This article was originally published on 12.11.2020 and has now been updated with new information.

Whether a dose form is a tablet, capsule, injection, suspension, or any another formulation, API’s physical properties play a key role in determining whether the finished dosage form will perform effectively. 

Particle size distribution, or PSD, is probably one of the most important physical properties of an API. Most of the time, it is a critical parameter that can affect your formulation process and bioequivalence.  

To meet the specifications, the API provider must possess expertise in crystallization and size reduction processes. At Teva api, our experience has taught us that it is essential to collaborate closely with pharmaceutical manufacturers to set the right specifications that suit the formulation needs. This collaboration will ensure the API is manufactured flawlessly and that there will be a consistent supply. 

The approach for setting PSD specifications is different from setting chemical specifications, in several ways: 

• Physical quality is a tailor-made property based on the drug product 

Specifications usually define an acceptable upper limit of a certain impurity (i.e., percentage of impurity, residual solvent, etc.). With particle sizing, limits on sizes are based on what impacts your formulation process or drug product profile. For instance, in some cases you may require exclusively fine particles or a more flowable powder with coarse particles, while in other cases, particle size will be a less important parameter. 

• Physical quality is related to your formulation process  

The limits will often be well defined in pharmacopoeias and official quality guidelines, guiding the definition of a specification limit that is accepted by many authorities and manufacturers. However, physical quality is client specific. Your formulation can be complex and sensitive to small changes in particle shape and size. For that reason, particle size specification can be specific for formulation process. 

• There are no universal methods for PSD measurements

Pharmacopoeias do not define universal methods for PSD measurements, and different methods such as sieving, or laser diffraction microscopy, will deliver different results. Even different instruments working on the same principle, such as different models of laser diffraction instruments, might deliver different results. In addition, each method is product-specific depending on various factors potential solubility and morphology. 

As a result, the API provider should adopt a case-by-case approach and work closely with the pharmaceutical manufacturer to ensure specific needs are met. 

Details are Essential 

As the particle size increases, its surface area decreases, resulting in a decline in the rate of dissolution over time. The dissolution curve may have a “tail” of longer dissolution times that is dominated by the last few coarse particles to dissolve.  

For that reason, it is necessary to control the content of both average and coarse particles. 

Besides affecting dissolution, particularly for poorly soluble APIs with low bioavailability, particle size can influence the behavior of the bulk powder while being stored or formulated.  

Presence of agglomerates and aggregates should be evaluated to make sure that the particle size method is fit for the purpose. Whether you need to monitor the size of the primary particles for better dissolution control or want to control the presence of agglomerated and aggregated particles, Teva api develops the materials and methods that are relevant to your product. 

Besides using laser diffraction measurements, we employ optical and scanning electron microscopy to learn more about the shapes and sizes of the particles. This allows us to better define the powder and our particle sizing methods.  

Particles are three-dimensional objects while particle size distribution gives only one dimension as a result, the diameter of an equivalent sphere. Thus, microscopy is an essential part of interpreting the results, especially for particle shapes that are far from spherical, for example needle-like, columnar, plate-like, or flake-like. We make sure that the results we obtain are representative of the powder. 

When it comes to the dosage form’s manufacturability, other properties are also important. Material needs to be free-flowing, non-sticky, and must easily blend with excipients.  

Dissolution occurs faster with fine particles while manufacturability is easier with coarser particles. A well-defined specification that balances these requirements is the key to production robustness. 

It is important to remember that the different estimators for PSD are not mutually exclusive. If the API is milled in order to reduce d(0.9), the d(0.5) will decrease as well. 

In addition to PSD, other physical properties that may play an important role in pharmaceutical manufacturing, will be specified as well such as Bulk Density and Tapped Density.

Statistics Rule! 

APIs are powders that contain a multitude of particles, each with a different size. The population of the particles is commonly called a statistical point estimator. For example, the term d(0.5) is the population’s median particle size and is a statistical point indicator. 

One of the most important concepts that applies to these terms is the central limit theorem. This fundamental statistical rule implies that statistical point estimators will always be distributed normally, regardless of the distribution of the population they describe.  

This concept can be easily illustrated by the following simple dice-throwing game: when a single die is thrown, the distribution is uniform. The chances of obtaining any value from one to six are equal. However, the arithmetic mean of many rounds with several dice will converge in a normal (Gaussian) distribution with a given average and standard deviation. 

So, although API manufacturing is a well-controlled process, the median PSD [d(0.5)] of many batches will always have a certain normal distribution with a given average and standard deviation. Tight control over the crystallization parameters and particle size reduction technique settings may reduce the standard deviation, but some variance will always be there. The same applies to d(0.9), d(0.1), etc. 

Therefore, a product specification is best defined when it is based on statistical data from many batches. Teva api scientists have developed a methodology to generate specifications with statistical significance based on a wide database of many commercial batches, as well as on a limited number of lab and pilot batches for new products under consideration. 

Trends in Regulatory Requirements

Today, most health authorities recognize that PSD and other bulk physical properties should be defined in specifications.  

The current trends include: 

• Requiring three-tiered specifications. For example, requiring limits on d(0.1), d(0.5) and d(0.9). 
• The limits may be one-sided or in some cases a bi-sided limit will be required. 
• Other physical properties should be defined if it been found to be a Critical Quality Attribute (CQA). For example, Bulk Density and Tapped Density. 

Wide or Narrow? 

The range of bi-sided specifications should be carefully selected. Ranges that are too wide may cause the final dosage form to fail in dissolution testing. Therefore, the limits should be selected with some safety margins that are evaluated during the development of the formulation and the biostudy. 

On the other hand, ranges that are too narrow compared to the normal distribution of the provider’s API batches may make it difficult to consistently manufacture material that complies with the specifications. 

 Examples for PSD Specifications Format 

• Three tiers: d(0.1), d(0.5), d(0.9) 
• Control of coarse particles: Upper limit for d(0.9): d(0.9) NMT XX μm. This limit will ensure dissolution. 
• Control of average particles: d(0.5): NMT XX μm  and/ or  NLT XXμm This limit will ensure consistency. 
• Control of fine particles: Limit the bottom range for d(0.1): d(0.1) NLTXX μm. This will ensure manufacturability. 
• Bulk and Tapped Density: Set a bottom limit for these values. 

Accurate PSD Specifications Begin with Reliable Data 

For commercial products, Teva api maintains a statistical database of physical properties from at least 10 batches on a commercial scale. In many cases additional data is available from multiple sites, historical trends, etc.  

This data is used to propose specifications and recommend analytical methods to customers. If the customer uses a different PSD method, both should work together to align results and specification limits. 

Creating specifications for a new product is more challenging because of the absence of a statistically significant database. Teva api uses statistical tools to forecast the future variance of production batches based on limited commercial data, with additional data from smaller-scale manufacturing.  

Over time, this process has been proven to provide accurate limits for specifications. As with commercial products, it is essential that the API provider and customer align their PSD analytical methods. 

It takes a strong working relationship between the API provider and finished drug product manufacturer to produce and deliver high quality APIs. Careful planning, open communication and close collaboration with a trusted partner will ensure that you receive a consistent supply of superior products – the key to your success in today’s marketplace. 

Thank you to Oshrat Frenkel, Dario Klaric & Marina Ratkaj, for their contributions to this article.