280351 Formation of Stable Nanocarriers by Tuning Pharmaceutically Active Ingredient Properties Via an in Situ Salt Precipitation

Thursday, November 1, 2012: 10:42 AM
Oakmont (Omni )
Nathalie M. Pinkerton1, Arnaud Grandeury2, Andreas Fisch2, Jörg Brozio3, Bernd Riebesehl2 and Robert K. Prud'homme1, (1)Chemical and Biological Engineering, Princeton University, Princeton, NJ, (2)Novartis Pharma AG, Basel, Switzerland, (3)Pharmaceutical & Analytical Development, Novartis Pharma AG, Basel, Switzerland

NanoCarriers (NCs) are a promising drug delivery route, which offer increased active pharmaceutical ingredient (API) circulation times and enhanced bioavailability.  When formed via rapid precipitation techniques such as flashnanoprecipitation, NCs have higher API loading than their post-loaded delivery counterparts. The aqueous solubility and crystallinity of the API affects NC formation and stability. Generally, hydrophobic materials (logP > 3.5) can be successfully formulated as NCs because sufficient supersaturation can be achieved for nucleation-dominated particle growth. With weakly hydrophobic API, however, the required supersaturation cannot be achieved resulting in low encapsulation efficiency or loss of particle size control. Additionally, with weakly hydrophobic and highly crystalline API, instabilities can occur due to redissolution and recrystallization of the drug compound.  To modify API properties for successful encapsulation into NCs, two common routes exist. The first is to modify the drug molecular structure by creating a prodrug. The prodrug is considered a new compound and must undergo FDA approval. The other is to create a salt of the drug, which does not create a new compound and thus circumvents the need for new FDA approval.  The salt technique has been used for the formation of bulk salts to improve dissolution behavior, but never to aid in the formation and stability of NCs. We demonstrate the successful ion pairing of APIs to hydrophobic counterions to enable NC formation by rapid precipitation. No additional preparation steps prior to the precipitation process are needed, as the hydrophobic salt is formed in situ during the NC self-assembly. The rules for successful nanocarrier formation are presented using three model APIs, cinnarizine, clozapine and α-lipoic acid. This technique expands the types of APIs that can be successfully encapsulated in NC form for drug delivery.

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