Particle Identification and Particle Size Distribution in Drug Delivery

Particle size distribution (PSD) remains a vital characteristic of pharmaceutical products in every type of preparation, including sterile liquid products, solid oral drug products, semi-solids, and aerosols.

An active pharmaceutical ingredient (API) ranging from nanocolloids to millimeters may exist in the formulation of particles, with the distribution and size of these particles often influencing pharmaceutical products’ efficacy and safety.

In practice, PSD impacts on a drug’s dissolution rate and bioavailability, the deposition of particles in aerosol use, the drug’s release rate in controlled-release formulations, and the product’s long-term stability throughout storage and use.

Laser diffraction’s reproducibility and high accuracy have led to it being the most used method in the determination of particle size. This article explores how the use of Unchained Labs’ Hound - a unique device combining light microscopy with Raman spectroscopy - can improve the speed of particle identification while maintaining reliability.

Topical Semi-Solid Drug Delivery

Particle size also plays a key role in transdermal and topical drug delivery as it determines the product’s pharmacologic properties. For instance, if the API is suspended in a vehicle such as a cream or gel, the particle size will interact with the vehicle’s solubility to dictate the dissolution rate.

Particle size also impacts on the depth, rate, and pathway of absorption through the skin. Choosing the most appropriate particle size in topical preparations can assist in maximizing drug efficacy at the site of action while minimizing risks of systemic adverse reactions.

Drugs - particularly over the counter (OTC) medication – often include multiple APIs. As such, it is important that the right ratio is maintained if product efficacy and consistency are to be ensured. Confirming or clarifying the ratio can be more difficult where API particles are similar in size. PSD alone may be insufficient in these circumstances.

Research has shown that the Unchained Labs Hound can be employed to determine PSD in a topical acne treatment which contained two APIs in one formulation, also distinguishing each API from the other.

The product in question was a cream containing 2.5% benzoyl peroxide and 0.1% adapalene. A thin layer was placed on a gold-coated slide before optical imaging and Raman 532 nm laser spectroscopy was used to automatically analyze a 1.6 x 1.6 mm area. This analysis confirmed that 2,797 benzoyl peroxide particles and 1,203 adapalene particles were present in the sample area.

Following data collection, Hound was able to produce a cumulative particle size distribution analysis that returned the D50 and D90 values for adapalene. This showed that adapalene particles were smaller than benzoyl peroxide particles, while also being present in a narrower size range.

Particle Identification and Particle Size Distribution in Drug Delivery

The researchers needed a relatively large sample area because of the sample’s low concentration of adapalene. Thanks to Hound’s image-directed Raman spectroscopy capabilities, the analysis was completed in approximately three hours – significantly quicker than the 17 hour analysis time from ultra-fast Raman spectroscopy working with a sample area of this size.

This analysis method may be helpful in determining PSD and identity at every stage of semi-solid pharmaceutical formulation production – including development, quality control, and storage.

Aerosol Drug Delivery

In inhalation devices like asthma inhalers, controlling particle size enables drug delivery to be targeted towards certain regions of the airways, thus optimizing therapeutic responses.

Different particle sizes are able to reach different parts of the airway. Bronchodilators work best when particle sizes are in the larger range, for example, because the site of action is found in the proximal airway.

In contrast, fine particle sizes disperse more widely within the lungs, meaning they could be more effective in the treatment of distal lung disease, such as with steroids.

Researchers have demonstrated that the Unchained Labs Hound can be used to successfully characterize particle size distribution for an inhaler which includes both a steroid (fluticasone) and a bronchodilator (salmeterol).

The medication in this instance was actuated three times from a dry powder inhaler via a cascade impactor. Particles were sampled over a 1 x 1 mm area before being analyzed with a 532 nm Raman laser. Data were acquired on 15,000 particles from 2-10 micrometers, then evaluated using the device’s integrated spectra library to facilitate identification.

452 of the particles were found to contain API, with PSD analysis confirming a far smaller average size for the bronchodilator (3.2 micrometers) in contrast with the steroid (6.0 micrometers).

Because the PSD of the APIs overlapped, the instrument’s Raman capabilities were vital in distinguishing between the two particles and confirming the mixture’s composition.

Particle Identification and Particle Size Distribution in Drug Delivery

Researchers conducting a similar study were able to characterize the API distribution in a nasal spray which contained a single API and an inert ingredient (cellulose) over a 4 x 4 mm sample area.

The concentration of API particles was found to be very low, at 2%. Spending time identifying each individual particle using Raman would not be practical, but because cellulose particles were more elongated, it was possible to utilize morphology characteristics to exclude cellulose particles, therefore allowing the researchers to generate a selective sample.

Identifying the particles with Raman revealed a concentration of API at 34%. This enabled the PSD of 1,011 API particles to be analyzed within a 4-hour timeframe - substantially less time than a non-selective approach would have taken.

Here, the researchers anticipated that using a non-selective method would have taken approximately 66 hours to complete.


Where PSD methods rely solely on shape and size, these may not provide sufficient data to accurately characterize an API in a mixture. To address this, the Hound from Unchained Labs begins its analysis by using brightfield or darkfield imaging to automatically characterize each particle within the sample for shape, size, morphology, and fibrosity.

Hound then employs Raman spectroscopy at either 785 or 532 nm to capture the particles’ chemical signature before identifying them using its built-in, customizable database of spectra.

This combination of two techniques is able to ensure that PSD can be rapidly performed on complex samples, with an orthogonal analysis method available to confirm identity.

References and Further Reading

  1. Elder D, Pacowski G, Nelson P, et al. (2018) The importance of particle size analysis. Available at: Accessed: July 2020.
  2. Shekunov BY, Chattopadhyay P, Tong HHY, et al. Particle Size Analysis in Pharmaceutics: Principles, Methods and Applications. Pharmaceutical Research 2007; 24: 2. DOI: 10.1007/s11095-006-9146-7.
  3. Unchained Labs (2018) Chemically specific particle sizing for topical formulations with Hound. Available at: Accessed: July 2020.
  4. Unchained Labs (2018) Chemically specific particle size distribution for nasal spray with Hound. Available at: Accessed: July 2020.
  5. Unchained Labs (2018) Chemically specific particle sizing of dry powder inhalers by Hound. Available at: Accessed: July 2020.
  6. Usmani OS, Biddiscombe MF, Barnes PJ. Regional Lung Deposition and Bronchodilator Response as a Function of β2-Agonist Particle Size. American Journal of Respiratory and Critical Care Medicine 2005; 172: 1497-504. DOI: 10.1164/rccm.200410-1414OC.

This information has been sourced, reviewed and adapted from materials provided by Unchained Labs.

For more information on this source, please visit Unchained Labs.


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