When considering whether particle size reduction will provide added value, a rule of thumb is that the particle size diameter in microns should be less than the solubility in mcg/mL. Therefore, compounds with solubilities < 100 mcg/mL are likely to benefit from some sort of particle size reduction and those with solubilities < 10 mcg/ml will almost certainly benefit from some sort of milling or micronization. If the solubilities are approaching 1 mcg/mL, then micronization will be a must and nanoparticulates are probably preferred. A more careful analysis like the one described by Rohrs in the following chapter (see Figure 6 in Rohrs' chapter), based on the dissolution rate being inversely proportional to the square of the particle radius and a conservative criteria for dissolution time, should be used for a safer and more accurate assessment of the particle size needed. In comparison to the rule of thumb, Rohrs' analysis would require particle size of < 16 um for 50 mcg/mL, < 5 um for 5 mcg/mL and <1.5 um for 0.5 mcg/mL, i.e. providing similar numbers to rule of thumb over this solubility range. However as you begin to approach higher solubilities, the particle size estimates from Rohrs' analysis would indicate a need to have particle sizes no greater than 50 um, even with solubilities of 1 mg/ml. Simple methods such as a milling, mortar and pestle attrition or high shear suspension homogenization can typically yield particle sizes down to 50 um. To get below 15 um, micronization is often required, and to get below 2-3 um, specialized techniques are often necessary, being a challenge during optimization when compound is limited.
The above discussion assumes that the particles are all of one size, monodisperse, when in reality there is generally a distinct distribution of particle sizes. It is generally the small fraction of larger particles present that really limit the composite rate of dissolution. (Rohrs' subsequent chapter, Higuchi and Hiestand, 1963; Johnson and Swindell, 1996) This is primarily due a very large fraction of the total compound mass is in the small number of larger particles and the surface area to mass ratio of these particles is small. Therefore, it is really the minimization of the number of large particles that should be sought.
The characterization of milled or micronized solids can be carried out in abbreviated fashion during lead optimization to make sure that large particles have been eliminated. This can often be assessed by simple microscopy for size ranges greater than a couple of microns. Another common testing method at this stage may be simple filtration using appropriate pore sized membranes and assaying total solution concentrations before and after, then coupling that information with supernatant assessments after centrifugation. More extensive characterization to obtain mean particle size information can be carried out as appropriate. The important point of the characterization during lead optimization is to make sure that you have in fact reduced the particle size below some threshold and that you have some sort of means to compare future formulations of the same material.
The potential for particle size reduction to enhance dissolution and oral absorption has been recognized for some time (Levy, 1963). However, it can also result in other changes in pharmacokinetics and on occasion reductions in exposure if not careful with characterization or formulation of the milled solid. While the enhanced oral exposure is typically measured by the area under the curve (AUC) for plasma concentration versus time curves, it is also possible to significantly impact the shape of the PK profile. The maximum plasma concentration (Cmax) and time at which it is reached (Tmax) can be shifted to higher levels and shorter times with increased rates of dissolution following particle size reduction. Even in cases where the extent of absorption may be relatively high, there may be advantages in altering Cmax or Tmax without significant gains in AUC (Bihanzadeh et al., 1996).
Particle size reduction does not always result in formulation performance consistent with an increase in dissolution rates. With reductions in particle size, increase surface energies are generated and there is an increased driving force for agglomeration of the primary particles to form higher order aggregates. There also can be greater difficulty in wetting the surface of the smaller particles, an obvious prerequisite to dissolution of the solid. If the primary particles are not regenerated through disruption of the aggregates, the advantages of particle size reduction can be lost and actual reductions in exposure can be noted with milling of the solids (Jindal et al., 1995). It is critical that the selection of excipients, typically polymers and surfactants, and their level, are appropriate to facilitate wetting and minimize aggregate formation. During lead optimization, the need for any sort of long term physical stability of the suspension is somewhat obviated by ability to coordinate suspension preparation and dosing. This requires a close communication and coordination between the dosing groups and the pharmaceutical chemistry group.
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