Modification of the zeta potential of montmorillonite to achieve high active pharmaceutical ingredient nanoparticle loading and stabilization with optimum dissolution properties

摘要

Nanoparticles (NPs) of three poorly water-soluble BCS class II active pharmaceutical ingredients (APIs) (clozapine (CLO), curcumin (CUR) and carbamazepine (CBMZ) with zeta potentials -28.5 +/- 2.5, -33 +/- 1.5 and -13 +/- 1.5 mV respectively) were produced, stabilized and isolated into the solid state with the help of Montmorillonite (MMT) clay carrier particles. The nanoparticles of clozapine (27 nm), curcumin (170 nm) and carbamazepine (30 nm) were produced and stabilized in suspension using a reverse antisolvent precipitation technique in the presence of `as received' MMT carrier particles (similar to 30 mu m) and/or MMT carrier particles whose surface had been slightly modified with a cationic protein, protamine sulphate salt (PA). The resulting nano-particle carrier composites were isolated directly from suspension into a solid state form by simple filtration followed by air-drying. The API dissolution rates from these dried NP-carrier composites were comparable with those of the respective stabilized API nanoparticles in suspension up to maximum CLO, CUR and CBMZ loadings of 23%, 21.8% and 33.3% (w/w) respectively, although surface modification of the MMT carrier particles with PA was needed for the CLO and CUR NP-carrier composites in order to preserve the fast API nanosuspension-like dissolution rates at higher API loadings. For both of these APIs, the optimal loading of PA on MMT was around 4 mg/g, which likely helped to limit aggregation of the API nanoparticles at the higher API loadings. Interestingly, no MMT surface modification was needed to preserve fast API dissolution rates at higher API loadings in the case of the CBMZ NP-carrier composites. This discrimination among the three APIs for carrier particle surface modification was previously observed in reported studies by our group for three other APIs, namely valsartan, fenofibrate and dalcetrapib. When examined together, the data for all six APIs suggest a general trend whereby API nanoparticles with zeta potentials more positive than around -25 mV do not require carrier particle surface modification with PA in order to preserve their fast dissolution rates from NP-carrier composites at higher API loadings. Thus, this study offers a potentially effective means of transforming poorly water soluble BCS Class II APIs into fast dissolving solid dosage NP-carrier composites, whereby the surface properties of the carrier particle can be tuned with prior knowledge of the zeta potential of the API nanoparticles.