3 Takeaways from the API Scale-up Strategies webinar series

So, your discovery team has found an efficacious active pharmaceutical ingredient (API), or perhaps a few APIs, and they’ve handed their precious findings over to you to figure out how to scale up that API’s synthesis, from milligrams to grams and kilograms without changing any of the vital properties.

There are many analytical tools that process development scientists can use to support this process, so choosing the right ones for your API scale-up strategy is not as straight forward as it seems.

That’s why we held a four-part webinar series on the subject! In the first webinar, we explored three main challenges in API scale-up: controlling particle shape and size, crystallization and polymorphism, and elemental impurities.

Our experts discussed how the combination of laser diffraction, automated image analysis, X-ray diffraction (XRD) and X-ray fluorescence (XRF) can help develop effective scale-up strategies to solve these challenges. Didn’t have time to join us – no worries, the whole series is available to view on-demand or read on for a quick recap!

Watch the API Scale-up Strategies roundtable

What’s the role of particle size and shape in API analysis?

API processability is critical to scaling up production – and particle size affects many processing parameters, such as how well the API blends and mixes with other compounds. The go-to particle sizing technique for this task is, of course, laser diffraction (LD), which provides the widest measurement range: from below 100nm to a few mm. Mastersizer has been the market leader for laser diffraction analysis for a long time, and now with its host of new features, the Mastersizer 3000+ offers even deeper insights into your samples.

However, particle size isn’t the end of the story: particle shape also affects performance and processability. Optical microscopy techniques are highly effective for monitoring particle shape. In the second webinar of the series, we presented automated image analysis as a solution that provides high resolution, individual particle detail, and shape information. The Morphologi 4 is effective -tool for both finding outlier particles that have different shape from the main particle fraction as well as  for automated quality control analysis when robust, user-independent results and validation are necessary.

Watch the API particle size and shape webinar to:

• Learn more about the Mastersizer 3000+ and the Morphologi 4
• Dive into the details of how particle size and shape affect API processability
• Discover our expert tips for improving processability parameters like flowability

Carefully monitoring API polymorphs

Turning to the interior properties of APIs, we examined X-ray diffraction as an effective solution for monitoring crystallization and polymorphic behavior. Indeed, small molecule drug substances require structural homogeneity, so monitoring the formation of crystalline and amorphous forms is a key challenge.

Such polymorphic forms of a drug substance can lead to very different chemical and physical behavior. Polymorphs thus have a direct effect on the ability to process the drug substance and on the quality, safety, and efficacy of the drug end-product.

X-ray diffraction (XRD) probes distances between atoms, analyzing whether these are arranged into crystalline or amorphous structures and whether the crystalline structures are homogenous. XRD pattern will be different for each of the polymorphs, which allows one to identify whether a sample consists of a single or multiple forms. It is also possible to quantify the amounts of these forms. XRD also allows to access stability of particular polymorph by monitoring its structure over time and at variable temperature. These experiments make it possible to predict shelf life of drug products and thus play crucial role drug development process.

With the Aeris compact XRD system, operators don’t need to be experts in crystallography to reliably measure and analyze polymorphic composition and crystallinity. The Morphologi 4-ID can then provide additional value, by showing how polymorphic form can affect particle shape using morphologically-directed Raman spectroscopy (MDRS).

Watch the API crystallization webinar to:

• Learn more about the benefits provided by the Aeris XRD and Morphologi 4-ID
• Discover case studies where polymorphisms led to expensive clinical failures
• Follow detailed walk-throughs for XRD and MDRS analysis

XRF as an alternative to ICP for elemental analysis

Elemental impurities can find their way into API compounds at every step of the drug development and manufacturing process. For example, remaining catalysts used in the formation of certain compounds must be removed upon completion of the reaction as they can be toxic for human consumption.

XRF technology has been widely adopted as a precise, rapid, and easy-to-use technique in many highly regulated industries, but not the pharmaceutical industry. During the elemental impurities webinar, we presented the operational and strategic benefits XRF analysis provides compared to inductively-coupled plasma (ICP) spectrometry, the go-to technique for elemental analysis in pharmaceutical applications.

ICP spectroscopy involves using very hazardous acids to strip ions from atoms in a sample, and then measuring those ions to identify the elements present. XRF instruments, by contrast, simply use high-energy radiation to excite the electrons around the atoms, which leave fluorescent ‘fingerprints’ that indicate elemental composition. XRF analysis is therefore non-destructive, allowing samples to be re-analyzed with other analytical techniques (LD, XRD) or even returned to production.

What’s more, ICP requires a highly specialized operator, the handling of dangerous acids such as hydrofluoric acid causes health and safety concerns, and sample preparation can take several days. In contrast, XRF samples can be prepared and measured within 30 minutes, without requiring extensive training.

Watch the API elemental impurities webinar to:

• Compare the benefits of XRF to those of ICP techniques
• Learn more about the regulations concerning elemental impurity screening for pharmaceutical applications
• Learn more about our XRF solutions, including the compact Revontium instrument and our pharmaceuticals