Suitabaility assessment of in-line image analysis method for monitoring mini-tablet film thickness

Mini tablete predstavljajo sodobno farmacevtsko obliko, ki omogoča prilagodljivo odmerjanje za dosego želenega učinka in olajšano peroralno aplikacijo. Za njihovo izdelavo lahko uporabimo dobro uveljavljene proizvodne procese, med katere uvrščamo tudi oblaganje. Cilj magistrske naloge je bil oceniti primernost medprocesne slikovne analize določanja debeline obloge mini tablet za nadzor in vodenje procesa oblaganja. Poleg sestave obloge sta za njeno funkcionalnost ključna tudi njena debelina in enakomernost. V ta namen smo v vrtinčnoslojni komori z disperzijo tartrazina in acidorezistentne obloge oblagali različne oblike mini tablet in primerjalno še pelete. Debelino filmskih oblog smo poleg medprocesne slikovne analize (\u27\u27in-line\u27\u27) spremljali še s statično slikovno analizo (\u27\u27off-line\u27\u27), s pomočjo kljunastega merila in stereo mikroskopa, ki je zaradi neposrednih meritev debeline predstavljal referenčno metodo. Funkcionalnost posameznih nanosov obloge smo preverjali s sproščanjem v medijih z relevantnimi pH vrednostmi in tako preverili zagotavljanje acidorezistence v odvisnosti od nanosa anionskega kopolimera metakrilne kisline in etil akrilata. Točnost posameznih meritev smo ovrednotili z izračunom korena povprečne kvadratne napake. Metodo smo ocenili za točno, če je bila vrednost korena povprečne kvadratne napake manjša kot 5 µm. Ugotovili smo, da nam realnočasna in statična slikovna analiza v primerjavi z referenčno metodo podata dovolj točne rezultate za debelino nanosa na bikonveksnih in ploščatih mini tabletah. Z realnočasno slikovno analizo smo kot točno ocenili tudi nanos filmske obloge na peletah, medtem ko nam enako s statično slikovno metodo ni uspelo. Meritve, ki smo jih opravili s kljunastim merilom so bile glede na rezultate referenčne metode v večini primerov precenjene, napaka pa ni konstantna, zato ocenjujemo, da ta metoda ni primerna za vrednotenje debeline obloge. Na podlagi analiz sproščanja mini tablet in pelet smo ugotovili, da Eudragit®-na obloga z vsaj 15 µm debelo filmsko oblogo zagotavlja acidorezistenco. Za ponovljiv disolucijski profil je v primeru bikonveksnih mini tablet potreben nanos vsaj 19 µm debele filmske obloge. Na proces oblaganja in sproščanja ima vpliv tudi oblika mini tablete. Ugotovljeno je bilo, da bikonveksne mini tablete zagotavljajo acidorezistenco pri nižjih nanosih Eudragit®-ne obloge v primerjavi s ploščatimi mini tabletami.Mini tablets are a contemporary pharmaceutical formulation characterized by a flexible dosing to achieve the desired effect and are patient-friendly. We can use a number of already well-established manufacturing processes for their manufacture, including film coating. In addition to the coating composition, one of the most important coating parameters is its thickness and uniformity. The purpose of the master\u27s thesis was to assess the appropriateness of the in-line image analysis method with purpose of real-time mini-tablets coating thickness evaluation, in order to monitor and control the coating process. Different shapes of mini tablets and additionally pellets were coated in a fluid bed coater with a dispersion containing tartrazine and with various amounts of acid-resistant coatings. In addition to image analysis (in-line, off-line), the thickness of film coatings was also assessed by using a vernier caliper and a stereo microscope. The latter, due to direct thickness measurements, represented the reference method. The functionality of individual coatings was verified by dissolution testing in physiologically relevant media and thus checking the provision of acid-resistance in dependence on the amount of applied Eudragit® coating. Gathered coating thickness measurements from all methods have been analysed with root mean square error (RMSE) analysis. The method was estimated to be accurate if the value of the root mean square error was less than 5 μm. By comparing to the results of the reference stereo microscope method we found out that real-time image analysis with the PATVIS APA system gave us in overall the most accurate results. The thickness of the film coating obtained with static image analysis on the scanner gives precise but not always accurate results. Measurements are in case of pellets about 5-8 μm lower than the true value. Measurements that were performed with the vernier caliper were completely erroneous in the vast majority of cases, therefore we estimate that this method is not suitable for evaluating the thickness of the film coating. Requirements for delayed release of mini tablets in acid stage were met, if the Eudragit® film average coating was at least 15 µm thick. It was estimated that for a reproducible delayed dissolution profile of the biconvex mini tablet, it is necessary to apply at least 19 µm thick Eudragit®coating. Coating application and dissolution depends heavily on the shape of the mini tablets. It has been found that biconvex mini tablets provide acid resistant function at lower amounts of the same Eudragit® coating, when compared to flat mini-tablets