Joseph W Lubach1, Jonathan Hau2. 1. Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080, USA. lubach.joseph@gene.com. 2. Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080, USA.
Abstract
PURPOSE: To investigate the nature of drug-excipient interactions between indomethacin (IMC) and methacrylate copolymer Eudragit® E (EE) in the amorphous state, and evaluate the effects on formulation and stability of these amorphous systems. METHODS: Amorphous solid dispersions containing IMC and EE were spray dried with drug loadings from 20% to 90%. PXRD was used to confirm the amorphous nature of the dispersions, and DSC was used to measure glass transition temperatures (Tg). 13C and 15N solid-state NMR was utilized to investigate changes in local structure and protonation state, while 1H T1 and T1ρ relaxation measurements were used to probe miscibility and phase behavior of the dispersions. RESULTS: Tg values for IMC-EE solid dispersions showed significant positive deviations from predicted values in the drug loading range of 40-90%, indicating a relatively strong drug-excipient interaction. 15N solid-state NMR exhibited a change in protonation state of the EE basic amine, with two distinct populations for the EE amine at -360.7 ppm (unprotonated) and -344.4 ppm (protonated). Additionally, 1H relaxation measurements showed phase separation at high drug load, indicating an amorphous ionic complex and free IMC-rich phase. PXRD data showed all ASDs up to 90% drug load remained physically stable after 2 years. CONCLUSIONS: 15N solid-state NMR experiments show a change in protonation state of EE, indicating that an ionic complex indeed forms between IMC and EE in amorphous solid dispersions. Phase behavior was determined to exhibit nanoscale phase separation at high drug load between the amorphous ionic complex and excess free IMC.
PURPOSE: To investigate the nature of drug-excipient interactions between indomethacin (IMC) and methacrylate copolymer Eudragit® E (EE) in the amorphous state, and evaluate the effects on formulation and stability of these amorphous systems. METHODS: Amorphous solid dispersions containing IMC and EE were spray dried with drug loadings from 20% to 90%. PXRD was used to confirm the amorphous nature of the dispersions, and DSC was used to measure glass transition temperatures (Tg). 13C and 15N solid-state NMR was utilized to investigate changes in local structure and protonation state, while 1H T1 and T1ρ relaxation measurements were used to probe miscibility and phase behavior of the dispersions. RESULTS: Tg values for IMC-EE solid dispersions showed significant positive deviations from predicted values in the drug loading range of 40-90%, indicating a relatively strong drug-excipient interaction. 15N solid-state NMR exhibited a change in protonation state of the EE basic amine, with two distinct populations for the EE amine at -360.7 ppm (unprotonated) and -344.4 ppm (protonated). Additionally, 1H relaxation measurements showed phase separation at high drug load, indicating an amorphous ionic complex and free IMC-rich phase. PXRD data showed all ASDs up to 90% drug load remained physically stable after 2 years. CONCLUSIONS:15N solid-state NMR experiments show a change in protonation state of EE, indicating that an ionic complex indeed forms between IMC and EE in amorphous solid dispersions. Phase behavior was determined to exhibit nanoscale phase separation at high drug load between the amorphous ionic complex and excess free IMC.
Authors: Sanela M Đorđević; Tamara S Radulović; Nebojša D Cekić; Danijela V Ranđelović; Miroslav M Savić; Danina R Krajišnik; Jela R Milić; Snežana D Savić Journal: J Pharm Sci Date: 2013-09-23 Impact factor: 3.534
Authors: Yang Song; Dmitry Zemlyanov; Xin Chen; Ziyang Su; Haichen Nie; Joseph W Lubach; Daniel Smith; Stephen Byrn; Rodolfo Pinal Journal: Int J Pharm Date: 2016-06-28 Impact factor: 5.875
Authors: Joseph W Lubach; Brian E Padden; Stephanie L Winslow; Jonathon S Salsbury; David B Masters; Elizabeth M Topp; Eric J Munson Journal: Anal Bioanal Chem Date: 2004-03 Impact factor: 4.142