Manufacture and Characteristics of Pastilles and Their Coating by Crystallization Process
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MANUFACTURE AND CHARACTERISTICS OF PASTILLES AND THEIR COATING BY CRYSTALLIZATION PROCESS DISSERTATION zur Erlangung des akademischen Grades Doktor-Ingenieur (Dr.-Ing.) genehmigt durch die Mathematisch-Naturwissenschaftlich-Technische Fakultät (Ingenieurwissenschaftlicher Bereich) der Martin-Luther-Universität Halle-Wittenberg von Herrn M.Sc. Jung-Woo Kim geb. am 20.08.1972 in KyoungNam / Süd Korea Dekan der Fakultät: Prof. Dr. Ludwig Staiger Gutachter: 1. Prof. Dr. -Ing. habil. Joachim Ulrich 2. Prof. Dr. habil. Karsten Mäder 3. Dr. -Ing. Ulrich Teipel Halle (Saale), den 15. 12. 2003 urn:nbn:de:gbv:3-000006229 [http://nbn-resolving.de/urn/resolver.pl?urn=nbn%3Ade%3Agbv%3A3-000006229] CONTENTS CONTENTS 1. INTRODUCTION ……………………………………………......…………... 1 2. TECHNICAL BACKGROUND AND THEORY ………………………….. 3 2.1. Melt solidification ……………………………………………………..... 3 2.1.1. Technical background of melt solidification processes ………..…. 3 2.1.2. Approximation of crystallization rate ………………………..…… 5 2.1.3. Degree of deformation ………………………………………..…... 5 2.2. Porosity ……………………………………………………………..…... 7 2.3. Nucleation and crystal growth in solution …………………………..….. 11 2.3.1. Nucleation ……………………………………………………..….. 11 2.3.1.1. Types of nucleation …………………………………..……... 11 2.3.1.2. Kinetic of nucleation …………………………………..……. 12 2.3.1.3. Surface nucleation ……………………………………..……. 14 2.3.2. Growth rate …………………………………………………..…… 16 2.3.2.1. Theory of crystal growth ………………………………..…... 16 2.3.2.2. Kinetic of crystal growth ………………………………..…... 17 2.4. Agglomeration mechanism ………………………………………...…….. 19 2.5. Interfacial tension …………………………………………………..……. 21 2.6. Seeding technology ………………………………………………..…….. 23 3. STATE OF ART AND OBJECTIVES OF THESIS ………………....…….. 24 3.1. State of art …………………………………………………………..…... 24 3.1.1. Crystallization time of drops ………………………………..…….. 24 3.1.2. Coating mechanism in a crystallization process ……………..…… 25 3.1.2.1. Zone of surface nucleation ……………………………..…… 25 3.1.2.2. Growth mechanism in a crystallization process ……..……… 26 3.2. Objectives of thesis ……………………………………………..………. 28 i CONTENTS 4. CONTACT ANGLE AND CRYSTALLIZATION TIME ………...…..…… 30 4.1. Introduction …………………………………………………………..…. 30 4.2. Experimental setup and procedure …………………………………..….. 31 4.3. Measurement of contact angle ………………………………………..… 34 4.3.1. Shape and size of pastilles ……………………………………..…. 34 4.3.2. Surface and internal structure of pastilles ……………………..….. 35 4.3.3. Spreading and rebounding phenomena ………………………..….. 35 4.3.4. Measurement of contact angle ………………………………..…... 36 4.3.4.1. Influence of viscosity ……………………………………..… 36 4.3.4.2. Influence of Reynolds number …………………………….... 37 4.3.4.3. Influence of surface properties …………………………….... 39 4.3.4.4. Influence of degree of subcooling ………………………..…. 41 4.4. Determination of normalized deformation and crystallization time ……. 43 4.4.1. Degree of deformation …………………………………………..... 43 4.4.2. Crystallization time ……………………………………………..… 45 5. INVESTIGATION OF POROSITY IN THE PASTILLES …………...…... 48 5.1. Introduction …………………………………………………………..…. 48 5. 2. Preparation of solid drugs and mercury incursion porosimeter ……..…. 49 5.2.1. Preparation of pastille and tablet ………………………………… 49 5.2.2. Technique of mercury porosimetry …………………………...…… 50 5.3. Structure and size distribution of pores in pastilles and tablets ……..….. 51 5.3.1. Pores structure of pastilles and tablets …………………………..... 51 5.3.2. Pore size distribution of pastilles and tablets …………………..…. 52 5.4. Total porosity ………………………………………………………..….. 54 5.4.1. Total porosity in tablets ………………………………………..….. 54 5.4.2. Total porosity in the pastille …………………………………..…... 55 5.4.2.1. Effect of degree of subcooling …………………………..….. 56 5.4.2.2. Effect of surface properties ………………………………..... 57 5.4.2.3. Effect of Reynolds number ………………………………..... 59 5.5. Correlation between total porosity and overall growth rate ………….…. 61 ii CONTENTS 6. COATING OF PASTILLES BY A CRYSTALLIZATION PROCESS .….. 64 6.1. Introduction …………………………………………………………..…. 64 6.2. Material and experiment setup ……………………………………..…… 66 6.2.1. Metastable zone width of coating materials ……………………….. 66 6.2.2. Core materials and procedure of the crystallization coating process 67 6.3. Measurement of metastable zone width ……………………………...….. 68 6.4. Surface nucleation and formation of a coating ………………………….. 71 6.4.1. Surface nucleation ……………………………………………...….. 71 6.4.2. Formation of a coating …………………………………………...... 71 6.4.3. Structure of coating …………………………………………...…… 75 6.5. Surface morphology and thickness of coating ………………………...… 75 6.5.1. Interfacial tension ………………………………………………….. 76 6.5.1.1. Effect of surface properties ………………………………...... 76 6.5.1.2. Effect of concentration of solution ………………………..… 79 6.5.2. Effect of degree of subcooling …………………………………...... 81 6.5.2.1. Degree of subcooling ……………………………………...… 81 6.5.2.2. Growth rate versus supersaturation in a coating process ……. 84 6.5.3. Effect of agitation speed. …………………………………………. 85 7. SUMMARY ………………………………………………………………...…. 88 8. ZUSAMMENFASSUNG ................................................................................... 91 9. NOTATIONS ..................................................................................................... 94 10. REFERENCES ................................................................................................ 98 iii INTRODUCTION 1. INTRODUCTION The development of the chemical process industry has accounted for increasing requirements concerning both quality and physical properties of the final products. Crystallization is one of the fundamental process steps in the final treatment of chemical, pharmaceutical and food products. During the last several decades crystallization technologies have wildly been applied in fields of purification and separation of substances. The field of application for crystallization processes is enlarging. Interest is coming from areas such as the crystalline-formed medicines and the drug delivery system. Complex tablet technologies and coating by spray drying technologies have been wildly employed in the pharmaceutical industry to control the drug dissolution rate. Tableting techniques are commonly used in the production of a solid complex of pharmaceutical materials. The solid complex is, however, still not optimal since there are problems such as fast dissolution, side effects (excipient and binder) and instabilities. To help to solve these problems here a solidification technology is introduced. E.g., the pastillation process is used to obtain the crystalline dosage form (pastilles). This technology brings melts into dispersed crystalline dosage form in high-speed, mono-size distribution and dust free. Crystalline-formed medicines should improve the stability and control the drug delivery system. The contact angle of drops in the field of metal alloys, paintings and coating of materials are wildly investigated as tool to control the size and shape of drops. However, only in a few papers a pastillation technology is examined in the field of pharmaceutical industry. Moreover, no one has considered the crystallization time as an important parameter. The crystallization time is the important parameter for the selection of the optimum production rate and the design of the solidification technology. During the pastillation process the pores and the cracks should be formed in the bodies or on the surface of pastilles. The main reason therefore is the temperature difference between the cooled surface of substrate and the warm molten drops. Both porosity and micro-cracks are critical surface features of pastilles, especially, in drug delivery systems concerning stability. However, investigations of porosity (micro-pores and cracks) in pastilles have not been studied until today. A mercury porosimeter and SEM 1 INTRODUCTION technologies are employed to characterize the porosity in the pastilles. The first and second part of this work therefore describes the rule of the contact angle, the crystallization time of drops, the phenomenon of formation of pores in pastillation processes and the correlation between the porosity and the crystallization kinetics. Another common method to control dissolution rates of drugs in pharmaceutical industry is a coating. Often the coating results from a spay drying coating process with an atomizer. It is one of the oldest pharmaceutical coating processes that still is used today. These processes are, however, not suitable for an application to all areas of pharmaceutical materials because of non-uniformities and non-crystallinities of the coatings. A cracking phenomenon takes place in the coatings and the coatings are sticking on each other. One of the technologies to solve these problems is a production of a crystalline-formed coating. Here comes the option of an application of crystallization processes into the game. The merits of a coating process by crystallization are compact equipment, no necessity to use binders and/or additives and the ability to control the coating thickness. The main idea of a crystallization coating process is that core materials (drugs/foods) act as heterogeneous seeds in supersaturated solutions. One prior study [DOR97] has reported results of crystal growth on a surface of heterogeneous seeds and the formation of coatings in the supersaturated solution. Dorozhkin elucidated that the mechanism of coating formation is only an agglomeration. Here, however, it will be clarified that the formation of coatings in the supersaturated solutions is a combination