Although fully-solubilized lipid-based formulations generally provide optimal absorption, drugs that cannot be completely solubilized in the lipid excipient matrix may be formulated as partially-solubilized lipid suspensions. Maintaining the physical stability of the dispersed drug in the lipid phase requires control of factors including formulation viscosity, drug particle size, and total solids content, all of which are interdependent with processing times and temperatures.
The physical stability of the dispersion of a solid in a liquid is dependent on the relationship between fluid viscosity and particle diameter, which governs the particle settling rate and in dilute suspensions, and is described by the Stokes Einstein equation:
V = [d2(p- po)g)/18tf where, d is the particle diameter, n is fluid viscosity, p and p0 are the densities of the particle and fluid respectively, g is the gravity constant, and V is the settling velocity. Although this relationship best applies to dilute suspensions with less than 2% solids content, it illustrates the fundamental concept that settling velocity is proportional to the square of particle diameter and inversely proportional to fluid viscosity. Using this relationship as a guide, the formulator can assess the potential impact of these parameters on a formulation's physical stability or content uniformity and institute controls during development and scale-up of mixing, pumping, and hold time operations.
Predicting the physical and chemical shelf life of suspension formulations from accelerated storage conditions is more challenging than for traditional solid dosage forms, since changes in formulation viscosity and drug solubility induced by elevated testing temperatures may create conditions not reflective of those encountered during product use and storage, thereby leading to erroneous conclusions.
Formulation viscosity, a critical parameter governing the physical stability of suspension formulations, will increase in a nonlinear manner with solids content and will be affected by particle shape and size distribution. The drug particle size, relative crystallinity, and specific crystalline form can all be influenced by changes in the chemical synthetic process, the batch size, or when scaling the milling procedure from bench top to production batches. Since most low solubility drugs will be milled, it is important to understand the impact of different particle size distributions or amorphous content on product performance so that an appropriate control strategy can be established.
From a manufacturing perspective, viscosity has a significant influence on the ease and accuracy of capsule filling and should be closely controlled. Differences in processing temperature, mixing time, shear rate, mixer design and capacity will influence formulation viscosity and can lead to variation in the rate and extent of size attrition of suspended drug particles leading to dosing inaccuracy during filling operations. The mixing rate and shear force required to disperse the solid drug material in the suspending vehicle can be influenced by the formulation batch size, the drug physical properties, the drug loading in the suspending vehicle and the rate of addition of the drug to the vehicle. The formulation scientist should also be aware that the hydrophobic drug particles might aggregate to a greater extent during process scale-up if the rate of addition to the suspending vehicle changes relative to the shear force of the mixer. In this situation, attempting to disrupt the aggregates by mixing at a higher rate of speed may not achieve the intended result if the geometry of the mixing vessel and placement of the mixing blade relative to the surface of the fluid phase are improperly selected. For example, placement of the blade too near the surface could result in incorporation of air into the suspension leading to chemical instability or drug particle aggregation. An increased exposure to heat resulting from longer mixing times with larger batch size, may potentially result in degradation of heat sensitive drug substances. Drug particle size and loading in the suspending vehicle are other factors that can impact required mixing time or shear force necessary to prepare an adequate dispersion. For example, the viscosity of a PEG6000 suspending vehicle at 68°C is typically 300 to 500 centipoise in the absence of suspended drug particles. Introduction of drug particles with a mean diameter of 10 ^m at 30% loading may produce a viscosity of approximately 8,000 centipoise, while equivalent loading at an average particle size of 40 microns may increase the viscosity to approximately 10,000 centipoise. Process scale-up of suspensions, particularly from bench scale to first time manufacture, should take into account processing parameter values that are outside of the anticipated manufacturing ranges for time, temperature, and shear rate. This will allow the formulator to compensate for unexpected changes in chemical stability and product performance as the formulation evolves during the development process (36).
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