Vpliv pH modifikatorja na stabilnost in raztapljanje hidroklorotiazida v dvoplastnih dostavnih sistemih : doktorska disertacija

Urek, Sandra (author), Srčič, Stanko (mentor)

Farmacevtska podjetja povečujejo razvojno raziskovalne aktivnosti na področju fiksnih kombinacij, na drugi strani pa regulatorne agencije postavljajo vse strožje zahteve v vsebinah (kakovosti, varnosti in učinkovitosti) za pridobitev dovoljenja za promet. Namen te disertacije je proučiti vpliv pH okolja na hidroklorotiazid v zdravilu za peroralno dajanje. V ta namen smo izdelali šest različnih sistemov: (i) sistem dveh tablet (ena s HCTZ in druga placebo z modifikatorjem pH-ja), (ii) dvoplastna biplanarna tableta (HCTZ plast, plast s pH modifikatorjem), (iii) dvoplastna ovalna tableta (HCTZ plast, plast s pH modifikatorjem), (iv) tableta enostavna (zmes HCTZ in pH modifikatorja), (v) troplastna tableta (HCTZ plast, vmesna plast in pH modifikator plast) in (vi) troplastna modificirana tableta (HCTZ plast, vmesna plast z dodatkom super razgrajevala in pH modifikator plast). Rezultati časov razpadnosti so pokazali razliko dvo- in troplastnih tablet v primerjavi s sistemi z dvema mono tabletama. Profili raztapljanja dveh mono tablet kažejo hitrejše raztapljanje v primerjavi z dvoplastnimi in troplastnimi tabletami. Tipičen razgradni produkt HCTZ je nečistoča B, kar posredno pomeni, nastanek formaldehida kot hidrolitske nečistote, ki pa ni deklarirana v monografiji Evropske farmakopeje. Nečistot je kvantitativno več v dvoplastnih tabletah z bazično in nevtralno placebo plastjo. Rezultati kažejo, da se je hitrost raztapljanja HCTZ potencialno lahko še zmanjšala zaradi tvorbe netopnih snovi kot rezultat reakcije med HCTZ in formaldehidom. Tablete s kislim pH modifikatorjem izkazujejo boljšo stabilnost HCTZ. Stabilnost HCTZ je izboljšana tudi v primeru troplastne tablete, kjer je vmesna plast glicerol monostearat. V sistemih troplastnih tablet je še vedno prisotna določena stopnja razgradnje, ki pa jo povezujemo z reakcijo manitola s hidroklorotiazidom ali nastankom soli hidroklorotiazida v bazičnem mikrookolju. Maillardovo reakcijo opazimo v vseh dvoplastnih tabletah, kjer je dodan bazični pH modifikator in poteče med hidroklorotiazidom in eno izmed pomožnih snovi, laktozo monohidratom. Maillardova reakcija je manj izražena v troplastnih tabletah.Rezultati disertacije potrjujejo, da zahteva razvoj večplastnih tablet sistematično raziskovalno in razvojno delo in je specifično za vsako kombinacijo učinkovin, vključenih pomožnih snovi in uporabljano tehnologijo.

• Language: Slovenian
• Keywords: zdravila, peroralna aplikacija, hidroklorotiazid, dostavni sistemi, večplastne tablete, ph modifikatorji, stabilnost, razrapljanje, disertacije
• Work type: Doctoral dissertation
• Typology: 2.08 - Doctoral Dissertation
• Organization: FFA - Faculty of Pharmacy
• Place of publishing: Ljubljana
• Publisher: [S. Urek Blatnik]
• Year: 2015
• Number of pages: 156 str.
• PID: 20.500.12556/RUL-143749
• UDC: 661.12-4(043.3)
• COBISS.SI-ID: 281589504
• Publication date in RUL: 11.01.2023

Secondary language

• Language: English
• Title: Influence of pH modifiers on stability and dissolution of hydrochlorothiazdie [!] in bi-layer delivery system

Abstract

Pharmaceutical companies increase research and development on fixed dose combination and regulatory agencies set strict demands in the content of requirements for obtaining the Marketing Authorization for fixed dose combinations, using several tools to prove quality, safety and efficacy. The aim of the present study is to compare hydrochlorothiazide as a model drug and study the influence of pH environment on the behavior of hydrochlorothiazide. For this purposes six different systems were introduced: (i) two conventional tablets (HCTZ and pH modifying placebo), (ii) bi-layer round tablets (HCTZ, pH modifying placebo), (iii) bi-layer oval tablets (HCTZ, pH modifying placebo), (iv) comprimates (mixture of HCTZ and pH modifying placebo), (v) three-layer tablets (HCTZ, barrier and pH modifying placebo) and (vi) tree-layer tablets (HCTZ, barrier with addition of super desintigrator and pH modifying placebo). Results of desintegartion showed the differences in bi-layer and three-layer tablets in comparison to two conventional tablets. The difference between dissolution profiles of conventional two tablets system (HCTZ tablet and pH modifying tablet) and the decrease in the dissolution rate of bi-layer and three-layer tablets is signifficant. Typical degradation product of HCTZ is formed, impurity B, which implies the formation of formaldehyde as hydrolytic impurity that is not reported in the Ph. Eur.. Impurities are raised by bi-layered tablet with alkaline and neutral placebo layers. It is presumed that HCTZ dissolution rate was decreased due to formation of non-soluble substances because of HCTZ degradation in the presence of alkaline layer. Stability of HCTZ was improved in the case of three-layer tablet, where the intermediate separation layer of glycerol monostearate was present, but still exhibit certain degree of degradation which might happened due to incompatibility of hydrochlorothiazide and manitol. Millard reaction is noticed in all bi-layered tablets where alkaline pH modifiers is added. Millard reaction is reduced in the three-layer tablets, but not completely suspended. It can be concluded, that development of multi-layer tablets demand systematic research and development work and it is specific for each combination of active substances, excipients and used technology.