Water mediated solid state transformations of a polymorphic drug – effect on pharmaceutical product performance
Date
2015-07-06
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Abstract
Raviained võivad esineda erinevate tahke aine vormidena (polümorfsed vormid, solvaatvorm, amorfne aine). Kuna erinevatel tahke aine vormidel on erinev molekulide paigutus struktuuris, siis võivad neil esineda erinevad füsikokeemilised omadused nagu lahustuvus, lahustumiskiirus ja füüsikaline stabiilsus. Käesoleva uurimistöö eesmärgiks oli uurida halva vesilahustuvusega polümorfse raviaine piroksikaami (PRX) erinevate tahke aine vormide omadusi. Samuti tehti kindlaks vee mõjul toimuvad tahke aine vormide omavahelised üleminekud ning uuriti antud üleminekute biofarmatseutilist mõju.
Kasutatud mudelraviaine lahustuvus ja lahustumiskiirus sõltusid kasutatud tahke aine vormist. PRX-I tahke aine vormidest vabanes in vitro dissolutsioonikatsetes kapslitest kõige kiiremini amorfse tahke dispersioonina valmistatud PRX (SD). Raviaine vabanemiskiiruselt paremuselt teine tulemus saadi PRX-i veevaba esimese polümorfse vormiga (AH) ja kõige aeglasem vabanemiskiirus oli piroksikaam monohüdraadil (MH). Kasutades Raman spektroskoopiat tuvastati, et MH jäi lahustumiskeskkonnas stabiilseks, samas kui AH ja SD kristalliseerusid vastavalt 220 ja 10 minuti jooksul MH-na. Samuti tuvastati, et amorfse PRX kasutamine SD-na parandas märgatavalt raviaine biosaadavust võrreldes kristalliliste tahke aine vormidega (AH ja MH). PRX säilitas amorfse vormi SD-s kuue kuu jooksul, kui teda säilitati madala õhuniiskuse juures. Kõrgema õhuniiskuse juures (40% ja 75% suhtelist õhuniiskust) toimus raviaine kristalliseerumine AH ja MH-na vastavalt ühe ja kolme kuu jooksul. Raman spektroskoopia võimaldas uurida vee mõjul toimuvaid PRX-i tahke aine vormide muutuseid pelletite katmise ajal. Katse käigus tuvastati, et AH ja MH säilitavad oma algse tahke aine vormi, samas kui amorfne piroksikaam SD-s kristalliseerus 10 minuti jooksul MH-na.
Many drugs can exist in different solid-state forms (e.g., crystalline, amorphous, hydrates/solvates, co-crystals). As given forms differentiate from each other by the arrangement of molecules towards each other in three-dimensional space, they have different physicochemical properties such as dissolution rate, solubility and physical stability. The main goal of the present study was to investigate the properties of the solid state forms of a poorly water-soluble model drug piroxicam (PRX). Emphasis was given on the water-mediated solid state transformations that may occur during pharmaceutical processing and storage. Also the biopharmaceutical relevance of these solid state transformations was revealed. The model drug exhibits a clear solid-state dependent dissolution. Amorphous PRX (in solid dispersion, SD) was shown to have an improved dissolution rate compared to its crystalline counterparts (PRX anhydrate form I, AH and monohydrate, MH). It was also discovered that MH remained stable in a dissolution medium while AH and SD recrystallized as MH within 220 and 10 minutes, respectively. Amorphous PRX (in SD) was shown to have an improved oral bioavailability in rats compared to its crystalline counterparts AH and MH). The present SDs were physically stable in powder form under low humidity (0% RH) and low to room temperature (6 °C and 25 °C) conditions for at least six months. Aging at higher humidity (40% and 75% RH) and at room temperature (25 °C) caused amorphous PRX (in SDs) to recrystallize as a AH or MH within one month and two to three months, respectively. Water-mediated solid- state process-induced transformations (PITs) of amorphous PRX can occur during aqueous-based drug-layer coating of pellets, and solid-state change can be verified using Raman spectroscopy. AH and MH were stable during drug-layer coating, but amorphous PRX in solid dispersion (SD) crystallized as MH already after 10 minutes of coating.
Many drugs can exist in different solid-state forms (e.g., crystalline, amorphous, hydrates/solvates, co-crystals). As given forms differentiate from each other by the arrangement of molecules towards each other in three-dimensional space, they have different physicochemical properties such as dissolution rate, solubility and physical stability. The main goal of the present study was to investigate the properties of the solid state forms of a poorly water-soluble model drug piroxicam (PRX). Emphasis was given on the water-mediated solid state transformations that may occur during pharmaceutical processing and storage. Also the biopharmaceutical relevance of these solid state transformations was revealed. The model drug exhibits a clear solid-state dependent dissolution. Amorphous PRX (in solid dispersion, SD) was shown to have an improved dissolution rate compared to its crystalline counterparts (PRX anhydrate form I, AH and monohydrate, MH). It was also discovered that MH remained stable in a dissolution medium while AH and SD recrystallized as MH within 220 and 10 minutes, respectively. Amorphous PRX (in SD) was shown to have an improved oral bioavailability in rats compared to its crystalline counterparts AH and MH). The present SDs were physically stable in powder form under low humidity (0% RH) and low to room temperature (6 °C and 25 °C) conditions for at least six months. Aging at higher humidity (40% and 75% RH) and at room temperature (25 °C) caused amorphous PRX (in SDs) to recrystallize as a AH or MH within one month and two to three months, respectively. Water-mediated solid- state process-induced transformations (PITs) of amorphous PRX can occur during aqueous-based drug-layer coating of pellets, and solid-state change can be verified using Raman spectroscopy. AH and MH were stable during drug-layer coating, but amorphous PRX in solid dispersion (SD) crystallized as MH already after 10 minutes of coating.
Description
Väitekirja elektrooniline versioon ei sisalda publikatsioone.
Keywords
piroksikaam, ravimidisain, tahked ravimvormid, amorfsed ained, lahustuvus, biosaadavus, stabiilsus, piroxicam, drug design, solid drugs, amorphous state of matter, solubility, bioavailability, stability