Študij vpliva formulacijskih in procesnih parametrov kompaktiranja na kritične atribute kakovosti granulatov in tablet

Dular Vovko, Aleša (author), Vrečer, Franc (mentor)

Pomen kompaktiranja v farmacevtski industriji v zadnjem času narašča, predvsem ker gre za enostavno, okolju prijazno in stroškovno učinkovito tehnologijo, ki je primerna tudi za zdravilne učinkovine, občutljive na povišano vlago in temperaturo. Zaradi omenjenih prednosti je uporaba te tehnologije smiselna tudi pri izdelavi ogrodnih tablet s hipromelozo. V okviru doktorske naloge smo proučevali vpliv formulacijskih spremenljivk (delež hipromeloze, tip polnila – laktoza in mikrokristalna celuloza) in procesnih parametrov kompaktiranja (sila stiskanja, hitrost valjev), mletja kompaktatov (tip mlina – oscilirajoči, konični mlin, kladivar; hitrost mletja, velikost odprtin mreže) in tabletiranja (trdnost tablet) na lastnosti granul (porazdelitev velikosti delcev (PSD), poroznost, krušljivost, trdnost, oblika) in zmesi za tabletiranje (kompresibilnost, kompaktibilnost) ter na sproščanje karvedilola iz ogrodnih tablet s hipromelozo. V sklopu doktorske naloge smo preverili tudi možnost implementacije tehnike prostorskega filtra (SFT) kot metode za spremljanje PSD granulata, pri čemer smo potrdili dobro korelacijo rezultatov SFT in konvencionalnih tehnik. Dobljene rezultate smo vrednotili tudi s programskim orodjem za multivariatno analizo podatkov ter postavili modele za napoved ključnih lastnosti granul in sproščanja iz tablet. Pri modelih za napovedovanje PSD smo potrdili dobro napovedno moč za vrednosti d50 in d90 v realnem času, s čimer smo potrdili možnost uporabe SFT kot orodja procesno analizne tehnologije za spremljanje in vodenje kompaktiranja. V nadaljevanju smo pokazali, da lahko rezultate SFT skupaj z upoštevanjem formulacijskih spremenljivk in procesnih parametrov uporabimo za napovedovanje profila sproščanja karvedilola. Potrdili smo, da na sproščanje poleg sestave znatno vplivajo tudi proces kompaktiranja (hitrost valjev) ter atributi kakovosti granulata (PSD) in tablet (trdnost). V nadaljnji študiji smo ugotovili, da je hitrost sproščanja karvedilola odvisna tudi od tipa mlina za mletje kompaktatov, vendar je vpliv povezan s tipom polnila in velikostjo ter obliko delcev granulata. Rezultati dopolnjujejo poznavanje področja ogrodnih tablet s hipromelozo in kompaktiranja ter podajajo nekaj novih usmeritev pri razvoju trdnih farmacevtskih izdelkov.

• Language: Slovenian
• Keywords: kompaktiranje, hipromeloza, ogrodne tablete, sproščanje zdravilne učinkovine, procesno analizna tehnologija, tehnika prostorskega filtra
• Work type: Doctoral dissertation
• Organization: FFA - Faculty of Pharmacy
• Year: 2023
• PID: 20.500.12556/RUL-148530
• Publication date in RUL: 26.08.2023

Secondary language

• Language: English
• Title: Investigation of influence of roller compaction formulation and process parameters on critical quality attributes of granules and tablets

Abstract

The importance of roller compaction in the pharmaceutical industry has been growing recently, especially because it is a simple, environmentally friendly, and economically efficient technology that is suitable for moisture- and temperature-sensitive active pharmaceutical ingredients. Due to its advantages, it is reasonable to utilize it in manufacturing hypromellose-based matrix tablets. This doctoral dissertation studied the influence of formulation factors (hypromellose content, filler-type lactose, and microcrystalline cellulose), process parameters of roller compaction (compression force and roll speed), milling of ribbons (type of mill: oscillating, conical, or hammer mill; milling speed; and size of screen apertures), and tableting (hardness) on granule properties (particle size distribution or PSD, porosity, friability, hardness, and shape), the properties of compression mixtures (compressibility and compactibility), and the release of carvedilol from hypromellose-based matrix tablets. The dissertation also investigated use of the spatial filtering technique (SFT) in monitoring the PSD of the granulate. It confirmed good correlation of SFT results and the results of conventional methods. The data obtained have also been assessed with multivariate data analysis tools, and models have been developed for predicting key properties of granules and drug release from tablets. The models for PSD showed good predictive value for d50 and d90 values in real time, which confirmed the use of SFT as a process analytical technology tool for monitoring and control of the roller compaction process. Further analyses confirmed that SFT results can be used together with formulation factors and process parameters for predicting carvedilol drug release. It was confirmed that drug release is affected not only by composition but also by the roller compaction process (roll speed) and quality attributes of granules (PSD) and tablets (hardness). Additional studies demonstrated that carvedilol drug release is affected by the mill type used for milling ribbons; however, the effect is strongly related to the filler type and to the size and shape of granules. The results presented add to the body of knowledge about hypromellose-based matrix tablets and roller compaction, and they present some new considerations for the development of solid dosage forms.

• Keywords: roller compaction, hypromellose, matrix tablets, drug release, process analytical technology, spatial filtering technique