Characterization of hypromellose hydrophilic matrix tablets swelling with a texture analyzer

Hidrofilni ogrodni dostavni sistemi so pomemben del inovativne in generične industrije, tako v fazi razvoja novega izdelka, kot v fazi podaljšanja njegovega življenjskega cikla. Najpogosteje uporabljen funkcionalni polimer za dosego podaljšanega sproščanja zdravilne učinkovine (ZU) iz tovrstnih sistemov je hipromeloza. Ta ob stiku z medijem hitro hidratira in na površini sistema tvori gelsko plast, ki preko mehanizmov difuzije in erozije pogojuje sproščanje ZU. V sklopu magistrskega dela smo proučevali vpliv s funkcionalnostjo povezanih lastnosti hipromeloze (viskoznost, stopnja substitucije in velikost delcev), nazivne viskoznosti 4000 mPas in substitucijskega tipa 2208 na sproščanje dobro topne modelne ZU. Da bi bolje razumeli mehanizem in posledično kinetiko sproščanja ZU, smo poleg testov sproščanja (USP II, 150 rpm, obteževalci, pH 6,8) in modeliranja dobljenih rezultatov raziskali lastnosti formirane gelske plasti. Za namene vrednotenja njene debeline in mehanske odpornosti smo ovrednotili uporabo naprave za merjenje natezne trdnosti. Ugotovili smo, da sta profila sproščanja ZU iz direktno stiskanih hidrofilnih ogrodnih tablet na osnovi hipromeloze z večjimi delci in nižjim deležem hidroksipropoksi funkcionalnih skupin različna. Torej je formulacija nerobustna, občutljiva na razlike s funkcionalnostjo povezane lastnosti hipromeloze. Sproščanje ZU sledi anomalnemu (ne-Fickov) transportu. Viskoznost je edina s fukcionalnostjo povezana lastnost hipromeloze, ki vpliva na mehanizem – prispevek difuzije ZU in erozije ogrodja k sproščanju ZU. V debelini gelske plasti v pozitivni smeri izstopata vzorca hipromeloze z večjimi delci in nižjim deležem hidroksipropoksi skupin, ki z nezadostno hitrostjo vzpostavita manj koherentno gelsko plast, kar ima za posledico hitrejši privzem medija v tableto in večji obseg raztopljenih komponent. V začetnih točkah profila sproščanja se pokaže predvsem vpliv velikosti in oblike delcev na privzem medija oz. debelino gelske plasti. Debelina gelske plasti je funkcija časa hidratacije oz. nabrekanja polimernega sistema, s časom se privzem medija upočasni. Formulacija z večjimi delci je manj odporna na penetracijo tipala v primerjavi s formulacijo, v katero vstopajo delci hipromeloze z večjim deležem hidroksipropoksi skupin, kar korelira z večjo debelino gelske plasti. Gelska plast formulacije z nižjim deležem hidroksipropoksi skupin je manj mehansko odporna od formulacije z večjim deležem hidroksipropoksi skupin, posledično bolj dovzetna na erozijo v preizkušanih pogojih. Korelacija med mehansko odpornostjo in časom hidratacije oz. nabrekanja je negativna. Z dodatno testiranimi vzorci smo pokazali, da izbira tehnološkega postopka pomembno vpliva na lastnosti gelske plasti, ki so tudi časovno odvisne.Hypromellose is the most commonly used functional polymer to achieve a prolonged release of active ingredient (API) from these systems. In contact with the medium, hypromellose quickly hydrates and forms a gel layer on the surface of the system that determines the release rate of API through the mechanism of diffusion and erosion. This thesis examines the influence of functionality-related characteristics of hypromellose (viscosity, degree of hydroxypropyl substitution, and particle size), the apparent viscosity of 4000 mPas and the 2208 substitution type on the release of the soluble model API. Apart from testing the drug release (USP II, 150 rpm, sinkers, pH 6,8) and modelling the obtained results, the characteristics of the formed gel layer were studied to better understand the mechanism and consequently the kinetics of API release. The use of texture analyser was evaluated to determine the thickness and mechanic resistance of the gel layer. It has been established that there was a difference in the profiles of API release from the directly compressed hydrophilic matrix tablets based on the hypromellose with larger particles and with a lower proportion of hydropropoxy functional groups. Therefore, the formulation was non-robust and sensitive to differences in the functionality-related characteristics of hypromellose. The release of API followed the anomalous (or non-Fickian) transport. Viscosity was the only functionality-related characteristic of hypromellose which affected the mechanism – the contribution of the API diffusion and the matrix erosion to the release of API. Regarding the thickness of the gel layer, there were two formulations that stood out in a positive direction: with larger particles and with a lower degree of hydropropoxy groups. These two established a less coherent gel layer with insufficient speed, which caused a faster water penetration into the matrix and a higher proportion of dissolved components. The gel layer thickness was a function of hydration or swelling time of the systemin time the medium penetration slowed down. The formulation with larger particles was less resistant to the probe penetration than the formulation with hypromellose with a higher degree of hydropropoxy substitution. This was in correlation with a thicker gel layer. A gel layer of the formulation with a lower degree of hydropropoxy substitution had lower gel layer rigidity than the formulation with a higher degree of hydropropoxy substitution and was consequently more susceptible to erosion in the testing conditions. The correlation between the gel layer rigidity and the hydration or swelling time was negative. The additionally tested samples have indicated that the choice of technology had a significant influence on the gel layer properties, which were also time-dependent