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Particle Size Analysis in Pharmaceutics: More Than Analyzing Drugs

Particle size is a critical parameter in the pharmaceutical industry and needs to be considered in several different aspects. Particles are present as powders, suspensions, or emulsions, and each state needs to be characterized and quality-controlled with high traceability and accuracy in order to avoid health risks. 

On the one hand, particle size is a major concern in drug development affecting absorption rate and bioavailability of active pharmaceutical ingredients (API). In this regard, the dissolution rate and thus the bioavailability of powdered APIs is particularly important in formulations requiring a controlled or delayed release in the organism. Drug delivery systems such as liposomes in the nanometer range need to be controlled in the sense of size and stability in order to guarantee high drug efficiency or targeting of specific cell types. 

But on the other hand, as for most other applications, particle size also affects the flow behavior of pharmaceutical products, influencing production, storage, transport, and packaging properties of the formulations.

Active pharmaceutical ingredients

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.

Figure 1: Intensity-weighted particle size distribution of insulin. Measurements at room temperature (RT) show a monomodal distribution with a peak size below 10 nm. Heating to 80 °C leads to insulin aggregation and multiple higher order peaks. CC BY 4.0 licensed

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.

Figure 2: Zeta potential measurement of a 5 mg/mL antibody solution at pH = 5.9. A mean zeta potential of 10.5 mV could be obtained. CC BY 4.0 licensed

Drug delivery systems

The effectiveness of a particular medication is often limited due to physiological barriers, such as transport in the circulation system, crossing the blood brain barrier, or just cells and tissues. Severe side effects can be observed caused by drugs interacting with healthy tissue. Drugs with very low water solubility often come along with delivery issues, such as limited bio availability or less diffusion capacity into the outer membrane, which requires higher dosing (1). Small molecule therapeutics, including proteins and peptides, monoclonal antibodies (mAbs), and nucleic acids, have certainly provided new therapeutic functions. But these have also presented various challenges, including stability or intracellular delivery requirements (2).

Drug delivery systems are engineered to overcome these issues by targeted delivery and/or controlled release of therapeutic agents (3). The range of delivery systems is very broad and increases more and more with the development of new drugs and their special delivery and release needs. Just to mention a few of them: coated microparticles, lipid-based nanoparticles (micelles, liposomes, virus-like particles), solid nanoparticles, micro-encapsulations, hydrogels, and controlled release implants (2). For the nanoscale delivery systems, particle size is a critical parameter affecting and defining body and cellular uptake. Here, the dynamic light scattering technique enables development, optimization, and quality control of nanoscale delivery systems, such as liposomes. Temperature, pH, and stability issues can be monitored and addressed.

For details please follow the links below.

Liposomes: Size Measurements with the Litesizer™ 500

Monitoring the Formation of Small Unilamellar Liposomes Generated by the Detergent Removal Method

Micro-RNA Nanoparticles for Gene Silencing: Measuring Size and Zeta Potential with Light Scattering Technology

Excipients and excipient complexes

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.

Figure 3: Volume weighted particle size distribution of two different excipients measured in dry mode. CC BY 4.0 licensed

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.

Figure 4: Dissolution of Vitamin C granules from retard capsules in water, displayed as volume-weighted D50 values over time. CC BY 4.0 licensed


  1. J.K. Patra, G. Das, L.F. Fraceto, E.V.R. Campos, M.D.P. Rodriguez-Torres, L.S. Acosta-Torres, L.A. Diaz-Torres, R. Grillo, M.K. Swamy, S. Sharma, S. Habtemariam and H.S. Shin, "Nano based drug delivery systems: recent developments and future prospects," Journal of Nanobiotechnology, vol. 16, article number 71, 2018.

  2. A.M. Vargason, A.C. Anselmo and S. Mitragotri, "The evolution of commercial drug delivery technologies," Nature Biomedical Engineering, vol. 5, pp 951-967, 2021.

  3. National Institute of Biomedical Imaging and Bioengineering, "Drug Delivery Systems," 2022. [Online]. Available: www.nibib.nih.gov/science-education/science-topics/drug-delivery-systems-getting-drugs-their-targets-controlled-manner. [Accessed July 2022].

  4. Wikipedia, "Excipient," 2022. [Online]. Available: en.wikipedia.org/wiki/Excipient. [Accessed July 2022].