A comparative study between hot-melt extrusion and spray-drying for the manufacture of anti-hypertension compatible monolithic fixed-dose combination products

Int J Pharm. 2018 Jul 10;545(1-2):183-196. doi: 10.1016/j.ijpharm.2018.05.008. Epub 2018 May 3.


The purpose of this work was to investigate the application of different advanced continuous processing techniques (hot melt extrusion and spray drying) to the production of fixed-dose combination (FDC) monolithic systems comprising of hydrochlorothiazide and ramipril for the treatment of hypertension. Identical FDC formulations were manufactured by the two different methods and were characterised using powder X-ray diffraction (PXRD) and modulated differential scanning calorimetry (mDSC). Drug dissolution rates were investigated using a Wood's apparatus, while physical stability was assessed on storage under controlled temperature and humidity conditions. Interestingly both drugs were transformed into their amorphous forms when spray dried, however, hydrochlorothiazide was determined, by PXRD, to be partially crystalline when hot melt extruded with either polymer carrier (Kollidon® VA 64 or Soluplus®). Hot melt extrusion was found to result in significant degradation of ramipril, however, this could be mitigated by the inclusion of the plasticizer, polyethylene glycol 3350, in the formulation and appropriate adjustment of processing temperature. The results of intrinsic dissolution rate studies showed that hot-melt extruded samples were found to release both drugs faster than identical formulations produced via spray drying. However, the differences were attributable to the surface roughness of the compressed discs in the Wood's apparatus, rather than solid state differences between samples. After a 60-day stability study spray dried samples exhibited a greater physical stability than the equivalent hot melt extruded samples.

Keywords: Amorphous solid dispersions; Continuous manufacture; Fixed dose combinations; Hot melt extrusion; Spray drying.

Publication types

  • Comparative Study

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / chemistry*
  • Antihypertensive Agents / chemistry*
  • Calorimetry, Differential Scanning
  • Crystallography, X-Ray
  • Diuretics / chemistry*
  • Drug Carriers
  • Drug Combinations
  • Drug Compounding
  • Drug Liberation
  • Drug Stability
  • Hot Temperature*
  • Hydrochlorothiazide / chemistry*
  • Kinetics
  • Microscopy, Electron, Scanning
  • Particle Size
  • Plasticizers / chemistry
  • Polyethylene Glycols / chemistry
  • Polyvinyls / chemistry
  • Powder Diffraction
  • Pyrrolidines / chemistry
  • Ramipril / chemistry*
  • Solubility
  • Surface Properties
  • Technology, Pharmaceutical / methods*
  • Vinyl Compounds / chemistry


  • Angiotensin-Converting Enzyme Inhibitors
  • Antihypertensive Agents
  • Diuretics
  • Drug Carriers
  • Drug Combinations
  • Plasticizers
  • Polyvinyls
  • Pyrrolidines
  • Vinyl Compounds
  • poly(vinylpyrrolidone-co-vinyl-acetate)
  • polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer
  • Hydrochlorothiazide
  • Polyethylene Glycols
  • polyethylene glycol 3350
  • Ramipril