In the pharmaceutical industry, many materials are produced in a crystalline state, obtained by nucleation and growth from solutions in industrial crystallisation processes.

Whether for formation or purification purposes, investigation of intermediates, study of hemi-hydrates or prevention of crystallisation leading to amorphous products, crystallisation processes play an integral part in pharmaceutical manufacturing and development, having a significant impact on the efficiency and profitability of the overall process.

Presently, costs for a single batch of active pharmaceutical ingredients could range from $1-2 million, while undetected fluctuations in the crystallisation process can alter the crystal structure, affecting the safety and bioavailability of the product. Failure to meet product specifications can mean significant costs; for instance, when the drug needs to be reprocessed or even destroyed. As a result, the ability to reliably monitor these precious crystallisation processes online has become highly sought-after across the industry.

"The ability to reliably monitor these precious crystallisation processes online has become highly sought after across the industry."

The capacity to fully understand crystallisation processes, and the parameters that influence the yield and stability of a polymorph, solvate or hydrate form (solvents, concentrations, pH, stirrer geometry and speed, reactor geometry, temperature, temperature ramps and pressure) is also of crucial importance when it comes to industrially crystallised compounds and their cost-effective scale-up.

In response to these requirements, PANalytical has conducted a set of experiments with a new slurry flow cell in order to prove the suitability of X-ray diffraction (XRD) techniques as an online sensor.

For the research, a slurry flow cell for research scale crystallisations was integrated into an XRD system, allowing for real-time monitoring and analysis of solid phase growth and polymorphic phase transformation during the crystallisation process.

Quality control

Because online analysis enables the detection and analysis of intermediate products, it is also useful for the understanding of the processes and kinetics needed to achieve the final product. This understanding has been identified as critical, in terms of quality by design (QBD) approval.

Research and analysis

PANalytical used a Malvern Hydro 2000SM dispersion unit, set to 1,500-2,000rpm, to pump the slurry through the measurement flow cell, which was integrated into a PANalytical Theta-Theta diffractometer system configured with an incident beam focusing mirror.

The crystallisation process was monitored in three solutions with different pH: the starting solution at a pH of 6.11 (pH of saturated DL-Alanine solution), one with a pH of approximately 9.5 (addition of NaOH) and one with a pH of around 3.5 (addition of HCl).

DL-Alanine grows in a needle-like crystal morphology, with its main growth direction along the c-axis. In the group’s experiments at a pH of 6.11 and at a pH of 9.5, first crystallisation was characterised by the appearance of the 002 and 311 reflections. Peaks became much sharper and higher in intensity over the course of the process, indicating increasingly larger crystals.

Following the crystallisation at pH 6.11 further, fast growth of the (210) reflection could be monitored indicating a change in the crystal growth characteristics. In very slowly crystallising condition at a pH of 3.5, the crystal morphology is less pronounced, while the broad peaks point towards smaller crystallites.

From these studies, PANalytical has demonstrated that X-ray diffraction is the most suitable QBD technique for the investigation of the parameters influencing the different stages of the crystallisation and the analysis of any crystallised compound – both qualitatively in its crystal forms, and quantitatively on the concentrations of the various solid forms present.

Ultra-fast detection systems allow for real-time monitoring and the analysis of crystal growth mechanisms from the early stages of nucleation and polymorphic phase transformation during the crystallisation process.