title: Pharmaceutical development of an amorphous solid dispersion formulation of elacridar hydrochloride for proof-of-concept clinical studies.
abstract: OBJECTIVE
  A novel tablet formulation containing an amorphous solid dispersion (ASD) of elacridar hydrochloride was developed with the purpose to resolve the drug's low solubility in water and to conduct proof-of-concept clinical studies.
  
  
  CONCLUSIONS
  Elacridar is highly demanded for proof-of-concept clinical trials that study the drug's suitability to boost brain penetration and bioavailability of numerous anticancer agents. Previously, clinical trials with elacridar were performed with a tablet containing elacridar hydrochloride. However, this tablet formulation resulted in poor and unpredictable absorption which was caused by the low aqueous solubility of elacridar hydrochloride.
  
  
  METHODS
  Twenty four different ASDs were produced and dissolution was compared to crystalline elacridar hydrochloride and a crystalline physical mixture. The formulation with highest dissolution was characterized for amorphicity. Subsequently, a tablet was developed and monitored for chemical/physical stability for 12 months at +15-25 °C, +2-8 °C and -20 °C.
  
  
  RESULTS
  The ASD powder was composed of freeze dried elacridar hydrochloride-povidone K30-sodium dodecyl sulfate (1:6:1, w/w/w), appeared fully amorphous and resulted in complete dissolution whereas crystalline elacridar hydrochloride resulted in only 1% dissolution. The ASD tablets contained 25 mg elacridar hydrochloride and were stable for at least 12 months at -20 °C.
  
  
  CONCLUSIONS
  The ASD tablet was considered feasible for proof-of-concept clinical studies and is now used as such.
authors.affiliation: a Department of Pharmacy and Pharmacology , Antoni van Leeuwenhoek Hospital/MC Slotervaart , Amsterdam , The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Sawicki
authors.affiliation: b Department of Clinical Pharmacology , the Netherlands Cancer Institute , Amsterdam , the Netherlands.|c Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology , Utrecht University , Utrecht , the Netherlands.
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: a Department of Pharmacy and Pharmacology , Antoni van Leeuwenhoek Hospital/MC Slotervaart , Amsterdam , The Netherlands.|b Department of Clinical Pharmacology , the Netherlands Cancer Institute , Amsterdam , the Netherlands.|c Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology , Utrecht University , Utrecht , the Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: a Department of Pharmacy and Pharmacology , Antoni van Leeuwenhoek Hospital/MC Slotervaart , Amsterdam , The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Nuijen
mesh_terms: D000166:Acridines / Q000737:chemistry* / Q000493:pharmacokinetics; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization / Q000379:methods; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D005612:Freeze Drying / Q000379:methods; D011205:Povidone / Q000737:chemistry; D011208:Powders / Q000737:chemistry; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D012995:Solubility; D013607:Tablets / Q000737:chemistry* / Q000493:pharmacokinetics; D013678:Technology, Pharmaceutical / Q000379:methods; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D000166:Acridines; D005079:Excipients; D011208:Powders; D013607:Tablets; D044005:Tetrahydroisoquinolines; D012967:Sodium Dodecyl Sulfate; D011205:Povidone; C083501:Elacridar
keywords: Elacridar; GF120918; GG918; P-gp; absorption; brain penetration; dissolution; freeze drying; solid dispersion; spray drying