Interplay of formulation and process methodology on the extent of nifedipine molecular dispersion in polymers

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 characte...

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Bibliographic Details
Published in:International journal of pharmaceutics 2011-11, Vol.420 (1), p.59-67
Main Authors: Huang, Jingjun, Li, Ying, Wigent, Rodney J., Malick, Waseem A., Sandhu, Harpreet K., Singhal, Dharmendra, Shah, Navnit H.
Format: Article
Language:English
Subjects:
Amorphous solid dispersion
Calorimetry, Differential Scanning
Cellulose - analogs & derivatives
Cellulose - chemistry
Chemical Precipitation
Chemistry, Pharmaceutical
coprecipitation
Crystallography, X-Ray
dispersibility
dispersions
Drug Carriers
Drug Compounding
drugs
Drug–polymer interactions
Formulation
Fourier transform infrared spectroscopy
glass transition
Kinetics
Molecular dispersibility
Nifedipine - chemistry
polymers
Polymers - chemistry
Powder Diffraction
Process technology
processing technology
solidification
Solubility
Solvents - chemistry
Spectroscopy, Fourier Transform Infrared
Technology, Pharmaceutical - methods
thermodynamics
Transition Temperature
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Summary: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.
ISSN:0378-5173
1873-3476
DOI:10.1016/j.ijpharm.2011.08.021