Tayana Solutions

Understanding API Changes in Pharmaceutics: What You Need to Know 

For pharmaceutical experts, the journey of an active molecule from its endpoint at the end of its synthetic pathway to the crystallization and ultimate site of action is fascinating and necessary to understand. Book a free cloud ERP demonstration. Book Now 

Scientists and regulators alike are interested in understanding how a drug performs as it passes through different phases of its life cycle, from initial development to eventual use. Quality by Design (QbD) initiatives bring these two groups together to provide a thorough understanding of the manufacturing process of a dosage form, ensuring that it is adequate and fit for purpose. 

Advances in the science of crystal formation have led to a better understanding of how a molecule is added and incorporated into the crystal that is its home until it reaches the gastric intestinal (GI) tract. Even though the instant of nucleation remains a moment of magic or mystery, scientists have been able to model the growth of crystals and study the process of isolating and drying formed crystals. 

In recent years, the milling process has opened to a greater understanding of the mechanism and extent of crystal fracture, which allows the properties of the resultant particles to be predicted with greater accuracy. A particle characterization technique called microscopy can examine the output material with its particles, agglomerates or aggregates by size, shape and surface area. The disintegration of a dosage form can be followed after ingestion in a range of model shapes. This data can be mixed with other observations to develop models of how drugs will reach the bloodstream and eventually be eliminated. 

Many drug development processes are amenable to mechanical modelling. Statistical modelling is used to understand those processes that will never be modelled mechanistically. Recent work in the United Kingdom has led to the creation of the ADDoPT (Advanced Digital Design of Pharmaceutical Therapeutics) initiative, which combines all sizes of pharmaceutical companies, top academic departments and Government organizations, such as the Hartree Computing Centre. This initiative provides an overview of the manufacturing and performance of drug particles. 

A pharmaceutical industry study found that 66.8% of all prescription drug purchases in 2012 were for oral solid dosage forms, which include tablets and capsules. 

Several routes to developing a tablet are available, some requiring fewer processing steps and thus superficially making them more attractive. However, it is unclear if ‘equivalent’ processes result in differing extents of ‘mistreatment’ caused to particles during the journey; regimes that are superficially attractive but complex in practice are limited by such lack of knowledge. 

 In this article, we’ll look at the role of excipients in the pharmaceutical industry.

When a drug is consumed orally, it must be formulated into a solid dosage form that can withstand the rigours of the digestive tract. Excipients are added to modify the properties of the drug particles, lubricants are added to facilitate manufacturing steps, and disintegrants help to break down the tablet when it reaches the stomach. 

The active pharmaceutical ingredient is the molecule or compound that makes a drug effective. Excipients are ingredients used in creating pharmaceutical medications, but they differ from APIs because they are larger, chemically distinct from APIs and often microcrystalline or amorphous. 

After a drug particle’s journey through a pharmaceutical tablet, it may be possible to determine whether the API is distributed within the tablet and whether it exists as agglomerates or not. However, the level of scrutiny does not allow the size and shape of unprocessed particles to be determined with the detail afforded by processing techniques. A recent review covers the potential understanding of unprocessed drug particles. 

A gap in understanding exists regarding how particles behave within blends. A particular area of interest for researchers is the phenomenon of sticking, in which pharmaceutical particles adhere to the faces of tablet punches. Sticking leads to downtime and increases the expense and complexity of tablet manufacture. 

The particles’ physical and chemical properties are thought to affect the sticking behaviour. One method is to choose a contact surface for the punch with lower surface energy. Another way is to increase the particle size and reduce particle density, which may decrease sticking. However, there is no direct correlation between observed particle properties before processing and overall sticking potential. The API may change en route from the initial measurement of its properties to the punch face it attaches to. Fresh surfaces are more adhesive, and a higher surface area leads to a higher likelihood of adhesion. 

The ability to determine whether a particle or agglomerate changes during standard pharmaceutical processing could provide new insights into pharmaceutical processing methods and potentially improve end-to-end understanding. 

Challenges in developing drugs 

Chemical imaging has been used to investigate the distribution of single components within a formulated sample; however, due to limitations in optical resolution, the particle sizes were not directly measured, and pixels often contained more than one of the components. Pixels were colour-coded to indicate relative concentrations, and domains were identified by examining the relationship between domain size and particle size. 

A new approach for image-based particle characterization with integrated Raman capability has recently addressed the difficulty of characterizing the primary particle characteristics of single components within multi-component systems. This approach enables the definition of particles in terms of size and shape. It thus allows sub-classification of composite samples into their members, which is particularly helpful for determining actual particle size distributions rather than domain sizes. 

Image-based particle characterization with integrated Raman capability can be used to characterize the primary particle characteristics of individual components within composite samples. This approach enables the sub-classification of particles in terms of size and shape, thus allowing the actual particle size distribution of individual members to be determined rather than the domain size. 

Researchers investigated particle size and shape changes, along with data from the two processing systems. The combination of the two datasets provided insight into the attrition mechanisms within the unit processes. For the milling process, minor shifts in both size and shape could suggest a surface abrasion mechanism where the elongated particles underwent ‘chipping’. However, the more significant change in size and shape proposed for the powder feed system suggests a bulk fracture mechanism where the particles experienced a complete fracture. 

The work demonstrates that the process affected the size distribution of input API particles. However, characterizing the particle characteristics of intermediate API/blend particles showed that the mechanism behind this change is related to changes in particle morphology. This improved understanding of intermediate blend characteristics could be applied to subsequent processing steps, removing the requirement to rely on initial particle characterization data. 

Later work used the measured particle-size distribution of the feedstock to determine where attrition took place in the unit process. This effort applied the understanding that the blend characteristics were affected by the degree of erosion and used those results to understand the process better and investigate how varying conditions affected decline. The study showed that increasing the feed rate increased attrition levels, providing an example of how changing a tool used for control could be a significant source of variation in the process. 

Hoffmann combined various imaging techniques with more traditional chemical analysis to demonstrate the dispersion of micronized API, present in a formulation as cohesive aggregates. The use of jet-milling is every day for APIs with low solubility. The process results in beautiful particles that are commonly cohesive/adhesive and thus can be challenging to disperse uniformly. However, the study observed that a particular powder feed system could disperse the particles, leading to a homogeneous blend without altering the primary particle size of the API. 

Studies have shown that materials are prone to attrition during processing. If this occurs, the input particle characterization is no longer representative of the material in the process or the dosage form. For these materials, an important characteristic may be their propensity for process-induced attrition. Several particle strength measurements are available; however, further research is needed. The authors have observed that “highly friable” particles can survive processes intact where less friable materials do not. This would suggest that we need to consider the strength of the primary particles and their nature within a formulation.  


New tools are being developed that will provide further insight into the inner workings of pharmaceutical processes. These may enable a more rational choice of formulation route and help fit with the goals of the Manufacturing Classification System.  

Get a detailed walkthrough of a system that meets all your need in the most budgeted amount. Book your schedule for a detailed walkthrough demo. BOOK NOW