Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 540, Issue 1-2, Pages 150-161Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijpharm.2018.02.011
Keywords
Nanosuspensions; Nanocrystals; Wet media milling; Experimental design; Molecular modelling; Crystal polymorphism
Categories
Funding
- Ministry of Education, Science and Technological Development, Republic of Serbia [TR 34007]
- Ministry of Education, Science and Technological Development, Republic of Serbia
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The aim of this study is to develop nanosuspension of carvedilol (CRV) by wet media milling. Concentration of polymeric stabilizer (hydroxypropyl cellulose-HPC-SL), milling speed and size of milling beads were identified as critical formulation and process parameters and their effect on CRV particle size after 60 min of milling was assessed using a Box-Behnken experimental design. Optimized nanosuspension was solidified using spray drying and freeze drying and subjected to solid state characterization. Low stabilizer concentration (10%), low milling speed (300 rpm) with small milling beads (0.1 mm) were found as optimal milling conditions. Crystal lattice simulation identified potential slip plane within CRV crystals, where fractures are the most likely to occur. Calculated mechanical properties of CRV crystal indicates that low energy stress is sufficient to initiate fracture, if applied in the correct direction, explaining the advantage of using smaller milling beads. Only spray dried nanosuspension redispersed to original nanoparticles, while particle agglomeration during freeze drying prevented sample redispersion. Wet milling and spray drying did not induce polymorphic transition of CRV, while there is indication of polymorphic transition during freeze drying, making spray drying as the preferred solidification method.
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