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