1 Abstract Charles University in Prague, Faculty of Pharmacy in Hradci Králové Department of: Pharmaceutical Technology Consultant: Doc. PharmDr. Zdeňka Šklubalová, Ph.D. Student: Barbora Jonášová Title of Thesis: Flow equation. Sorbitol and magnesium stearate. This thesis describes influence of the addition of magnesium stearate on bulk properties to size fractions of sorbitol for direct compression in the range 0,100 - 0,346 mm. I studied influence of particle size and the size of the opening hopper to the gravitational speed of flow. The dependence of the flow rate (g/s) on the size of the opening conical hopper was modeled by the squares equation Jones-Pilpel. No significant effect of addition of magnesium stearate 0,5% and 1,0% for the exponent equation was found. This model allows the re-estimation of the flow rate with an accuracy about 11% for the size fraction regardless of the amount of added magnesium stearate; for polydisperse MS200 is the deviation of the experimentally determined values of the flow rate of approximately 19%.

Charles University in Prague, Faculty of Pharmacy in Hradci Králové Department of: Pharmaceutical technology Consultant: doc.PharmDr.Zdeňka Šklubalová, Ph.D Student: Hana Čermáková Title of Thesis: Flow equation. Sorbitol In this diploma thesis, the granulometric, bulk and consolidation properties of sorbitol for direct compression are studied. The effect of particle size on bulk and tapped density, angle sprinkles and the flow rate through the model conical hopper with a different orifice diameter are examined. The relationship of the flow rate (g/s) of particle size fractions on the orifice diameter is modelled by the Jones-Pilpel equation with the accuracy of the flow rate prediction approximately 10 %.

In some diseases it is preferable that the drugs used in their treatment are released in the colon. The colon is also suitable for systemic delivery of a variety of drugs. A variety of systems have been developed for the purpose of achieving colonic targeting. These approaches are either drug-specific (prodrugs) or formulation specific (coated or matrix preparations) and depends on the pH, transit time and pressure or bacteria in the colon. Different polymers, like chitosan, have been evaluated for their susceptibility to degradation by these bacterial enzymes. Chitosan is considered a good candidate for bacterial degradation and is widely available at low cost and has favourable biological properties. To investigate the influence of formulation factors on the properties of chitosan minitablets, it was necessary to ensure that the chitosan had satisfactory powder flow characteristics to ensure uniform compression in the tablet press and to prevent unacceptable variation in the tablet properties such as weight, thickness, disintegration and strength. Moisture content of the powder, particle size and the inclusion of glidants had an effect on the flowability and it could be improved from a composite flow index value of 32.7 to a value of 58.8. The compressibility of chitosan is very poor and different factors that might influence it, was investigated. Compression forces of between 15 and 20 bar resulted in tablets with acceptable physical characteristics. An increase in moisture content, using the powder fraction > 212 ym as well as a decrease in powder weight resulted in tablets with a higher tensile strength. Lower compression forces resulted in tablets that are extremely porous. This suggests that the chitosan can only be compressed at high compression forces which are difficult to obtain using a standard tablet press. The standard tablet press was therefore modified to fill more powder in the die and generate higher compression forces. Minitablets were compressed and the dissolution of isoniazide from these tablets was investigated. Varying the punch depth or the compaction of the powder did not result in the desired slower release of the drug as a result. The porosity of the tablets compressed at all the punch depth settings and compaction percentages was probably too high to have an effect on the wettablity of the tablets and as a result on the dissolution of the isoniazide from the tablets. The inclusion of excipients such as citric acid (an organic acid which would lower the pH in the tablet, allowing the chitosan to form a gel) and pectin (which would form an insoluble complex with the chitosan) into the formulation delayed the dissolution of the isoniazide from the minitablets. Coating of the minitablets with an enteric coating (Eudragit S ®) initially delayed the dissolution of the isoniazide and would protect the tablets from the harsh environment of the stomach so that the tablets will reach the colon and release the drug. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007

Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007

In some diseases it is preferable that the drugs used in their treatment are released in the colon. The colon is also suitable for systemic delivery of a variety of drugs. A variety of systems have been developed for the purpose of achieving colonic targeting. These approaches are either drug-specific (prodrugs) or formulation specific (coated or matrix preparations) and depends on the pH, transit time and pressure or bacteria in the colon. Different polymers, like chitosan, have been evaluated for their susceptibility to degradation by these bacterial enzymes. Chitosan is considered a good candidate for bacterial degradation and is widely available at low cost and has favourable biological properties. To investigate the influence of formulation factors on the properties of chitosan minitablets, it was necessary to ensure that the chitosan had satisfactory powder flow characteristics to ensure uniform compression in the tablet press and to prevent unacceptable variation in the tablet properties such as weight, thickness, disintegration and strength. Moisture content of the powder, particle size and the inclusion of glidants had an effect on the flowability and it could be improved from a composite flow index value of 32.7 to a value of 58.8. The compressibility of chitosan is very poor and different factors that might influence it, was investigated. Compression forces of between 15 and 20 bar resulted in tablets with acceptable physical characteristics. An increase in moisture content, using the powder fraction > 212 ym as well as a decrease in powder weight resulted in tablets with a higher tensile strength. Lower compression forces resulted in tablets that are extremely porous. This suggests that the chitosan can only be compressed at high compression forces which are difficult to obtain using a standard tablet press. The standard tablet press was therefore modified to fill more powder in the die and generate higher compression forces. Minitablets were compressed and the dissolution of isoniazide from these tablets was investigated. Varying the punch depth or the compaction of the powder did not result in the desired slower release of the drug as a result. The porosity of the tablets compressed at all the punch depth settings and compaction percentages was probably too high to have an effect on the wettablity of the tablets and as a result on the dissolution of the isoniazide from the tablets. The inclusion of excipients such as citric acid (an organic acid which would lower the pH in the tablet, allowing the chitosan to form a gel) and pectin (which would form an insoluble complex with the chitosan) into the formulation delayed the dissolution of the isoniazide from the minitablets. Coating of the minitablets with an enteric coating (Eudragit S ®) initially delayed the dissolution of the isoniazide and would protect the tablets from the harsh environment of the stomach so that the tablets will reach the colon and release the drug. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007

Charles University, Faculty of Pharmacy in Hradec Králové Department of: Department of Pharmaceutical Technology Consultant: doc. PharmDr. Zdeňka Šklubalová, Ph.D Student: Kristýna Kýhosová Title of Thesis: Study of flow and consolidation behaviour of lactose This diploma thesis studies flow and consolidation behaviour of three types of lactose, which differed in the methode of manufacture (crystalization, milling, spray drying). Particle size distribution was characterized by the sieve analysis. The bulk and tapped density, the angle of repose, the flow rate through an orifice of the hopper and true density measured by helium pycnometer were evaluated. The volume changes of powder bed and porosity during consolidation in the relationship on gravitational tapping were studied. To describe the consolidation process, the exponentional mathematical model was used, which made possible to calculate N1/2, that shows the number of taps needed to reach one half of the powder volume reduction. The values noted for lactose were in the range of 3-5.8.

7 2 Abstract Charles University in Prague, Faculty of Pharmacy in Hradci Králové Department of: Pharmaceutical Technology Consultant: doc. PharmDr. Zdeňka Šklubalová, Ph.D. Student: Alexandra Šofranková Title of Thesis: Fractal aspects of flow and consolidation behaviour of microcrystalline cellulose The object of this diploma thesis was to study the flow and consolidation characteristics of three types of microcrystalline cellulose. The granulometric characteristics, including the linear fractal dimension, were estimated using the optical microscopy. The bulk and tapped density, the angle of repose and the flow rate through an orifice of the hopper were evaluated. True density of the materials and the porosity of a loose powder bed were determined by helium pyknometry. The changes of density by the gravity consolidation were studied; the relationship of Hausner ratio on the number of taps describes best the differences in the consolidation behaviour of the substances. Modelling the consolidation kinetic by the exponential law allowed to determine the parameter N1/2, which shows the number of taps needed to reach one half of the powder volume reduction. The values of N1/2 within a range of 6,9-18 correlated well with the particle size of the used types of microcrystalline cellulose.

Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of: Pharmaceutical Technology Consultant: doc. PharmDr. Zdeňka Šklubalová, Ph.D. Student: Michaela Bérešová Title of Thesis: Study of consolidation behaviour of lactose and its blends Flow behaviour and consolidation properties are important characteristics of the powder substances. The aim of this thesis was to evaluate these properties for four types of lactose with different particle size and for the mixtures of two lactoses with different flow properties. The density and porosity of the powder bed and their changes during the consolidation due to the gravitational tapping were studied. The non-linear regression equation was used to describe the consolidation process for the samples and the parameter N½, which expresses the number of taps needed to achieve a half reduction of a powder bed volume. The value of N½ increased with the decrease in the particle size.

Yes / Objectives: Cocrystallization of sulfadimidine (SDM) with suitable coformers, such as 4-aminosalicylic acid (4-ASA), combined with changes in the crystal habit can favourably alter its physicochemical properties. The aim of this work was to engineer SDM:4-ASA cocrystals with different habits in order to investigate the effect on dissolution, and the derived powder properties of flow and compaction. Methods: Cocrystals were prepared in a 1:1 molar ratio by solvent evaporation using ethanol (habit I) or acetone (habit II), solvent evaporation followed by grinding (habit III) and spray-drying (habit IV). Key findings: Powder X-ray diffraction showed Bragg peak position was the same in all the solid products. The peak intensity varied, indicating different preferred crystal orientation confirmed by SEM micrographs: large prismatic crystals (habit I), large plate-like crystals (habit II), small cube-like crystals (habit III) and microspheres (habit IV). The habit III exhibited the fasted dissolution rate; however, it underwent a polymorphic transition during dissolution. Habits I and IV exhibited the highest Carr’s compressibility index, indicating poor flowability. However, habits II and III demonstrated improved flow. Spray drying resulted in cocrystals with improved compaction properties. Conclusions: Even for cocrystals with poor pharmaceutical characteristics, a habit can be engineered to alter the dissolution, flowability and compaction behavior. / Science Foundation Ireland. Grant Number: SFI/12/RC/2275

Approximately 80% of pharmaceutical products and the ingredients required for their manufacture are in powder form. The solid dosage form (tablets and capsules) is manufactured by either dry-blending of fine powder ingredients or combining the ingredients in a wet granulation step, followed by drying. Arching, ratholing, caking, segregation and flooding are some of the commonly encountered flow problems in the handling of fine powders. These problems lead to losses worth thousands of dollars at production scale. Poor powder flowability is a consequence of the combined effects of many variables, including improper equipment design, particle size, size distribution, shape, moisture content and surface texture. In the present work, a systematic study has been performed to determine the relationship between the flowability of fine powders and their physical properties of mean size and size distribution, density and shape.<p> Flowability studies were done on six different powders: the NutraSweet® Brand sweetener (aspartame), Respitose ML001, Alpha-D-Lactose monohydrate, the pharmaceutical binder Methocel (R) F50 Premium Hydroxypropyl methylcellulose- HPMC, a placebo pharmaceutical granulate, and common pastry flour. Scanning electron microscopy (SEM) and stereomicroscopy were used for particle shape and size analysis. Particle size distribution was determined using the laser light scattering technique. Powder flowability was measured using shear strength, angle of repose, and tapped-to-bulk density measurements. A novel method of measuring the dynamic angle of repose using electrical capacitance tomography (ECT) was developed. <p> Analysis of the images from microscopy revealed that the particles of aspartame and HPMC powders were elongated, the particles of ML001, pastry flour and lactose monohydrate powders were irregular, and the particles of placebo granulate were nearly spherical. Particle size was found to be the most reliable indicator of powder flowability, with decreasing particle size corresponding to lower flowability; however other parameters such as particle elongation and irregularity, were also found to have an influence on powder flowability. Although HPMC and pastry flour had similar particle sizes, they exhibited differences in flowability. This can be explained by the greater irregularity of the flour particles. Particle irregularity may cause mechanical interlocking between the particles, thus reducing powder flowability. ECT was found to be a promising non-intrusive tool for the measurement of the dynamic angle of repose. Unlike other methods for the measurement of dynamic angle of repose, the results obtained from ECT were not influenced by the effect of end caps. The present technique could be used by pharmaceutical industries in process analytical technology (PAT) for the detection and elimination of potential flow problems early in the manufacturing process.