Highly Potent Active Pharmaceutical Ingredients (HPAPIs) play an increasingly important role in modern pharmaceutical development, particularly for therapies targeting serious diseases such as cancer. Their high pharmacological activity allows therapeutic efficacy at very low doses, but this potency also introduces significant challenges for handling, containment, and analytical characterization. One of the most important considerations is particle morphology, as particle size and shape can directly influence dissolution behavior, bioavailability, and overall formulation performance.
For poorly soluble compounds, controlling particle characteristics is often a critical strategy for improving drug performance. According to dissolution theory, increasing particle surface area can enhance dissolution rates when other physicochemical properties remain constant. As a result, accurate particle morphology characterization is a valuable tool during formulation development and process optimization.
Several analytical techniques are routinely used to evaluate pharmaceutical particles, but each presents limitations when applied to HPAPIs.
Laser diffraction is widely used for particle size analysis because it offers excellent reproducibility and can evaluate broad particle size distributions. However, it provides limited information about particle shape and often requires relatively large quantities of material. For highly potent compounds, this can create practical challenges due to material costs and containment requirements.
Manual microscopy can provide both particle size and shape information, but the approach is time-consuming and subject to operator variability. Acquiring sufficient particle counts to achieve statistical confidence may require significant analyst effort, reducing efficiency in routine development workflows.
These challenges have driven interest in alternative approaches that can provide comprehensive morphology data while reducing sample consumption, improving safety, and increasing analytical throughput.
A recently developed workflow combines Wet Dispersion–Thinly Encapsulated Sample Observation (WD–TESO) with Automated Particle Image Analysis (APIA). This approach is designed to enable safe and efficient characterization of particle morphology while maintaining statistical robustness.
The WD–TESO sample preparation method uses a small quantity of material dispersed within a low-volatility liquid medium and encapsulated beneath a cover glass. The prepared sample can then be analyzed using automated imaging technology capable of measuring thousands of particles within a short period of time.
By combining automated image acquisition with morphology-based filtering, the workflow supports simultaneous evaluation of particle size and particle shape while minimizing observer bias. The method is particularly relevant for HPAPI applications where containment, sample availability, and analytical efficiency are important considerations.
Particle morphology provides insights that extend beyond particle size alone. Shape-related parameters such as circularity and aspect ratio can help characterize particle populations, differentiate materials, and monitor the effects of manufacturing or formulation processes.
Advanced image analysis techniques allow researchers to assess particle populations using statistically meaningful datasets rather than relying on observations from a limited number of particles. This can improve confidence in development decisions and help ensure that particle engineering strategies are based on representative measurements.
For pharmaceutical scientists working with highly potent compounds, obtaining this level of information while reducing sample handling and exposure risks can offer substantial operational advantages.
The combination of WD–TESO and Automated Particle Image Analysis offers several potential benefits:
Together, these capabilities make the methodology particularly relevant for researchers seeking efficient particle characterization workflows for highly potent pharmaceutical materials.
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The particle size and shape of Active Pharmaceutical Ingredients (APIs) in solid dosage forms are critical quality attributes that directly influence dissolution behavior and bioavailability. Highly Potent Active Pharmaceutical Ingredients (HPAPIs) are expected to be effective against serious diseases such as cancer, as they exhibit effective pharmacological effects at low doses. However, as they possess high toxicity even at low doses, strict containment measures and safe handling are essential. Furthermore, HPAPIs are often poorly soluble, making the control of particle morphology particularly important from the perspective of improving dissolution performance. Assuming the Noyes–Whitney model, when the physicochemical solubility of the sample is constant, the dissolution rate depends on the solid surface area. Consequently, the control of particle morphology constitutes an effective formulation design strategy for poorly soluble drugs.
Traditionally, methods such as Laser Diffraction (LD) have been used to evaluate these particle characteristics. LD offers high reproducibility and is suitable for evaluating a wide range of particle size distributions; however, it cannot provide information on particle shape. Furthermore, it requires relatively large sample quantities (>100 mg) and necessitates equipment such as large isolators. Alternatively, image analysis using a manual microscope can simultaneously determine particle size and shape, but it is subject to significant observer bias and requires long times to secure a sufficient number of particles to meet statistical validity criteria.
To address these issues, a method combining Wet Dispersion–Thinly Encapsulated Sample Observation (WD–TESO) with Automated Particle Image Analysis (APIA) has recently been developed [1]. This method enables the evaluation of particle characteristics for HPAPIs while balancing safety, cost-effectiveness, and statistical validity.
Acetaminophen (Act) and Ibuprofen (Ibp) powders were used as model samples, and insoluble liquid paraffin with low vapor pressure was selected as the dispersion medium. A small volume of approximately 1 mm3 of sample was placed onto a microscope slide, gently dispersed using a needle in approximately 200 µL of dispersion medium, and then sealed using commercially available cosmetic nail polish with a cover glass to form a thin layer. An overview is shown in Fig. 1 and Fig. 2. Automated measurements were performed using a Morphologi 4 under transmitted light conditions with a 5× objective lens, using a Standard Operating Procedure (SOP). Approximately 4,500–8,000 particles per sample were measured in about 7 minutes. For image analysis, a morphology filter with a solidity threshold of <0.90 was applied to exclude overlapping and aggregated particles to select primary particles for further analysis.
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No significant differences in particle size distributions were observed between samples prepared using the WD–TESO method and the Dry-Dispersed (DD) samples used as controls, with example particles shown in Fig. 3. The DD samples were dispersed using the built-in Sample Dispersion Unit (SDU) of the Morphologi 4.
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Visualization using dendrograms confirmed that, compared to the differences between acetaminophen and ibuprofen, the differences between the dry and wet methods within the same sample were negligible (Fig. 4). Based on the above, the effectiveness of this method was demonstrated.
Furthermore, analysis of shape parameters revealed that ibuprofen exhibits higher circularity and aspect ratio values than acetaminophen, indicating a more isotropic shape. Consequently, it was confirmed that, under appropriate dispersion conditions, the WD–TESO method enables morphological analysis equivalent to that of the dry method. The target particle size range of WD-TESO is defined as approximately 10–500 μm.
![[AN260723-figure4-a.png] AN260723-figure4-a.png](https://dam.malvernpanalytical.com/fb26fb85-970a-4c7e-a039-b490004fc39f/AN260723-figure4-a_Original%20file.png)
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![[AN260723-figure4-c.png] AN260723-figure4-b.png](https://dam.malvernpanalytical.com/b79852c7-2d17-41f7-b705-b490004ff236/AN260723-figure4-b_Original%20file.png)
This method (WD–TESO + APIA) enables significant cost reductions in terms of sample consumption, capital expenditure, and processing time compared to conventional laser diffraction (LD) methods.
The WD–TESO method allows measurements to be performed using ultra-trace amounts of sample—approximately 0.2–0.6 mg—by sampling a volume of about 1 mm3. In contrast, LD generally requires approximately 100 mg of sample; consequently, sample costs are reduced to approximately >99% of the cost in theory.
HPAPI measurements using the LD method require large-scale isolator facilities, with installation costs running into tens of thousands of dollars. In contrast, the WD–TESO method can be performed in a small or simple containment environment, and even when equipment installation costs are included, total costs can be reduced to approximately a few % of those of the LD method under the scenario proposed in published study.
While conventional manual image analysis typically takes more than an hour to analyze around 5,000 particles, the analysis is completed in approximately less than 10 minutes using APIA. As a result, working time is reduced by approximately 90% to 95%, thereby reducing the operator’s workload and improving throughput.
Furthermore, simplifying the containment environment enables a reduction in the use of personal protective equipment (PPE) and cleaning solvents. Additionally, the introduction of wet dispersion helps to minimize the risk of powder dispersion and contributes to reducing dependence on large-scale dedicated equipment.
The combination of the WD–TESO method and APIA significantly transforms the cost structure of particle morphology evaluation, while maintaining safety for high-cost, high-risk materials such as HPAPIs. Specifically, sample consumption is reduced by approximately 99% of the original amount, equipment costs are reduced by approximately >95%, and processing time is reduced to approximately one-twentieth compared to manual microscopy methods. The WD-TESO method is particularly useful as an efficient evaluation tool in the early stages of formulation development.
[1] Sasakura, D. (2026). Cost-effective particle characteristics for highly potent active pharmaceutical ingredients using particle image analysis with thinly encapsulated sample observation methods. Journal of Drug Delivery Science and Technology, 116, 107905. https://doi.org/10.1016/j.jddst.2025.107905