Flow and injection characteristics of pharmaceutical parenteral formulations using a micro-capillary rheometer

Int J Pharm. 2004 Feb 11;270(1-2):139-48. doi: 10.1016/j.ijpharm.2003.10.008.

Abstract

A micro-capillary rheometer consisted of a fine needle with an internal diameter of 347 microm attached to a 1 ml removable-needle syringe within an Instron device that operated in compression mode to provide various crosshead speeds ranging from 150 to 950 mm min(-1) covering typical clinical injection rates, and that determined the resulting force on the plunger. The crosshead speed and the resulting force were used to calculate the shear rate and the shear stress respectively. These were used in standard capillary flow expressions together with an independent measurement of the wall frictional force and allowed the viscosity of parenteral Newtonian solutions and non-Newtonian suspensions to be measured quantitatively and their rheological behaviour in needles of clinical dimensions to be established. Commercial pharmaceutical parenteral formulations consisting of three oil-based solutions and three aqueous suspensions were chosen for this study. The net injection forces were also obtained and it was shown that both the oil-based solutions and the aqueous suspensions covered similar ranges. The viscosities for the parenteral solutions were determined from the slope of the linear regression (R(2)>0.97) between shear stress and shear rate and ranged between 0.029 and 0.060 Pas. For the aqueous suspensions examined, viscosities decreased from low shear rate to high shear rate, following a power-law model and indicating a pseudo plastic behaviour. Standardisation of the micro-capillary rheometer with Newtonian silicone oils calibrated with a Rheometrics Fluids Spectrometer showed viscosity values consistent between the rotational flow measurements and capillary flow measurements which were within 5% and showed very high degrees of reproducibility between replicate samples. This degree of reproducibility allowed differences in the contribution of the wall frictional force to the required plunger force for both the oil-based and aqueous parenteral formulations to be determined reliably. The wall frictional force values for all formulations were similar (0.6-1.6 N) but the frictional forces of aqueous systems were found to decline significantly with plunger speed. The micro-capillary rheometer has been used to evaluate the impact of concentration changes due to sedimentation on the injectability of one of the aqueous suspensions, where it was shown that not only the viscosity increased but the shear thinning behaviour ceased at higher shear rates. The micro-capillary rheometer which was able to operate in clinical shear rate ranges has been shown to detect deteriorations in the injectable rheology of suspensions, which in the case here was due to pre-injection sedimentation.

MeSH terms

  • Capillary Action
  • Chemistry, Pharmaceutical
  • Flow Injection Analysis
  • Flupenthixol / chemistry*
  • Fluphenazine / analogs & derivatives*
  • Fluphenazine / chemistry*
  • Haloperidol / chemistry*
  • Infusions, Parenteral
  • Medroxyprogesterone Acetate / chemistry*
  • Rheology / instrumentation
  • Rheology / methods
  • Suspensions
  • Viscosity

Substances

  • Suspensions
  • Medroxyprogesterone Acetate
  • Flupenthixol
  • fluphenazine depot
  • Haloperidol
  • Fluphenazine