title: Sodium Lauryl Sulfate Competitively Interacts with HPMC-AS and Consequently Reduces Oral Bioavailability of Posaconazole/HPMC-AS Amorphous Solid Dispersion.
abstract: Sodium lauryl sulfate (SLS), as an effective surfactant, is often used as a solubilizer and/or wetting agent in various dosage forms for the purpose of improving the solubility and dissolution of lipophilic, poorly water-soluble drugs. This study aims to understand the impact of SLS on the solution behavior and bioavailability of hypromellose acetate succinate (HPMC-AS)-based posaconazole (PSZ) ASDs, and to identify the underlying mechanisms governing the optimal oral bioavailability of ASDs when surfactants such as SLS are used in combination. Fluorescence spectroscopy and optical microscopy showed that "oil-out" or "liquid-liquid phase separation (LLPS)" occurred in the supersaturated PSZ solution once drug concentration surpassed ∼12 μg/mL, which caused the formation of drug-rich oily droplets with initial size of ∼300-400 nm. Although FT-IR study demonstrated the existence of specific interactions between PSZ and HPMC-AS in the solid state, predissolved HPMC-AS was unable to delay LLPS of the supersaturated PSZ solution and PSZ-rich amorphous precipitates with ∼16-18% HPMC-AS were formed within 10 min. The coprecipitated HPMC-AS was found to be able to significantly delay the crystallization of PSZ in the PSZ-rich amorphous phase from less than 10 min to more than 4 h, yet coexistent SLS was able to negate this crystallization inhibition effect of HPMC-AS in the PSZ-rich amorphous precipitates and cause fast PSZ crystallization within 30 min. 2D-NOESY and the CMC/CAC results demonstrated that SLS could assemble around HPMC-AS and competitively interact with HPMC-AS in the solution, thus prevent HPMC-AS from acting as an effective crystallization inhibitor. In a crossover dog PK study, this finding was found to be correlating well with the in vivo bioavailability of PSZ ASDs formulated with or without SLS. The SLS containing PSZ ASD formulation demonstrated an in vivo bioavailability ∼30% of that without SLS, despite the apparently better in vitro dissolution, which only compared the dissolved drug in solution, a small fraction of the total PSZ dose. We conclude that the bioavailability of ASDs is highly dependent on the molecular interactions between drug, surfactant, and polymer, not only in the solution phase but also in the drug-rich "oily" phase caused by supersaturation.
authors.affiliation: School of Pharmaceutical Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, China.
authors.forename: Yuejie
authors.initials: Y
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, China.
authors.forename: Shujing
authors.initials: S
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, China.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liu
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company , Lawrenceville, New Jersey 08648, United States.
authors.forename: Ching
authors.initials: C
authors.lastname: Su
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company , Lawrenceville, New Jersey 08648, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Hageman
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb Company , New Brunswick, New Jersey 08903, United States.
authors.forename: Munir
authors.initials: M
authors.lastname: Hussain
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
authors.forename: Roy
authors.initials: R
authors.lastname: Haskell
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company , Lawrenceville, New Jersey 08648, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Stefanski
authors.affiliation: School of Pharmaceutical Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
mesh_terms: D065546:Drug Liberation; D065347:Hypromellose Derivatives / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D019999:Pharmaceutical Solutions / Q000737:chemistry; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry*; D012995:Solubility; D013050:Spectrometry, Fluorescence; D017550:Spectroscopy, Fourier Transform Infrared; D014230:Triazoles / Q000737:chemistry*
chemical_list: D019999:Pharmaceutical Solutions; D014230:Triazoles; D012967:Sodium Dodecyl Sulfate; D065347:Hypromellose Derivatives; C101425:posaconazole
keywords: amorphous solid dispersion; bioavailability; molecular interaction; posaconazole (PSZ); sodium lauryl sulfate