title: Interplay of formulation and process methodology on the extent of nifedipine molecular dispersion in polymers.
abstract: The aim of this study is to evaluate effects of formulation and process technology on drug molecular dispersibility in solid dispersions (SDs). Nifedipine solid dispersions with ethylcellulose (EC) and/or Eudragit RL (RL) prepared by co-precipitation, co-evaporation, and fusion methods were characterized with FTIR, DSC, and XRPD for the content of nifedipine as molecular dispersion, amorphous and/or crystalline suspensions. A method was developed based on regular solution and Flory-Huggins theories to calculate drug-polymer interaction parameter in solid dispersion systems. A synergic effect of RL and EC on nifedipine molecular dispersibility in solid dispersions was observed. Increasing RL/EC ratio resulted in a higher degree of drug-polymer interaction that thermodynamically favored molecular dispersion, which, however, was counteracted by a corresponding decrease in the matrix glass transition point that kinetically favored phase-separation. Process methodology was found to play an important role in the formation of amorphous SD. The ranking of technologies with respect to the extent of molecular dispersion from high to low is fusion>co-evaporation>co-precipitation, wherein the solidification rate of polymeric solution and non-solvent effects were linked to kinetic entrapment of drug molecules in polymeric networks. Since nifedipine molecular dispersibility in EC/RL polymer(s) is a result of interplay between thermodynamic and kinetic factors, nifedipine molecular dispersions prepared for this study are thermodynamically metastable systems. To explore those supersaturation systems for use in drug delivery of poorly water soluble drugs, it is critical to balance drug-polymer interactions and matrix glass transition point and to consider a process technology with a fast solidification rate during formulation and process development of amorphous SD.
authors.affiliation: Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, 600 S 43rd Street, Philadelphia, PA 19104, USA. jingjun.huang@roche.com
authors.forename: Jingjun
authors.initials: J
authors.lastname: Huang
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Wigent
authors.forename: Waseem A
authors.initials: WA
authors.lastname: Malick
authors.forename: Harpreet K
authors.initials: HK
authors.lastname: Sandhu
authors.forename: Dharmendra
authors.initials: D
authors.lastname: Singhal
authors.forename: Navnit H
authors.initials: NH
authors.lastname: Shah
mesh_terms: D002152:Calorimetry, Differential Scanning; D002482:Cellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D011232:Chemical Precipitation; D002626:Chemistry, Pharmaceutical; D018360:Crystallography, X-Ray; D004337:Drug Carriers; D004339:Drug Compounding; D007700:Kinetics; D009543:Nifedipine / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D033362:Powder Diffraction; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared; D013678:Technology, Pharmaceutical / Q000379:methods*; D044366:Transition Temperature
chemical_list: D004337:Drug Carriers; D011108:Polymers; D012997:Solvents; C058665:Eudragit RL; C013517:ethyl cellulose; D002482:Cellulose; D009543:Nifedipine