Optimizacija procesa sferične kristalizacije s pristopom načrtovanja eksperimentov za maksimiranje deleža alfa-laktoze monohidrata

Gajšek, Ina (author), Planinšek, Odon (mentor), Lamešić, Dejan (co-mentor)

Sferična kristalizacija je tehnika oblikovanja delcev, pri kateri pod nadzorovanimi pogoji kristalizacija in aglomeracija potečeta hkrati v enem koraku. Nastali sferični aglomerati imajo številne prednosti, kot so npr. izboljšane pretočne lastnosti in manjša segregacija učinkovine v farmacevtski obliki zaradi večje poroznosti aglomeratov. V nalogi smo želeli na podlagi predhodnih raziskovanj procesa sferične kristalizacije laktoze in preliminarnih poskusov z metodo načrtovanja eksperimentov pridobiti delce, ki bi imeli čim višjo vsebnost α-laktoze monohidrata v produktu, ki ustreza vsebnosti kristalno vezane vode v produktu, ob hkratnem čim večjem izkoristku, čim nižji porabi etanola in primerni razporeditvi velikosti delcev. V ta namen smo postavili in izvedli prvi eksperimentalni načrt - dokončni presejalni načrt s 13 eksperimenti. Izmed štirih neodvisnih spremenljivk smo na podlagi analize določili tiste, ki imajo največji vpliv na lastnosti produkta (koncentracija laktoze v raztopini laktoze, temperatura kristalizacijskega sistema in hitrost dodajanja raztopine laktoze) in z njimi postavili drug eksperimentalni načt - faktorski načrt, ki je bil sestavljen iz 10 eksperimentov. Ključne prednosti načrtovanja eksperimentov so se pokazale v več primerih, ko smo lahko opažali nelinearne vplive, interakcije, kvadratne učinke. Izmed preiskovanih neodvisnih spremenljivk smo kot najpomembnejšo glede na vpliv na lastnosti produkta ovrednotili koncentracijo laktoze v raztopini laktoze. Njen vpliv je bil pozitiven na izkoristek, D90 in širino porazdelitve delcev ter negativen na vsebnost kristalno vezane vode. Velik vpliv koncentracije laktoze v raztopini laktoze smo opazili tudi pri SEM analizi na izgled osnovnih delcev, ki gradijo sferične aglomerate. Pri nižji koncentraciji so bili osnovni delci širši in ne tako podolgovati kot pri delcih, ki so nastali pri najvišji koncentraciji laktoze. Prav tako so bili takšni delci bolj enakomernih velikosti kot ostali. Manjši vendar še vedno izredno pomemben vpliv sta imeli hitrost dodajanja raztopine laktoze in temperatura kristalizacijskega sistema. Hitrost dodajanja je imela negativen vpliv na izkoristek in pozitiven vpliv na D10 ter kvadraten vpliv na D50. Temperatura KS je imela pozitiven vpliv na % kristalno vezane vode in D10. Pri omenjenima spremenljivkama očitnega vpliva na izgled delcev pri SEM analizi nismo opazili.

• Language: Slovenian
• Keywords: laktoza, sferična kristalizacija, načrtovanje eksperimentov, statistični model, lastnosti delcev
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2022
• PID: 20.500.12556/RUL-141544
• Publication date in RUL: 01.10.2022

Secondary language

• Language: English
• Title: Optimization of spherical crystallization with the design of experiments approach to maximize the alpha-lactose monohydrate proportion

Abstract

Spherical crystallization is a process of particle formation in which, under controlled conditions, crystallization and agglomeration occur simultaneously. Spherical agglomerates have many advantages, such as improved flow properties and less segregation of active substance in final dosage form due to higher porosity of agglomerates. In this study, we aimed to obtain particles with highest possible content of α-lactose monohydrate in the product, which corresponds to the content of crystalline bound water in the product, while at the same time targeting good yield, low ethanol consumption and suitable particle size distribution. For this purpose, we set up the first experimental design - a definitive screening design with 13 experiments. From the four independent variables, we determined those that have the greatest influence on the product properties (concentration of lactose in the lactose solution, temperature of crystallization system and addition rate) and with them we set up the second experimental design -factorial design with 10 experiments. Crucial advantages of DOE were shown in several cases where we could observe non-linear influences, interactions, quadratic effects. Among the studied independent variables, we evaluated the concentration of lactose in the lactose solution as the most important in terms of its influence on the product's properties. Its influence was positive on yield, D90 and particle distribution width, and negative on the content of crystaline bound water. A great influence of the lactose concentration in the lactose solution was also observed in the SEM analysis on the appearance of the particles that build the spherical agglomerates. At lower concentration, particles were wider and not as elongated as in the particles formed at the highest concentration of lactose. Also, such particles were more uniform in size than the rest. The addition rate of the lactose solution and the temperature of the crystallization system had smaller but still very important influence. Addition rate had a negative effect on yield and a positive effect on D10 and a quadratic effect on D50. Temperature of crystallization had a positive influence on the content of crystalline bound water and D10. We did not observe any obvious trends in the appearance of the particles in the SEM analysis of the mentioned variables.

• Keywords: lactose, spherical crystallization, design of experiments, statistical model, characteristics of particles