Formuliranje farmacevtskih učinkovin v polimere s plini visoke gostote

magistrsko delo

Barbara Ljubec (Author), Maša Knez Hrnčič (Mentor), Zoran Novak (Co-mentor), Darija Cör (Co-mentor)

Abstract

Učinkovina fenofibrat izkazuje slabo topnost v vodi in posledično nizko biološko uporabnost v človeškem telesu. Izboljšanje lahko med drugim dosežemo z zmanjšanjem velikosti delcev učinkovine ali formuliranjem v polimer. Ugodno in okoljsko sprejemljivo rešitev predstavljajo visokotlačni procesi z zgoščenimi plini. Za uspešno načrtovanje in izvedbo le teh pa je potrebno dobro poznavanje termodinamskih lastnosti materialov, ki jih želimo obdelati. Magistrsko delo prikazuje preliminarne raziskave termodinamskih lastnosti učinkovine fenofibrata v različnih zgoščenih plinih (CO2, C3H8 in CHF3), natančneje ravnotežne trifazne krivulje (do 40 MPa) in ravnotežne topnosti (pri 303 K, 323 K, 338 K in do 35 MPa) učinkovine v zgoščenem plinu. Vse ravnotežne trifazne krivulje imajo negativen dp/dT naklon in temperaturni minimum. Največji padec temperature tališča zasledimo v CO2 (43 K), nato v C3H8 in CHF3 (20 K). Ravnotežna topnost fenofibrata v plinu se zviša z zvišanjem tlaka oz. gostote pri konstantni temperaturi. Vpliv temperature je različen. Fenofibrat je najbolje topen v C3H8 (do 1,741∙10-4 mol∙mol-1), nato v CHF3 (do 0,671∙10-4 mol∙mol-1) in CO2 (do 0,552∙10-4 mol∙mol-1). Sledijo preliminarne študije termodinamskih lastnosti polimernega nosilca Brij S100. Ravnotežna trifazna krivulja Brij S100/CO2 ima v celotnem raziskanem območju tlakov negativen dp/dT naklon, krivulji Brij S100/C3H8 in Brij S100/CHF3 pa temperaturni minimum, in sicer pri 310,58 K in 30,41 MPa ter pri 326,05 K in 2,15 MPa. Ravnotežna topnost CO2 v Brij S100 je do 0,71 g∙g-1 pri 333 K in 0,64 g∙g-1 pri 353 K in v obeh primerih pri 34,91 MPa. Topnost se zviša z zvišanjem tlaka oz. gostote in z znižanjem temperature. Vpliv temperature je bolj izrazit pri višjih tlakih. Gostota Brij S100/CO2 se v območju tlakom 0,1–30 MPa giblje 1062,95–1076,97 kg∙m-3 pri 333 K in 1045,04–1060,70 kg∙m-3 pri 353 K. Gostota se torej zvišuje z zvišanjem tlaka in z znižanjem temperature. Medfazna napetost Brij S100/CO2 se znižuje s tlakom, in sicer od 29,14 nN∙m-1 pri 0,10 MPa do 3,03 nN∙m-1 pri 27,94 MPa za 333 K ter od 28,00 nN∙m-1 pri 0,10 MPa do 2,62 nN∙m-1 pri 28,05 MPa za 353 K. Vpliv temperature na medfazno napetost je minimalen pri nižjih tlakih in zanemarljiv pri višjih tlakih. Formulacijo fenofibrata v Brij S100 smo izvedli s pomočjo PGSSTM postopka. Na snovi preliminarnih študij smo to storili s plinom CO2, pri 333 K in 10–25 MPa, z 2 g ali 4 g učinkovine na 20 g polimera. Proučevali smo vpliv predekspanzijskega tlaka in koncentracije učinkovine na karakteristične lastnosti dobljenega produkta. Izkoristek procesa se zelo spreminja (31,19–78,48 %), učinkovitost procesa pa je visoka (do 91,12 %). Pri PGSSTM procesu ni prišlo do degradacije učinkovine ali tvorbe stranskih produktov, se pa stopnja kristaliničnosti vzorcev zniža tudi za 65 %. Najmanjša velikost delcev produkta je 47,62 µm; dobljeni pri tlaku 20 MPa in z 2 g učinkovine. Dobljeni delci so v obliki sfer ali poroznih aglomeratov nepravilnih oblik. Profil raztapljanja fenofibrata formuliranega pri optimalnih pogojih se v primerjavi s surovim fenofibratom izboljša za 11 %.

Keywords

fenofibrat;polimer brij S100;zgoščeni plini;termodinamske lastnost;magistrske naloge;

Data

Language:	Slovenian
Year of publishing:	2018
Typology:	2.09 - Master's Thesis
Organization:	UM FKKT - Faculty of Chemistry and Chemical Engineering
Publisher:	[B. Ljubec]
UDC:	544.6.018.47-036.5(043.2)
COBISS:	21791510
Views:	758
Downloads:	103
Average score:	0 (0 votes)
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Other data

Secondary language:	English
Secondary title:	Formulation of pharmaceutical compounds into polymers with gases of high density
Secondary abstract:	The compound fenofibrate is characterized by a low bioavailability in human bodies due to the poor solubility in aqueous solutions. This can be improved by, inter alia, particle size reduction of the substance or its formulation into polymers. Affordable and environmentally acceptable solution represent high-pressure processes with dense gases. For successful designing and performance of this processes, the knowledge of thermodynamic properties of processed materials is crucial. The current thesis represents preliminary studies of thermodynamic properties of compound fenofibrate in different dense gases (CO2, C3H8 in CHF3), particularly equilibrium three-phase curves (up to 40 MPa) and equilibrium solubilities (at 303 K, 323 K, 338 K and up to 35 MPa). All equilibrium three-phase curves have a negative dp/dT slope and a temperature minimum. Fenofibrate has the highest melting point depression under CO2 (43 K), then under C3H8 and CHF3 (20 K). The equilibrium solubility of fenofibrate in dense gas increases with increasing pressure or density at a constant temperature. The effect of temperature is more complex. Fenofibrate is most soluble in C3H8 (up to 1,741∙10-4 mol∙mol-1), then in CHF3 (up to 0,671∙10-4 mol∙mol-1) and CO2 (up to 0,552∙10-4 mol∙mol-1). Below preliminary studies of thermodynamic properties of polymer Brij S100 are presented. The equilibrium curve for Brij S100/CO2 has a negative dp/dT slove over the entire pressure range investigated, while on the contrary, the three-phase curve for Brij S100/C3H8 and Brij S100/CHF3 exhibits a temperature minimum at 310,58 K (30,41 MPa) and at 326,05 K (2,15 MPa), respectively. Equilibrium solubility of CO2 in Brij S100 was up to 0,71 g∙g-1 at 333 K and 0,64 g∙g-1 at 353 K. The solubility increases with increasing pressure or density and also with decreasing temperature. The effect of pressure on solubility is more pronounced at higher pressures. The density of Brij S100/CO2 (up to 30 MPa) is ranging between 1062,95–1076,97 kg∙m-3 at 333 K and 1045,04–1060,70 kg∙m-3 at 353 K. Therefore we can say that the density increases with increasing pressure and with decreasing temperature.The interfacial tension of Brij S100/CO2 decreases with pressure, particularly at 333 K from 29,14 nN∙m-1 at 0,10 MPa to 3,03 nN∙m-1 at 27,94 MPa, and at 353 K from 28,00 nN∙m-1 at 0,10 MPa to 2,62 nN∙m-1 at 28,05 MPa. The effect of temperature is minimal at lower pressures and negligible at higher pressures. The formulation of fenofibrate into Brij S100 was carried out with PGSSTM process. The operating conditions were chosen according to the preliminary studies. The process was performed with CO2 at 333 K and 10–25 MPa. The processing mixture consisted of 2 g or 4 g of fenofibrate and 20 g of Brij S100. The effect of pre-expansion pressure and concentration of the substance on characteristical properties of the precipitated product was investigated. The process yield varies (31,19–78,48 %) and the efficiency of loading is high (up to 91,12 %). No degradation of the substance occurred during the formulation process and the product crystallinity decreased even by 65 %. The smallest particle size of 47,62 µm was produced at 20 MPa and with 2 g of substance. Obtained particles are spherical or porous agglomerates of irregular shape. The dissolution profile of fenofibrate processed at optimum conditions improved for 11 % according to raw fenofibrate.
Secondary keywords:	substance fenofibrate;dense gases;thermodynamic properties;PGSS;
URN:	URN:SI:UM:
Type (COBISS):	Master's thesis/paper
Thesis comment:	Univ. v Mariboru, Fak. za kemijo in kemijsko tehnologijo
Pages:	XI, 97 str.
ID:	10955064