system but the coated core and the coating
procedure have a great impact on the characteristics of the drug release.
In the development of reservoir-type modified release products, the use of
pellets has become predominant since it provides an efficient method of maximizing
reproducibility and minimizing the risk of dose-dumping. Certain drugs — principally
those with a short half-life — are of more benefit when administered daily in a form
which maintains the drug blood level over the minimum effective level [72, 73].
Various methods of producing sustained release products from coated particles, have
been reported in the literature [74].
The main objective of the present chapter is to compare the coating procedures,
carried out in Kugelcoater and in Aeromatic equipments, and their effects on the
properties of the prepared coated particles. Table 9a and Table 9b summarize the
characteristics of the uncoated pellets and those of the coated ones. The results indicate
that the per cent amount of particle fractions of bigger size increased when the coating
procedure was carried out in Kugelcoater equipment. Figure 24 illustrates the inner core
of theophylline pellet while Figure 25 represents the differences in the surface
characteristics of coated pellets of 800-1000 m particle size. The surface of the pellets
prepared in Kugelcoater was more even than that of the pellets prepared in Aeromatic
Strea-1. The latter is more visualized with higher magnification (Figure 26, 27). Similar
results were obtained in the case of HPMC coatings (Pharmacoat 606) in Kugelcoater
(Figure 28). The uniform, continuous coating layer caused a more prolonged drug
84
release (increased to, �d values) in the case of pellets coated with Eudragit in
Kugelcoater (Table 9).
The results indicate the application of Kugelcoater HKC-5 fluidized bed
equipment resulted in more uniform coating layer on the surface of pellets and a more
prolonged drug release profile than the application of the Aeromatic equipment.
Figure 24
Scanning Electron Micrograph of theophylline pellet
Magnification: 2000x
Theophylline
85
Table 9a
Comparison of the characteristics of uncoated pellets (mean values, n=6)
Pellets prepared in laboratory rotofluidization equipment Flowability (s/100g) 10.48 Particle size distribution 0 -0.50 mm 0.49% 0.5-0.63 mm 26.59% 0.63-0.8 mm 10.30% 0.8 - 1.0 mm 30.99% 1.0 - 1.2 mm 29.82% 1.2 - 1.6 mm 1.81% Tapped density (g/100 cm3) 76.69 Loose density (g/100 cm3) 68.43
Table 9b
Comparison of the characteristics of coated pellets (mean values, n=6)
Coating material: Eudragit L100-55
Aeromatic STREA-1 Kugelcoater HKC-5 Flowability (100 g/s) 8.3 7.0 Dissolution characteristics: to (min) 1.8 2.3 �d (min) 15.6 22.3 � 0.48 0.86
86
a b
Figure 25
Scanning Electron Micrograph of coated caffeine pellets
Coating material: Eudragit L100-55, Magnification: 70 x
a: coated in Aeromatic STREA-1 equipment
b: coated in Kugelcoater HKC-5 equipment
87
Figure 26
Scanning Electron Micrograph of caffeine pellets coated in Aeromatic STREA-1
equipment
Coating material: Eudragit L100-55, Magnification: 1000x
88
Figure 27
Scanning Electron Micrograph of caffeine pellets coated in Kugelcoater HKC-5
equipment
Coating material: Eudragit L100-55, Magnification: 1000x
89
Figure 28
Scanning Electron Micrograph of theophylline pellets coated in Kugelcoater HKC-5
equipment
Coating material: Pharmacoat 606, Magnification: 2000x
90
SUMMARY
The final quality of the coated pellets was influenced by several factors, like the coating
process, the composition of the pellets and coating dispersion.
The new findings of the thesis are summarized below:
1. Our results indicate that the coating process in Kugelcoater HKC-5 equipment
resulted in more even pellets than the coating in Aeromatic STREA-1 fluidized-bed
equipment.
2. The coated pellet is a multicomponent system, consequently the drug release from
these coated particles can be very sensitively influenced by the changes of the
composition of the coating dispersion.
3. The quality (water-solubility, molecular structure, weight) and the quantity of the
applied plasticizer changed the extent of drug release.
�� The increasing concentration of the water-soluble plasticizer (various types
of PEGs, triacetin) increased the rate of drug release from the coated pellets.
�� The water-insoluble plasticizer (dibutyl sebacate, dimethyl sebacate)
decreased the extent of drug release.
4. The reason for the changes of the extent of drug release was the polymer-plasticizer
interaction.
91
5. Along with the increase of dibutyl sebacate concentration of the free films, the free
volume of the polymer was also increased. With increasing free volume, the
molecular mobility of the polymer was also increased, thus enthalpy relaxation
could be measured at the glass transition temperature of the polymer.
6. The polymer-plasticizer interaction in polymer dispersion and in free films was
characterised by different physical chemical methods (dynamic surface tension
measurement, DSC, SEM, X-ray diffraction, PALS, FT-IR methods).
The applied methods were suitable for the analysis of the possible interaction
between the polymer and plasticizer.
92
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93
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100
ACKNOWLEDGEMENT
First of all I wish to express my sincere thanks to Professor István Rácz D.Sc. for
quiding me with his valuable advice and inspiring me in my work.
I am greatly indebted to Professor Sylvia Marton, Director of the Pharmaceutical
Institute of the Semmelweis University, for providing me with the opportunity to work in the
Pharmaceutical Institute.
Furthermore, I express my cpecial thanks to Dr. Károly Pataki, Technical Director of
EGIS Ltd. Lacta Pharmaceuticals, and Dr. Romána Zelkó for their interesting discussions and
collaboration. I am very thankful to Dr. Péter Tömpe for the valuable physico-chemical
discussions.
I am grateful to Dr. Mária Hajdú and Dr. Judit Dredán for their help with the
Sartorius dissolution measurements and for the analysis of the dissolution kinetics.
I would like to thank László Csernák, Head of the Pharmaceutical Technology
Formulation Department of Gedeon Richter Ltd and all members of the staff for the
encouragement and understanding attitude during my Ph.D. work.
101
PUBLICATIONS AND LECTURES Publications 1. Á. Orbán, E. Bihari, J. Dredán, R. Zelkó, D. Greskovits, I. Rácz:
Comparative evaluation of coated pellets produced by different fluidized bed equipments. Die Pharmazie 53(3), 274-275, (1998) IF: 0,419
2. Á. Orbán, J. Dredán, R. Zelkó, I. Antal, I. Rácz:
Effect of the plasticizer content on the dissolution characteristics of Eudragit coated Metoprolol pellets Die Pharmazie 53(11), 802-803, (1998) IF: 0,419
3. Á. Orbán, R. Zelkó, J. Dredán, S. Marton, I. Rácz: Polymer-Plasticizer Interactions:
Comparison of Experimental Data with Theoretical Results. Hung. J. Ind. Chem., 29, 7-9, (2001) IF=0,196
4. Orbán Á.: A magyar gyógyszeripar múltja, jelene és lehetőségei.
Gyógyszerészet, 43, 453-458, (1999). 5. R. Zelkó, Á. Orbán, J. Nagy, G. Csóka, I. Rácz: Polymer-plasticizer interaction in
relation to the enthalpy relaxation of polymer. Journal of Thermal Analysis and Calorimetry, 68 (2002). IF=0,390
6. R. Zelkó, Á. Orbán, K. Süvegh, Z. Riedl , I. Rácz: Effect of Plasticizer on the Dynamic Surface Tension and the Free Volume of Eudragit Systems.
Accepted to Int. J. Pharm. IF=1,024 Proceedings 7. Marton S., Bihari E., Orbán Á.,Greskovits D, Rácz I, Some technological factors influencing drug release from �-blocker containing polymer-coated particles
Proceedings of 1st World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, APV/APGI, Budapest, 1995, p.357
8. Á. Orbán, R. Zelkó, J. Dredán, E. Balogh, I. Rácz, S. Marton: Investigation of
polymer-plasticizer interactions in relation to drug release from film-coated pellets. Proceedings of 3rd World Meeting APV/APGI, Berlin, 3/6 April 2000, p.901-902.
102
9. Orbán Á.: A pelletezés és a pelletbevonás eljárásai és berendezései a gyógyszeriparban. Proceedings ISBN 963 00 2831 X o.194
10. Orbán Á., Zelkó R., Dredán J., Marton S., Rácz I.: A filmképző polimer-lágyító interakció hatása a bevonat stabilitására Proceedings ISBN 963 00 6467 7 o.128-129
Congress Abstracts 11. Orbán Á.: A granulálás végpontjelzése DIOSNA P50 típusú nagy sebességű gyúró-
granuláló berendezésben. Gyógyszerészet, 38, 246-247, (1993).
12. Orbán, Á.: A granulálás végpontjelzése Diosna P50 nagy sebességű gyúró-granuláló
berendezésben. Congressus Pharmaceuticus Hungaricus IX. Gyógyszerészet, p.39. (1993)
13. Orbán, Á., Bihari, E., Dredán, J., Zelkó, R., Rácz, I.:
Comparative evaluation of coated pellet formulations based on fluidized bed method IV. Semmelweis Tudományos Fórum, Budapest, 1995, Abstracts p. 40
14. Dredán, J., Zelkó, R., Orbán, Á., Antal, I., Rácz, I., Marton, S.:
Polyethylene glycol derivatives – physical characterization, formulation aspects VII. Semmelweis Tudományos Fórum, Budapest, 1998, Abstracts Addendum 151.
15. Orbán, Á., Zelkó, R., Dredán, J., Rácz, I., Marton, S.:
Examination of polymer films by physico-chemical methods VII. Semmelweis Tudományos Fórum, Budapest, 1998, Abstracts Addendum 149.
16. Orbán Á., Zelkó R., Dredán J., Rácz I., Marton S.:
Poli(etilénglikol)-ok alkalmazási lehetőségei szilárd gyógyszerformák bevonása során. Gyógyszerészet, 1996.
103
Lectures 17. Marton S., Bihari E., Orbán Á.,Greskovits D, Rácz I, Some technological factors influencing drug release from �-blocker containing polymer-coated particles
1st World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, APV/APGI, Budapest, 1995.
18. Orbán Á., Dredán J., Antal I., Péter I., Greskovits D.:
Interakciós lehetőségek befolyása a hatóanyagfelszabadulásra Congressus Pharmaceuticus Hungaricus X., Budapest, 1996.
19. Orbán Á., Bihari E., Dredán J., Zelkó R., Péter I, Greskovits D., Rácz I., Anyagátmeneti tulajdonságok befolyásolása a bevonó polimer-lágyító interakció által XIII. Gyógyszertechnológiai Konferencia, Hévíz, 1997 ápr. 26-28.
20. Zelkó R., Orbán Á., Csóka G., Dredán J., Marton S., Rácz I.:
Polimer kötőanyagot tartalmazó préselmények mechanikai szilárdsága és a kötőanyag termoanalitikai tulajdonságai közötti összefüggések vizsgálata Gyógyszerkémiai és Gyógyszertechnológiai Szimpózium ’99, Dobogókő, 1999. Szeptember 23-24.
21. Orbán Á., Zelkó R., Dredán J., Rácz I., Marton S.: Poli(etilénglikol)-ok alkalmazási lehetőségei szilárd gyógyszerformák bevonása során. GYOK IX - CPH XI, Siófok, 1999. október 6-10. 22. Orbán Á.: A pelletezés és a pelletbevonás eljárásai és berendezései a
gyógyszeriparban. Műszaki Kémiai Napok, Veszprém, 2000.
22. Orbán Á.: Filmképző polimer-lágyító interakció hatása a bevonat stabilitására.
Műszaki Kémiai Napok, Veszprém, 2001.
23. Orbán Á., Zelkó R., Dredán J., Antal I., Marton S.: Fizikai-kémiai módszerek alkalmazása filmbevonó rendszerek lágyító szereinek kiválasztására. Gyógyszerkémiai és Gyógyszertechnológiai Szimpózium 2001, Visegrád, 2001. szeptember 24-25.
