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

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Abstract

A micro-capillary rheometer consisted of a fine needle with an internal diameter of 347 μm 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 (R2>0.97) between shear stress and shear rate and ranged between 0.029 and 0.060 Pa s. 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.

Introduction

Pharmaceutical parenteral formulations can be classified into aqueous or oil-based solutions, emulsions and suspensions and are delivered in different ways including intravenous, intramuscular, intradermal, intralesional, intraarticular and subcutaneous injections (Chien, 1992). For injectable suspensions in particular, since they are thermodynamically unstable systems, physical stability becomes as important as chemical and biological stability. In addition, injectable suspensions require evaluation of their characteristics in the syringe (syringeability) and during injection (injectability), as well as the effectiveness of their isotonicity, sterility and preservation (Floyd and Jain, 1996). From a clinical viewpoint, behaviour in the syringe describes the ability to pass easily through a hypodermic needle from the vial prior to injection. It includes characteristics such as the ease of withdrawal, clogging and foaming tendencies and accuracy of dose measurements (Floyd and Jain, 1996). Important aspects of the behaviour during injection include factors such as pressure or force required during injection, evenness of flow, aspiration qualities and freedom from clogging (Akers et al., 1987). These characteristics of parenteral suspensions in the syringe and during injection are closely related to the viscosity and particle characteristics of the suspension (Akers et al., 1987). Poor responses of formulations result from an increase in the following factors: the viscosity and density of the vehicle, the size of the suspended material and the concentration of the suspended drug. Probably the most important of these factors are those that relate to viscous flow (Floyd and Jain, 1996). Most methods used for the evaluation of these phenomena are qualitative in nature. Simple ejection of the suspension into an open container, performed very slowly with intermittent application of pressure to the plunger, has provided useful information about the injection characteristics of such suspensions. Force measurements from a materials testing device such as an Instron have been reported by Floyd and Jain (1996). Ritschel and Suzuki (1979) developed a new instrument to assess the injection characteristics of parenteral materials by measuring the time required to smoothly inject a solution or suspension into a meat sample under specified pressure. Regression equations were obtained for different types of syringes and needle size when a test formulation was injected. These equations permit the calculation of the expected injection time for a given syringe-needle system and for a given vehicle of a certain viscosity (Ritschel and Suzuki, 1979). As such Ritschel and Suzuki introduced the idea of using the syringe-needle system as a viscometer, using viscometric equations to predict the injection flow time.

Here we apply a syringe-needle system with an Instron instrument to provide an evaluation of injection characteristics of commercial parenteral formulations. The aim of this research was to configure the force measuring Instron in conjunction with the syringe-needle assembly to provide a micro-capillary rheometer capable of quantitatively evaluating the rheological characteristics and forces needed to inject parenteral products within a range of clinical shear rates and conditions.

Section snippets

Materials

The commercial oil-based solutions used were Fluphenazine decanoate® (10%; F H Faulding & Co., Australia), Haldol decanoate® (5%; Janssen-Cilag Pty Ltd., Australia) and Fluanxol concentrated® (10% from H. Lundbeck, Denmark). The following aqueous suspensions were used, Cilicaine® aqueous suspension (44%; Sigma Pharmaceuticals Pty Ltd., Australia), Depo-Ralovera® (15%) and Depo-Provera® (5%) (Pharmacia & Upjohn Pty Ltd., Australia). The formulations of the vehicles in the aqueous suspensions

Micro-capillary rheometer development and validation

The micro-capillary rheometer has been developed and validated using the standard Newtonian oils as shown in Fig. 1. In the micro-capillary rheometer these standards demonstrated Newtonian behaviour over a broad shear rate range relevant to the injection process. The frictional forces (f) for these measurements were estimated from the intercept of the force-speed regressions. The measured viscosity values were found to be consistent with the viscosity values of these standards as measured with

Discussion

Eq. (3) for Newtonian liquids indicates that the relation between the injecting forces for two Newtonian liquids will depend on their injecting speeds and viscosities. Two approaches are possible in the use of the equation. First, if the injecting speed is constant, the injecting force ratio will be proportionally dependent on the viscosity ratio of the two Newtonian liquids. Second, when the injecting force for two Newtonian liquids is kept constant, the injecting speed will be proportionally

Conclusions

The micro-capillary rheometer was used to test the injectability of some commercial intramuscular injections, which are known for their good behaviour during injection. The data collected can be used to assess the injectability of any new parenteral formulation in a quantitative manner. Both the rheological behaviour and force measurements at different injection speeds can be used for this purpose. Concentration increases in the Depo-Ralovera® formulation resulting from sedimentation, was

Acknowledgements

The authors would like to thank the polymer group of Professor Robert Shanks in the Applied Chemistry Department in RMIT University for their generous help in giving access to the Instron.

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