Browsing by Subject "tabletti"

Tiivistelmä/Referat – Abstract Background: Biotin is marketed specifically for its hair and nail growth-promoting effects, and its use has become more common in recent years. High doses of 100 mg biotin have also been used to treat MS. There are no high-dose oral products on the Finnish pharmaceutical market. Biotin 100 mg tablets are not available on the global pharmaceutical market either. The University Pharmacy manufactures 100 mg biotin capsules for hospital use. Manual manufacturing of biotin capsules is a resource-intensive process. The physicotechnical properties of biotin such as crystal properties, flowability, hygroscopicity, true density and compressibility properties have not been previously published in the literature. Objectives: The aim of the thesis work was to investigate whether high-dose biotin tablets can be manufactured as an industrial-scale process. To support product development decision-making, the aim of the master's thesis was also to explore the physicotechnical properties of biotin. The main goal was to develop a method for the direct compression of biotin tablets, but also to study the applicability of the wet granulation method. Methods: The crystal form of the raw materials was examined by X-ray powder diffractometer, particle size and particle size distribution by laser velocimeter, and compression behavior by tabletability tests as well as Heckel analysis. The flowability of the raw materials was studied by bulk and tapped density measurements. The production of biotin tablets was studied with six test batches, two of which were high shear wet granulated and four were direct compression processes. The tablets were subjected to European Pharmacopoeia quality tests such as friability, disintegration, and dissolution tests. Results: The particle size distribution of the biotin grade used in the tablets was wide, with an average particle size of 58 μm. Biotin crystals are flaky in shape. Biotin used was the α-crystalline form and its crystalline form did not change as a result of high shear wet granulation. The flow of the biotin grade was extremely poor. Biotin was not found to be particularly hygroscopic. Biotin is brittle, and when compressed, it forms by fragmenting. Pure biotin cannot be compressed into a stable tablet, as even tablets made with high compression forces will form a lid from which the tablet will easily crumble. Biotin sticks to tablet machine’s punches and causes problems in the ejection phase due to high frictional forces. Test batches of the high shear wet granulation process were successful on both eccentric and rotary tablet machine. Two batches of direct compression tests performed on rotary tablet machines had to be stopped after the powder mass got stuck in tablet machine’s hopper. Biotin tablet’s dissolution was slow for all the manufactured batches, with an average of 63-73 % biotin dissolution at 45 min time point. Conclusions: Main property to be optimized for biotin tablet formulations proved to be mass flowability. High shear wet granulation improved significantly flowability. Weight variance of the tablets in the wet granulation batches was also very small. Biotin’s slow dissolution from the tablets was another significant challenge for all the test batches. Further development of biotin tablets should therefore focus on investigating, which measures accelerate biotin tablet’s dissolution. Product development would particularly benefit from the development of a more efficient, ultra-high performance liquid chromatography method for dose analysis of biotin tablets. Wet granulation test batches should be manufactured at different process parameter levels with different excipients and excipient concentrations. Design of experiments statistical approach should be utilized for these further studies so that factor interactions could be detected, and the manufacturing process and drug product could be efficiently optimized.

3D-imaging is based on combining two or more pictures to form one three-dimensional picture. Most of the methods used provide only surface pictures, but tomography acquires also information about the inside-structure of investigated material. Young's modulus is a method, which has been used for long time to determine toughness hard materials, such as steal. In traditional method a beam-shaped piece is bent. When the size of piece, used force and amount of bending are known, Young's modulus of piece can be calculated. Although the method has traditionally been used to research very hard materials, it has been applied without changes with pharmaceutical materials. It is, however, open to the question whether or not the method is appropriate for those materials. There are also methods to determine Young's modulus based on compressing a tablet or using ultrasound. Determining tablet's toughness with ultimate strength test is complicated because it breaks tablet. For that reason it would be good to find compensatory methods to measure strength of tablet. The aim of the study was to validate Flash Sizer 3D appliance, which is used in 3D-imiging. Another goal was to investigate possible correlations between 3D-imiging, Young's modulus and traditional ultimate strength method. Lastly, the feasibility of Young's modulus as a substitute for traditional ultimate strength measurement in self life studies was investigated. Flash Sizer 3D was validated by measuring particle size distribution of pellets, which were made of microcrystalline cellulose (Cellets). Sizes of the investigated pellets were 100 µm, 200 µm and 500 µm. Also binary mixture of 100 µm and 200 µm was investigated. From microcrystalline cellulose was made tablets and 3D-pictures were taken. Ultimate strength test was made for half of the tablets. Young's modulus was measured from half of the tablets in tableting day, day after that and nine days after tableting. Results show that Flash Sizer 3D is suitable for investigating bigger Cellet. With smaller particles distinguishing of tablets wasn't probably good enough. Still it seems to be quite good method to determine surface roughness of tablet. Young's modulus seems to be very promising as compensating method for traditional ultimate strength measurement. In future in self life studies tablets hardness might be able to investigate by measuring Young's modulus and not measuring ultimate strength. If correlation between Young's modulus and solubility meets the case, Young's modulus might also replace also solubility measurements in self life studies.