Mechanochemical preparation and characterization of polymeric dispersions and cocrystals of praziquantel

Mehanokemijska aktivacija mljevenjem uz dodatak različitih aditiva korištena je s ciljem poboljšanja nepovoljnih fizičkokemijskih i biofarmaceutskih svojstava prazikvantela (PZQ). Mljevenjem PZQ s limunskom (CA), jabučnom (MA), salicilnom (SA) i vinskom kiselinom (TA) pripravljeni su kokristali za koje je ustanovljeno da topljivost i brzina otapanja ovisi o pH. Najtopljiviji kokristal PZQ s MA kemijski je nestabilan. Najveće povećanje topljivosti i brzine otapanja uočeno je za ekvimolarne komplekse prazikvantela s amorfnim hidroksipropil--ciklodekstrinom (HPβCD) i nasumično metiliranim -ciklodekstrinom (MβCD), ali je jedino produkt PZQ/HPβCD pokazao prihvatljivu kemijsku stabilnost i fotostabilnost. Mljevenjem lijeka s MA i HPβCD u ekvimolarnim količinama također su pripravljeni topljivi amorfni produkti koji su bili kemijski nestabilni, a time neprikladni za farmaceutsku primjenu. Ispitivanja na Caco-2 monosloju potvrdila su biokompatibilnost kompleksa PZQ/HPβCD te da kompleksiranje nije utjecalo na intrinsičnu permeabilnost prazikvantela Papp(PZQ)=(3,72±0,33)10–5 cm s–1 i Papp(PZQ/HPβCD)=(3,65±0,21)10–5 cm s–1; p>0,05).Mechanochemical activation using different co-grinding additives was applied to improve physiochemical and biopharmaceutical properties of praziquantel (PZQ). Liquid assisted grinding with citric (CA), malic (MA), salicylic (SA) and tartaric acid (TA) gained in cocrystal formation, which all showed pH-dependent solubility and dissolution rate. The most soluble cocrystal of PZQ with MA was chemically unstable, as seen during the stability testing. Equimolar praziquantel complexes with amorphous hydroxypropyl-β-cyclodextrin (HPβCD) and randomly methylated β-cyclodextrin (MβCD) showed the highest improvement in drug solubility and the dissolution rate, but only PZQ/HPβCD product presented an acceptable chemical and photostability profile. Co-grinding the drug with both MA and HPβCD in equimolar ratio, also gave highly soluble amorphous product which was chemical instable and therefore not suitable for the pharmaceutical use. Studies on Caco-2 monolayer confirmed the biocompatibility of PZQ/HPβCD complex and showed that complexation did not adversely affect the intrinsically high PZQ permeability Papp(PZQ)=(3.72±0.33)10–5 cm s–1 and Papp(PZQ/HPβCD)=(3.65±0.21)10–5 cm s–1; p>0.05)