Stepwise use of additives for improved control over formation & stability of mefenamic acid nanocrystals produced by antisolvent precipitation

A method of introducing different additives at different times during the process, i.e., stepwise addition of additives, has been developed to produce stable nanoparticles of mefenamic acid (MEF) by antisolvent precipitation. In the absence of additives, at optimized conditions, MEF crystals were prepared in the size range of 0.25-3.05 μm; however, these crystals formed large agglomerates in suspension (∼12.1 μm). In the presence of all additives evaluated, with the exception of hydroxypropylmethylcellulose (HPMC), smaller particles were produced in suspension, the most effective additive being sodium docusate (DOSS), generating nanoparticles, ∼312 nm in size. However, the particle size was not stable but increased to ∼788 nm after 80 min in suspension associated with a polymorphic transformation. Combining the initial use of DOSS with the subsequent addition of HPMC or poly(vinyl alcohol) (PVA) allowed for the production of a stable suspension of MEF nanocrystals (∼317 and ∼311 nm, respectively). The interaction of HPMC and PVA with MEF particles delayed polymorphic transformation by inhibiting nucleation and/or growth of the stable MEF polymorph. The results show that using stepwise addition of additives, separately targeting nucleation and crystal growth/phase transformation, can improve the manufacturing and stabilization of nanocrystal suspensions.