Scaling up nano-milling of poorly water soluble compounds using a rotation/revolution pulverizer

Pharmazie. 2016 Feb;71(2):56-64.

Abstract

We previously reported that a rotation/revolution pulverizer (NP-100) could mill a small amount of a drug (0.1 g) into nanoparticles in several minutes. In this investigation, scale up from the milligram to the kilogram scale of the nano-milling process by the rotation/revolution pulverizer was studied. Phenytoin was used as a model drug with low solubility in water. After confirming the improvement of the phenytoin bioavailability by milling to nanoparticles using NP-100, scaling parameters were evaluated using NP-100 and the middle scale model of NP-100 (ARV-3000T). A theoretical equation for the specific collisional energy was adapted for wet milling; this suggested that the relative centrifugal acceleration of revolution (revolution G) and the drug concentration in the suspension were the two most important parameters. The results obtained using NP-100 and ARV-3000T correlated well when these two parameters were identical. These results were applied to the large scale model of NP-100 (ARV-10KT), where 2 kg (1 kg x 2) of phenytoin nanoparticles were obtained in 60 min. The results from PXRD and DSC indicated that the milled phenytoin by ARV-3000T and ARV-10KT maintained its crystallinity. These results suggest nano-milling using a rotation/revolution pulverizer will be widely applicable to the development of nano-medicine.

MeSH terms

  • Animals
  • Anticonvulsants / administration & dosage*
  • Anticonvulsants / chemistry
  • Anticonvulsants / pharmacokinetics*
  • Chemistry, Pharmaceutical
  • Drug Compounding / instrumentation*
  • Excipients
  • Male
  • Nanoparticles
  • Nanotechnology / instrumentation*
  • Particle Size
  • Phenytoin / administration & dosage*
  • Phenytoin / chemistry
  • Phenytoin / pharmacokinetics*
  • Rats
  • Rats, Sprague-Dawley
  • Solubility
  • X-Ray Diffraction

Substances

  • Anticonvulsants
  • Excipients
  • Phenytoin