API Micronization in the Early vs. Late Stages of Drug Development: Goals and Challenges

Sep 12, 2025

Small molecule API micronization is a key process throughout drug development, improving bioavailability in patients by increasing solubility. Using techniques such as jet milling, the API particle size decreases, with micronization typically resulting in a particle size of less than 10 microns. This increase in surface area impacts absorption, content uniformity, dissolution, and other properties, which are not only important for patients but also formulation and manufacturing.

Throughout the drug development process, the goals, challenges, and approach to API micronization must shift. The process requirements in preclinical studies and Phase I/II trials differ from those in Phase III trials and commercialization. Below, we examine how API micronization goals and challenges differ at these two stages and highlight Neuland Labs’ capabilities.

Early, Lab-Scale API Micronization: Goals and Techniques

The primary goal in the early stages of drug development – which include preclinical work and small phase I/II clinical trials – is to get a better understanding of a drug’s behavior using in vivo models and to translate those findings into humans, performing safety assessments first. APIs that exhibit poor solubility can have limited absorption in preclinical models or human volunteers, preventing accurate study of drug efficacy and pharmacokinetics (PK).

Therefore, the overall goal of API micronization in the early stages of drug development is to reduce particle size and improve solubility, enabling drug development teams to accurately perform preclinical PK/efficacy studies and clinical safety studies.

Approaches to Small-Batch Micronization

At the early stages of drug development, small quantities of API are needed, and so small-batch micronization is the main focus. Lab-scale jet mills provide precise control over particle size distribution (PSD) and are widely used for micronizing small-molecule APIs.

At Neuland Labs, we use a Microtech Midas-M50 model for jet milling and size reduction in a controlled environment, ensuring that the API particles are reduced to the desired size range (typically below 5 microns) for optimal bioavailability. It allows us to work on batches as small as 5-10 grams and still achieve a precise PSD. We also use multi-mills, Hammer mills and wet mills at this stage, depending on the API properties.

Challenges of Early-Stage Micronization

Achieving the desired PSD with limited amounts of API is the biggest challenge to early-stage micronization. To accomplish a PSD with d90 (that is, the particle size below which 90% of the particles are found) less than 5 microns, it may take multiple cycles of jet milling. This can lead to higher material costs and longer processing times.

Additionally, variability in polymorphism or bulk density can impact reproducibility, especially when using small batches. Since micronization and particle engineering decisions made early can be difficult and costly to change, ensuring consistency even in small-scale batches is vital for later stages of development.

Late-Stage API Micronization: Goals and Techniques

As a drug progresses to Phase III trials and commercialization, the goals for micronization change from particle size reduction and enhancing bioavailability to scaling the process while ensuring consistency and meeting regulatory standards.

Approaches to Large-Scale API Micronization

The micronization process needs to be scalable, consistent, and compliant for larger batches. To do this, the process is optimized, and feed rate, mill pressure, and other critical parameters are fine-tuned to achieve the same PSD as lab-scale production, but on a commercial scale. Hammer mills or conical mills can be used at this stage for coarse grinding and to reduce particle size to a size suitable for jet milling. These are particularly helpful when working with two- or three-tier specifications.

Following optimization, the next step is to transfer the technology to the commercial plant. This involves validating the process by conducting small-scale trials at the plant to confirm that the micronization process is consistent and can be successfully scaled up.

Additionally, micronization at commercial scales must be thoroughly documented, and manufacturers must demonstrate that their processes are capable of producing consistent results from batch to batch. This involves compliance with Good Manufacturing Practices (GMP) and may require submission of process validation data to ensure that the micronization process consistently meets regulatory expectations.

Challenges in Large-Scale API Micronization

The primary difficulty at this stage is ensuring process scalability. Minor discrepancies in scale-up can lead to variations in PSD and other solid-state characteristics, which can impact drug performance. To overcome this, several smaller-scale trials are run before processing the whole commercial batch. These trials ensure that the process is consistent and that any potential issues can be identified and addressed before mass production begins.

Neuland Labs: Delivering Precision, Scalable API Micronization

Effective small molecule API micronization is a critical step in both early- and late-stage drug development, enabling consistent, compliant, and scalable particle size reduction. From lab-scale trials to commercial-scale production, tight control over PSD ensures consistent performance and reproducibility. At Neuland Labs, we have robust experience in API micronization, including complex and novel APIs, achieving d90 values below 5 to 10 microns and meeting three-tier specifications. We support this process further with in-house material characterization, including SEM, PSD analysis, and flow property measurements.