Primerjava trdnih disperzij naproksena z mezoporoznim silicijevim dioksidom, izdelanih s tremi različnimi metodami

Drame, Katarina (author), Planinšek, Odon (mentor)

Eden izmed ključnih izzivov v farmaciji je izboljšanje raztapljanja slabo topnih zdravilnih učinkovin, ki spadajo po biofarmacevtski klasifikaciji v II. razred. Predstavnik tega razreda je nesteroidni antirevmatik naproksen, ki smo mu želeli izboljšati topnost s pomočjo izdelave trdne disperzije v mezoporoznem silicijevim dioksidu. Priprave trdnih disperzij naproksena s tem mezoporoznim ogrodjem smo se lotili po treh različnih metodah – metoda z odparevanjem topila pri znižanem tlaku, metoda adsorpcije zdravilne učinkovine iz raztopine in metoda segrevanja z infrardečim grelnikom. Pri tem smo uporabili silicijev dioksid dveh različnih proizvajalcev, in sicer Parteck® SLC 500 in Syloid® XDP 3150, v različnih masnih razmerjih. Zanimalo nas je, katera od naštetih metod je optimalna z vidika ponovljivosti izdelave, ekonomičnosti in nalaganja v pore nosilca. Pri oceni slednjega smo si pomagali z rezultati termične analize. Ugotovili smo, da je metoda segrevanja z infrardečim grelnikom v mnogih pogledih optimalna v primerjavi z metodama z uporabo topil. S pomočjo diferenčne dinamične kalorimetrije smo analizirali trdne disperzije pripravljene z odparevanjem topila pri znižanem tlaku, pred in po 6-tedenskem testu pospešene stabilnosti, in ugotovili, da s časom količina amorfne učinkovine narašča, kar bi lahko pripisali spontani amorfizaciji kristalnega naproksena oziroma nastanku koamorfa. Tretja razlaga je povezana s pomanjkljivo objektivnostjo naše metode. Iz trdnih disperzij z 20% in 30% deležem naproksena smo pripravili tablete s kratkim časom razpada in z njimi izvedli test sproščanja v 0,1 M raztopini HCl. Analizirali smo profile sproščanja vzorcev, pri katerih smo uporabili različne procesne parametre tabletiranja, različne količine zdravilne učinkovine, metode izdelave trdnih disperzij ter mezoporozna nosilca z različnimi lastnostmi. Zaključili smo, da obstajajo številni faktorji, ki vplivajo na hitrost in obseg sproščanja. To so trdnost formulacije, količina vgrajene učinkovine, metoda izdelave trdne disperzije in lastnosti uporabljenega mezoporoznega nosilca. Ugotovili smo, da velika večina formulacij s trdnimi disperzijami izkazuje izboljšano raztapljanje v primerjavi s fizikalnimi zmesmi, najoptimalnejši profil raztapljanja pa pripada 20% trdni disperziji naproksena s Parteckom, pripravljeni s segrevanjem z infrardečim grelnikom.

• Language: Slovenian
• Keywords: trdna disperzija, naproksen, mezoporozni silicijev dioksid, tabletiranje, raztapljanje
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2021
• PID: 20.500.12556/RUL-124227
• Publication date in RUL: 09.01.2021

Secondary language

• Language: English
• Title: Comparison of three different methods used for preparation of naproxen solid dispersions with mesoporous silica

Abstract

Improving the solubility of poorly water soluble active pharmaceutical ingredients that according to the biopharmaceutical classification system belong to class II is one of the main challenges pharmaceutical industry is facing nowadays. One of the drugs belonging to that group is nonsteroidal anti-inflammatory drug naproxen. We aimed to improve its solubility by making its solid dispersions in mesoporous silica. We used three different methods to prepare the solid dispersions – two solvent evaporation methods (rotavapor evaporation and immersion method) and the melt method, in which we used an infrared heater. Additionally, we used different proportions of mesoporous silica produced by two manufacturers – Parteck® SLC 500 and Syloid® XDP 3150. Our first aim was to determine which of the three methods was optimal regarding its repeatability, economy and how the molecules were loaded into the carrier. We assessed the latter by performing thermal analysis. Our conclusion was that the melt – infrared heater – method is in many ways better than the methods in which organic solvents are used. Secondly, we used differential dynamic calorimetry to analyze solid dispersions prepared by evaporating the solvent by the rotavapor. We analyzed freshly prepared dispersions and the dispersions that had been kept in accelerated stability test conditions for 6 weeks. Our conclusion was that with time there is an increasing amount of amorphous form of naproxen, which might be due to the spontaneous amorphization of the drug. Finally, we produced rapidly disintegrating tablets from the solid dispersions containing 20% and 30% of naproxen and tested how the drug was released in 0,1 M HCl solution. We analysed the release profiles of the samples, in the making of which we used various process parameters of tableting, different amounts of active ingredient, methods of preparation and two mesoporous carriers with different properties. We found out that there are numerous factors that affect the speed and rate of release. Those factors are the hardness of the formulation, the amount of active ingredient in it, the method we used to prepare solid dispersions and the properties of used mesoporous carriers. We can conclude that the formulations with solid dispersions had improved release when compared to physical mixtures and that the most optimal release profile belonged to the formulation containing 20% solid dispersion prepared with the melt method.

• Keywords: solid dispersion, naproxen, mesoporous silica, tabletting, dissolution