Development of a HPMC-based controlled release formulation with hot melt extrusion (HME).
The objective of this study was to develop hydroxypropyl methylcellulose (HPMC) based controlled release (CR) formulations via hot melt extrusion (HME) with a highly soluble crystalline active pharmaceutical ingredient (API) embedded In the polymer phase. HPMC is considered a challenging CR polymer for extrusion due to its high glass transition temperature (Tg), low degradation temperature, and high viscosity. These problems were partially overcome by plasticizing the HPMC with up to 40% propylene glycol (PG). Theophylline was selected as the model API. By using differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), dynamic mechanical analysis (DMA), and X-ray powder diffraction (XRPD), the physical properties of the formulations were systematically characterized. Five grades of HPMC (Methocel(®)) - E6, K100LV, K4M, K15M, and K100M - were tested. The extrusion trials were conducted on a 16 mm twIn screw extruder with HPMC/PG placebo and formulations containing theophylline/HPMC/PG (30:42:28, w/w/w). The dissolution results showed sustained release profiles without burst release for the HPMC K4M, K15M, and K100M formulations. The extrudates have good dissolution stability after being stressed for 2 weeks under 40°C/75% RH open dish conditions and the crystalline API form did not change upon storage. Overall, the processing windows were established for the HPMC based HME-CR formulations.
Pharmaceutical Science and Clinical Supply, Merck Sharp and Dohme Ltd., Shanghai, PR China. decheng_ma@merck.com
Decheng
D
Ma
Abdenour
A
Djemai
Colleen M
CM
Gendron
Hanmi
H
Xi
Michelle
M
Smith
Jessica
J
Kogan
Li
L
Li
D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D065347:Hypromellose Derivatives; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D008962:Models, Theoretical; D019946:Propylene Glycol / Q000737:chemistry; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods*; D013696:Temperature; D013806:Theophylline / Q000737:chemistry; D019415:Torque
D003692:Delayed-Action Preparations; D005079:Excipients; D065347:Hypromellose Derivatives; D019946:Propylene Glycol; D008747:Methylcellulose; D013806:Theophylline