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During the past few years, the studies of bi- and multi-layered tablets increased due to the consumption of several different drugs per day by a patient and requests for appropriate patient compliance. The demographic shift toward older population increases the use of combination therapy as polypharmacy. Hydrochlorothiazide (HCTZ), as a model drug, is most commonly used in the treatment of hypertension, congestive heart failure and as a diuretic. The aim of the present study is to investigate the effect of the local environment on dissolution and stability behaviour of HCTZ in fixed multi-layered tablet combinations, which are commonly used in polypharmacy. For this purpose, three different systems were introduced: (i) two conventional tablets (HCTZ and pH modifying placebo), (ii) 2-layer tablets (HCTZ, pH modifying placebo) and (iii) 3-layer tablets (HCTZ, barrier and pH modifying placebo). Disintegration of tablets, dissolution of HCTZ from tablets and HCTZ related substances were monitored for all systems. Results showed that there was a significant difference between dissolution profiles of the conventional two-tablet system (HCTZ tablet and pH modifying tablet) and the 2-layer and 3-layer tablets, which include the pH modifying layer. In the case of the conventional two-tablet system, 85 % of HCTZ was dissolved in less than 15 minutes. The dissolution profiles of HCTZ from 2-layered and 3-layered tablets showed a decrease in the dissolution rate. In addition, during the stability studies, it has been confirmed that the typical degradation product of HCTZ is formed, impurity B (4-amino-6-chloro-1,3-benzenedisulfonamide), which implies formation of formaldehyde as hydrolytic impurity not reported in the Ph. Eur. (16). Both impurities are particularly raised in 2-layered tablets with alkaline and neutral placebo layers. Stability of HCTZ was improved in the case of the 3-layer tablet, where the intermediate separation layer of glycerol monostearate was present. It

The objective of this work was to investigate the influence of selected individual variables (binder content, inlet air temperature, and product endpoint temperature) of in situ fluid bed melt granulation on the granule particle size distribution and percentage of dissolved carvedilol using a three-factor, five-level circumscribed central composite design. Increased binder content had the effect of increasing the granule particle size and drug dissolution rate. The effect of inlet air temperature and product endpoint temperature was found to be more pronounced in case of granule particle size parameters. Within the studied intervals, the optimal quantity of binder as well as optimal process parameters were identified and validated using response surface methodology. Utilizing these optimal process and formulation parameters, successful scaling up of the fluid bed melt granulation process was carried out. Granule characteristics obtained at pilot scale are comparable to those obtained at laboratory scale., V raziskovalnem delu smo z uporabo tri-faktorskega pet-nivojskega središčnega mešanega eksperimentalnega načrta proučevali vpliv izbranih procesnih spremenljivk (delež veziva, temperatura vhodnega zraka in končna temperatura produkta) in situ granulacije s talinami na porazdelitev velikosti izdelanih granul in na delež raztopljenega karvedilola. Ugotovili smo, da povečana količina veziva v formulaciji kaže učinek povečanja velikosti izdelanih granul kakor tudi hitrosti raztapljanja karvedilola. Prav tako smo ugotovili, da temperatura vhodnega zraka in končna temperatura produkta izkazujeta izrazit vpliv na parametre velikosti granul. Z metodo odgovornih površin smo znotraj proučevanih intervalov določili in validirali optimalno količino veziva in optimalne procesne parametre. Z uporabo optimalnih formulacijskih in procesnih parametrov smo tehnologijo in situ granulacije s talinami uspešno prenesli iz laboratorijskega v večje (pilotno) merilo, pri čemer smo zagotovili primerljivost proučevanih lastnosti granulata.