STUDIES ON MULTICOMPONENT COATING SYSTEMS IN RELATION TO PELLETS. Ph.D. THESIS ÁDÁM ORBÁN. Research Tutor: Prof. Dr. István Rácz, Ph.D., D.Sc.

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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

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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. 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 Polymers 18 C Physicochemical characteristics of latexes 20 C Minimum film-forming temperature (MFT) 20 C Plasticizers 21 C Colouring systems 23 C.2.2 Glass Transition Temperature of Polymers (T g ) 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 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 Preparation of pellets in Stephan UMC-5 apparatus 38 D Preparation of pellets in Pharmex 35T-Spheromat 39 extrusion-spheronization equipment D Preparation of pellets with rotofluidization equipment 39 D.2.3 Granulometric examination of pellets 40 D Study of flowability of pellets 40 D Study of the particle size distribution of pellets 40 D 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 I 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 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 II 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. 1 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. 2 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 m in size, near-spherical form, slightly uneven surface and compactness approximate to that of agglomerated materials (low porosity). Thus the 3 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 4 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. 5 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 gastrointestinal 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' 6 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 rotofluidisation 10-14, and with multi-step technology usually called 'extrusionspheronisation. 7 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: Powder mixing Preparation of cores granulation, milling, dispergation crystallization spray drying Cores Layering Powder Liquid Drying PELLET 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. 8 Diagram 2 Elementary growth mechanism of pellets Nucleation Coalescence Layering and abrasion transfer 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. 9 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. 10 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]. 11 Homogenization Kneeding Extrusion Spheronization Powders Liquid Drying PELLETS 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]. 12 Diagram 6. The build-up of an extruder [4] 13 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. 14 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. 15 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 position
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