Advancing Crystallization Process Development with In-line PAT Tools

At TAPI, innovation drives everything we do—from early development to commercial scale. Crystallization is one of the most critical steps in API manufacturing, and gaining control over this process is key to achieving consistent critical quality attributes (CQAs), such as polymorphic form and particle size distribution.

Traditionally, crystallization monitoring has depended on offline sampling, a time-consuming and complex approach that limits real-time insights and hinders process optimization. To overcome this, our R&D team implemented in-line process analytical technology (PAT) tools to solve a specific and scientifically challenging crystallization issue during the development of a novel API sulfonate salt.

The challenge? A late-appearing polymorphic form—an industry-recognized risk with major implications for product consistency and performance.

Leveraging Blaze high dynamic range (HDR) process microscopy in tandem with Raman spectroscopy, our scientists achieved rapid root-cause identification and developed a robust new crystallization process—demonstrating the power of real-time PAT integration.

From Insight to Impact: Background & Approach

During the first kilo-lab scale-up of the sulfonate salt, a new polymorphic form unexpectedly emerged—despite extensive prior screening. To tackle this, our team deployed advanced PAT tools, including HDR microscopy and Raman spectroscopy, for in situ monitoring of particle statistics and polymorphic transitions.

This data-driven approach allowed rapid, informed decision-making and accelerated the development of a new crystallization process.

Why PAT Makes the Difference

The Blaze 900 system integrates HDR microscopic imaging, turbidity measurement, and Raman spectroscopy into a single, multi-functional probe. Its advanced image analysis algorithm provides accurate particle statistics—significantly outperforming conventional tools like PVM and FBRM.

This capability enables real-time tracking of key crystallization phenomena, including nucleation, growth, attrition, oiling out, and polymorphic transformations—driving deeper process understanding and control.

Overcoming the Polymorphism Challenge

Lab investigations revealed that the anhydrous form of the compound could rapidly convert into either a monohydrate or a newly discovered methanolate, depending on the solvent system. These two novel forms, each with distinct crystal habits and thermal behaviors, were shown to be in an enantiotropic relation.

Figure 1. Microscopic images over time showing the crystallization of the anhydrous polymorph followed by spontaneous and gradual transformation into the monohydrate after reaching the transition temperature.

Figure 2. Microscopic images over time showing the crystallization of the anhydrous polymorph followed by spontaneous and gradual transformation into the methanolate after reaching the transition temperature.

With direct crystallization of the anhydrous form no longer feasible, our team pivoted to explore seeded cooling crystallization to obtain the monohydrate.

*Figure 3. Microscopic images over time showing the seeded cooling crystallization of the monohydrate polymorph.*

*Figure 4. Cube weighted particle statistics and chord length distribution (CLD) over time during monohydrate form crystallization.*

This was followed by extensive Raman-supported solvent screening to enable a solvent-mediated polymorphic transformation into the desired anhydrous form—unlocking valuable insight into conversion kinetics.

*Figure 5. Microscopic images of starting monohydrate and obtained anhydrous form in acetonitrile slurry.*

*Figure 6. Characteristic bands in the Raman spectra of monohydrate (red) and anhydrous (blue) solid forms and in-line spectra over time during the polymorphic conversion.*

A Smarter, Faster Path to Process Development

The integration of HDR microscopy and Raman spectroscopy enabled precise identification of transition points and streamlined the development of a robust crystallization pathway. This not only reduced development time but also improved product quality and ensured more reliable process control—highlighting the strategic value of in-line PAT.

The combination of Blaze 900 in-line process microscopy with Raman spectroscopy marks a significant step forward in crystallization process development. By enabling real-time, in-depth process insight, these tools reduce reliance on offline analytics, accelerate development, and strengthen product robustness.

At TAPI, we continuously invest in advanced technologies to drive smarter, faster, and more reliable API development—empowering our partners with solutions that deliver measurable impact.