Particle Size Analysis in Pharmaceutics: More Than Analyzing Drugs

The term ‘active pharmaceutical ingredients’ (API) defines the biologically active component of a drug product (tablet, capsule, cream, injectable) that induces the intended effects. Beside the intended therapeutic effect, pharmacokinetic and pharmacodynamic properties need to be considered.

For this reason, particle size is a major concern in drug development influencing stability, absorption rate and bioavailability in general. Active pharmaceutical ingredients (API) cannot be linked to a special type of molecule but cover proteins, nucleic acids, a wide range of small molecules, such as peptides, fatty acid derivates, steroids, glycosides, and much more. The stability and reactivity of these molecules often depend on environmental conditions. Temperature, pH, salt concentrations, or excipients affect their reactivity, surface charges might change, or inactive multimers and aggregates are formed. Particle size measurements by dynamic light scattering can be used to monitor, check, and control the particle size of APIs in order to judge size stability and optimize formulations. Coupling of APIs to nanoparticles or other nanodelivery systems can be monitored and checked for efficiency and stability. 

The graph in Figure 1 compares the particle size distribution of insulin, a peptide hormone, at room temperature and exposed to 80 °C. At room temperature, insulin shows a monomodal distribution with a mode around 5 nm. Heat exposure leads to the formation of inactive multimers appearing as higher order peaks.

Zeta potential measurements by electrophoretic light scattering shed further light on the electrostatic stability of pharmaceutical colloidal suspensions, but also and not less important on the surface charge of molecules in defined solvents.  A magnitude in zeta potential of higher than 30 mV is referred to be electrostatically stable. As a side note, beside electrostatic stabilization also kinetic and steric stabilization might have major impacts on suspension and/or emulsion stability.  Since the surface charge of cells is usually negative, the surface charge of molecules that are intended to interact and be taken up by cells is of high importance. The graph (Figure 2) shows a zeta potential distribution of a monoclonal IgG antibody in water. A slightly positive mean zeta potential of 10.5 mV could be obtained.

Solid dosage forms, such as granules, tablets, or capsules, are still the most prevalent dosage form on the market. They consist of a mixture of active pharmaceutical ingredients (API) and excipients. An excipient is a substance formulated alongside the API ensuring long-term stabilization, bulking up solid formulations that contain only small API amounts, or conferring a therapeutic enhancement on the API. The excipient type or the excipients combination not only influences flowability, compactability, and compressibility of the final product, but might change attributes of final dosage forms, such as content uniformity, viscosity, solubility, dissolution rate in the body, and drug absorption (4). The particle size distribution of two different excipients obtained by laser diffraction in dry mode is shown in Figure 3.

Density, porosity, and particle size distribution of granules are parameters to be considered in optimizing the packing before tablet compaction and filling capsules.

The dissolution time and rate of excipient-API complexes is critical for stability, dosing, and API-body uptake. As an example, the graph in Figure 4 shows the decrease in volume-weighted D₅₀-value of vitamin C granules in retard capsules dispersed in water over time determined by laser diffraction. Roughly 20 hours are needed to reach a stable minimal particle size.