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How to control crystal form transformation during drying

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The Problem

· Inconsistent crystal form and particle aggregation was observed following drying of an API in early development. These issues led to the need to reprocess a number of batches which had a significant impact on the time and cost of manufacture.

The Breakthrough

· In-depth characterization of the form stability landscape and optimization of the washing procedure drove development of a new isolation and drying strategy to avoid undesired form transformation, aggregation, and lengthy drying times.

The Impact

· A revised isolation and drying procedure was implemented in the next clinical supply campaign that enabled robust control of API crystal form, with diminished aggregation properties, and delivery of drug substance within specification targets. By solving this CMC issue, the asset could move forward for the next development phase with no delays.

Drying is often the final step of the API preparation. The procedure is quite simple: the pressure is reduced and the temperature increased to drive solvent evaporation from the API. Even though it is perceived as a relatively simple step, quality and manufacturing risks in the drying operation are often underestimated. The physicochemical properties of the API can be altered easily by the chosen environmental conditions of drying. Often, the product incurs the following issues:

-          Chemical instability and degradation

-          High residual solvent

-          Breakage/aggregation

-          Hydration/dehydration

-          Crystal form transformation

In this case study, the problem statement was to determine drying conditions that preserved the API physicochemical properties from the crystallization step, while minimizing the drying time.

APC’s full suite of drying platforms and technologies were mobilized to develop fundamental understanding of the kinetics of drying and support process fit to a lab-scale agitated dryer (0.5 kg). As many factors influence how a material will dry, it is important to assess the filtration and washing strategy alongside revisions to the drying procedure. Process modelling is routinely used as part of the drying development workflow to support fundamental process understanding and optimization of the conditions of drying.

In this particular case, form transformation and aggregation were observed for an API during the drying step at our client's site, resulting in frequent batch reprocessing. The client’s drying recipe leveraged a high drying temperature in an effort to reduce the cycle time. However, the temperature in combination with the initial solvent content caused form transformation and aggregation.

Using the aforementioned workflow, a deep understanding of the thermodynamic conditions needed to achieve the correct form was acquired. Studies into the impact of the wash solvent and strategy (i.e., solvent content entering the dryer) also uncovered the criticality of wash strategy in mitigating aggregation during the drying step.

By altering the washing procedure, understanding the role of temperature versus solvent content, and tuning of the environmental conditions of drying, robust form control was established with markedly reduced aggregate form action.

By implementing the new washing and drying protocol, the API could be manufactured consistently within specification. Clinical supply material of appropriate quality was delivered without delay or reprocessing, and the development phase progressed as scheduled.