title: The impact of polymeric excipients on the particle size of poorly soluble drugs after pH-induced precipitation.
abstract: Active pharmaceutical ingredients (APIs) with strongly pH-dependent aqueous solubility can face the problem of precipitating from solution when the pH changes from acidic in the stomach to neutral in the intestine. The present work investigates the effect of two polymeric excipients - polyvinylpyrrolidone (PVP) and Soluplus - on the ability to either prevent precipitation, or to control the size distribution of precipitated particles when precipitation cannot be prevented. Two different APIs were compared, Dabigatran etexilate mesylate and Rilpivirine hydrochloride. The effect of excipient concentration on the precipitation behaviour during pH titration was systematically investigated and qualitatively different trends were observed: in case of Soluplus, which forms a micellar solution when critical micelle concentration is exceeded, precipitation was inhibited in the case of Dabigatran etexilate, which partitioned into the micelles. On the other hand, Rilpivirine precipitated independently of Soluplus concentration. In the case of PVP, which does not form micelles, precipitation could not be avoided. Increased polymer concentration, however prevented the aggregation of precipitated particles into larger cluster. The observed effect of PVP was especially pronounced for Rilpivirine. The main conclusion of this study is that a suitably chosen polymeric excipient can either prevent precipitation altogether or reduce the size of the resulting particles. The mechanism of action, however, seems-specific to a given molecule. It was also shown that the polymer-stabilised particles have a potential to redissolve.
authors.affiliation: Department of Chemical Engineering, University of Chemistry and Technology Prague, Prague 6, Czech Republic; Zentiva, k.s., U Kabelovny 130, Prague 10, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Punčochová
authors.affiliation: Department of Chemical Engineering, University of Chemistry and Technology Prague, Prague 6, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Prajzlerová
authors.affiliation: Zentiva, k.s., U Kabelovny 130, Prague 10, Czech Republic.
authors.forename: Josef
authors.initials: J
authors.lastname: Beránek
authors.affiliation: Department of Chemical Engineering, University of Chemistry and Technology Prague, Prague 6, Czech Republic. Electronic address: Frantisek.Stepanek@vscht.cz.
authors.forename: František
authors.initials: F
authors.lastname: Štěpánek
mesh_terms: D011232:Chemical Precipitation / Q000187:drug effects; D000069604:Dabigatran / Q000737:chemistry* / Q000493:pharmacokinetics; D005079:Excipients / Q000737:chemistry* / Q000493:pharmacokinetics; D006863:Hydrogen-Ion Concentration; D010316:Particle Size; D011108:Polymers / Q000737:chemistry* / Q000493:pharmacokinetics; D011205:Povidone / Q000737:chemistry / Q000493:pharmacokinetics; D000068696:Rilpivirine / Q000737:chemistry* / Q000493:pharmacokinetics; D012995:Solubility / Q000187:drug effects
chemical_list: D005079:Excipients; D011108:Polymers; D000068696:Rilpivirine; D011205:Povidone; D000069604:Dabigatran
keywords: Aggregation; Crystal growth; Dissolution; Dynamic light scattering; Particle size distribution; Precipitation