Formation of stable nanocarriers by in Situ ion pairing during block-copolymer-directed rapid precipitation

Nathalie M. Pinkerton, Arnaud Grandeury, Andreas Fisch, Jörg Brozio, Bernd U. Riebesehl, Robert K. Prud'Homme

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

We present an in situ hydrophobic salt forming technique for the encapsulation of weakly hydrophobic, ionizable active pharmaceutical ingredients (API) into stable nanocarriers (NCs) formed via a rapid precipitation process. Traditionally, NC formation via rapid precipitation has been difficult with APIs in this class because their intermediate solubility makes achieving high supersaturation difficult during the precipitation process and the intermediate solubility causes rapid Ostwald ripening or recrystallization after precipitation. By forming a hydrophobic salt in situ, the API solubility and crystallinity can be tuned to allow for NC formation. Unlike covalent API modification, the hydrophobic salt formation modifies properties via ionic interactions, thus circumventing the need for full FDA reapproval. This technique greatly expands the types of APIs that can be successfully encapsulated in NC form. Three model APIs were investigated and successfully incorporated into NCs by forming salts with hydrophobic counterions: cinnarizine, an antihistamine, clozapine, an antipsychotic, and α-lipoic acid, a common food supplement. We focus on cinnarizine to develop the rules for the in situ nanoprecipitation of salt NCs. These rules include the pK as and solubilities of the API and counterion, the effect of the salt former-to-API ratio on particle stability and encapsulation efficiency, and the control of NC size. Finally, we present results on the release rates of these ion pair APIs from the NCs.

Original languageEnglish (US)
Pages (from-to)319-328
Number of pages10
JournalMolecular Pharmaceutics
Volume10
Issue number1
DOIs
StatePublished - Jan 7 2013

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Keywords

  • API
  • FNP
  • encapsulation
  • flash nanoprecipitation
  • hydrophobic salt
  • ion complexation
  • ion pairing
  • nano carrier
  • nanocarrier
  • nanoparticle
  • precipitation

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