Browsing by Subject "valuvuus"
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(2019)Background: Continuous manufacturing has been utilized for decades in many industries since it has many advantages compared to batch manufacturing. Therefore the interest towards continuous processes has arisen also in the pharmaceutical industry. Also, the strict regulations characteristic of pharma industry have started to change more favorable towards continuous manufacturing when the possibilities of continuous processes to produce higher quality products faster and more efficiently, have been proven in many researches. Objectives: Objectives of this thesis were to clarify the effect of the material characteristics on material flowability from continuous feeders and to study how different toolings, like feeding screws, affect the feeding of materials with different characteristics. Based on these results, a possibility to model the feeding results of a material based on only some measured material characteristics was also under investigation. The aim was to develop a clear and systematic procedure which would simplify the determination of the most suitable equipment when starting to feed a new material. Methods: The similarity of flowability of various pharmaceutical powders from continuous feeders was studied. First material characteristics affecting material flowability from a feeder based on literature was determined from 26 pharmaceutical powders. Following this, six materials were chosen to be studied with gravimetric powder feeders using different kinds of research frames. The six materials formed three material pairs, in which two materials had clear similarities in the flowability characteristics. The reason for this was that the flowability from feeders with similar materials could be compared. The feeding of materials was determined investigating the feed rate capacity and accuracy of feed rate of material. Also, the effect of feeder screws and the speed of the screws on the feeding capability of a material was investigated. A model to predict the feeding result based on material characteristics was built using PLSand MLR-methods. Results: The prediction of material feeding was not possible with PLS- and MLR-modeling methods. The feeding of similar materials was wound to be alike. Poor flow characteristics correlated with poor feeding results. PCA- and cluster analysis were found suitable to define the similarity of materials. Conclusions: The success of feeding of pharmaceutical powders is clearly affected by the material flowability properties. The feeding screws and screw speed affect the feeding accuracy, too. The prediction of feeding results of specific material, would need much more data to produce valid and trustworthy models. However, it seems highly possible to be able to build a model with more materials.
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(2019)Flowability of powders is in critical role when manufacturing the most popular dosage forms, tablets and capsules, of pharmaceutical industry. Re-formulation is expensive and time-consuming, so it is important to determine powder flow properties at the initial stage of drug development prior to tabletting and encapsulation processes. There are many different methods, like shear cell, flow through an orifice and bulk and tapped density, to examine powder flowability. Despite the methods, the most reliable means of examining powder flowability is often empirical. In early stages of drug development, it would be good to have faster, more reliable and cheaper methods to examine powder flowability. FT4 Powder Rheometer is a relatively new flowability characterization technique. The aim of this study is to find out whether the library created using the FT4 Powder Rheometer methods makes it possible to characterize the rheological properties of solids in the early stages of drug development. In addition, the aim is to investigate whether FT4 Powder Rheometer methods can predict the success of masses in tableting and encapsulation processes. The information gained from the research can be used in the future, for example, in continuous processes, because flowability plays an important role, especially in the supply of raw materials to the process, which is the most important division of continuous processes. To the library were selected for particle size and shape 15 different types of material. These materials were subjected to five different FT4 Powder Rheometer basic test methods. In addition, the particle size and shape of the materials and the flow through an orifice and the bulk and tapped density were determined to support the results of the powder rheometer. The principal component analysis was used to process the results. As the tablet and capsule masses examined, the masses of a previous study were utilized. Those masses were tableted and encapsulated in that previous study. These tablet and capsule masses contain a variable amount of cohesive drug substance. FT4 Powder Rheometer methods provide more complex information about materials and their behaviour than conventional flowability test methods. From the powder rheometer parameters pressure drop, compressibility and specific energy distinguish the cohesive and the non-cohesive materials, because the cohesive materials with these parameters obtain clearly higher values than non-cohesive materials. Additionally, the cohesion of FT4 Powder Rheometer shear cell test mainly distinguishes highly cohesive materials from other materials. The flow rate index makes it possible to separate the materials to which the change in flow rate particularly affects. Fluidizing materials, due to the air flow, are distinguished by the aeration test. Avicel PH-102 could be used as a rough limit value for well and poorly flowing materials in the created library (excluding the aeration and shear cell test). Stability index -, flow rate index -, specific energy -, pressure drop -, and compressibility-results of the FT4 Powder Rheometer correlated to the proportional proportion of the cohesive drug in the mixture. These parameters could possibly be used to distinguish mixtures containing the cohesive material. Additionally, specific energy, compressibility, pressure drop, basic flowability energy, stability index and flow rate index correlated with the weight variation of the tablets. With these parameters one could possibly assess the tabletability of the mixtures. A much larger library is needed to evaluate and predict the rheological properties of new materials. FT4 Powder Rheometer can possibly be used to predict the tableting success of tablet and capsule masses. This would be interesting to look more extensively, for example as part of a library. Additionally, it would be good to investigate whether the results of powder rheometer correlate to continuous production.
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(2020)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.
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(2020)Tiivistelmä/Referat – Abstract Tausta: Biotiinia markkinoidaan erityisesti sen hiuksien ja kynsien kasvua edistävien vaikutuksien perusteella, ja sen käyttö on yleistynyt viime vuosina. Suuriannoksista 100 mg:n biotiinia on käytetty myös MS-taudin hoidossa. Suomen lääkemarkkinoilla ei ole suuriannoksisia suun kautta otettavia valmisteita. 100 mg:n biotiinitabletteja ei löydy koko maailman lääkemarkkinoilta. Yliopiston Apteekki valmistaa 100 mg:n biotiinikapseleita sairaalakäyttöön. Manuaalinen biotiinikapseleiden valmistus on resursseja intensiivisesti kuluttava prosessi. Biotiinin fysikoteknisiä ominaisuuksia kuten kideominaisuuksia, valuvuutta, hygroskooppisuutta, todellista tiheyttä ja puristuvuusominaisuuksia ei ole aiemmin julkaistu kirjallisuudessa. Tavoitteet: Gradutyön tavoitteena oli kartoittaa, onko suuriannoksisia biotiinitabletteja mahdollistaa valmistaa teollisen mittakaavan prosessina. Tuotekehityksen päätöksenteon tukemiseksi gradutyön tavoitteena oli myös kartoittaa biotiinin fysikoteknisiä ominaisuuksia. Pääasiallisena tavoitteena oli kehittää biotiinitablettien suorapuristusvalmistusmenetelmä, mutta tutkia myös märkärakeistusmenetelmän soveltuvuutta. Menetelmät: Raaka-aineiden kidemuotoa tutkittiin röntgenjauhediffraktometrilla, partikkelikokoa ja partikkelikokojakaumaa laservelosimetrillä, ja puristumiskäyttäytymistä tabletoitavuuskokeilla sekä Heckel-analyysillä. Raaka-aineiden valuvuutta tutkittiin kaato- ja tärytiheysmittauksilla. Biotiinitablettien valmistusta tutkittiin kuudella tabletointikoe-erällä, joista kaksi oli high shear- märkärakeistuksella tehtyjä ja neljä suorapuristusprosesseja. Tableteille suoritettiin Euroopan farmakopean mukaisia laatutestejä kuten murenevuus-, hajoamis-, ja dissoluutiotestit. Tulokset: Tabletteihin käytetyn biotiinilaadun partikkelikokojakauma oli leveä, ja keskimääräinen partikkelikoko 58 µm. Biotiinikiteet ovat muodoltaan hiutalemaisia. Biotiini oli α-kidemuotoa, ja sen kidemuoto ei muuttunut high shear- märkärakeistuksen seurauksena. Biotiinilaadun valuvuus oli äärimmäisen huono. Biotiini ei osoittautunut erityisen hygroskooppiseksi. Biotiini on haurasta, ja puristuessaan se muotoutuu murtumalla. Puhdasta biotiinia ei saa puristettua koossa pysyväksi tabletiksi, sillä suurillakin puristusvoimilla valmistettuihin tabletteihin muodostuu kansi, josta tabletti lähtee herkästi murenemaan. Biotiini tarttuu tablettikoneen painimiin ja aiheuttaa ongelmia muotista poistettaessa suuren kitkavoiman takia. High shear- märkärakeistusprosessin tabletointikoe-erät onnistuivat sekä epäkesko- että rotaatiotablettikoneella. Kaksi rotaatiotablettikoneilla suoritettua suorapuristuskoe-erää jouduttiin keskeyttämään jauhemassan juututtua syöttöastiaan. Kaikkien koe-erien tablettien biotiinin liukeneminen oli hidasta, sillä keskimäärin 45 minuutin kohdalla tablettien biotiinista oli liuennut 63-73 %. Johtopäätökset: Biotiinitablettien formulaation tärkeimmäksi optimoitavaksi ominaisuudeksi osoittautui massan valuvuus. High shear- märkärakeistus paransi merkittävästi massan valuvuutta. Märkärakeistuskoe-erien tablettien painonvaihtelu oli hyvin pientä. Kaikkien koe-erien merkittävänä haasteena oli kuitenkin biotiinin hidas vapautuminen tableteista. Biotiinitablettien jatkokehityksen tulisikin keskittyä dissoluutiota nopeuttavien toimenpiteiden tutkimiseen. Tuotekehitys hyötyisi erityisesti uuden, tehokkaamman, ultrakorkean suorituskyvyn nestekromatografiamenetelmän kehittämisestä biotiinitablettien annosanalytiikkaan. Märkärakeistuskoe-eriä tulisi tehdä eri prosessiparametritasoissa sekä eri apuaineilla ja apuaineiden pitoisuuksilla. Koe-erien suunnittelussa tulisi hyödyntää tilastollista koesuunnittelua muuttujien välisien interaktioiden vaikutuksien havaitsemiseksi, ja tuotantoprosessin sekä lopputuotteen tehokkaan optimoinnin varmistamiseksi.
Now showing items 1-4 of 4