Pharmaceutical API Continuous Manufacturing with Taylor Vortex Flow Reactor 

The Importance of the Crystallization Step in Active Pharmaceutical Ingredient (API) Manufacturing 

March 12, 2024

The crystallization process plays an important role in the pharmaceutical industry for active pharmaceutical ingredient (API) manufacturing, as more than 90% of the APIs are synthesized as a crystalline product.

Crystallization is also regarded as one of the most important purification and separation methods in the production of APIs due to its potential direct and indirect downstream effects on the quality of the final product. The crystallization step in API manufacturing can significantly influence particle size distribution, morphology, and other critical factors. 

Importantly, for APIs with low solubility or permeability that fall into Class 3 or Class 4 on the biopharmaceutical classification system (BCS), particle size control during the production process is vital for the final API to achieve efficacy. 

Batch vs Continuous Crystallization for Pharmaceutical APIs

Due to the crucial role of the crystallization step in API production, there is a need for a new and improved production process to replace the conventional batch process. Continuous production process has been implemented by more and more companies. Novartis-MIT Center for Continuous Manufacturing is a notable pioneer in the field of continuous pharmaceutical manufacturing. The FDA has also emphasized the need to modernize the drug manufacturing process from batch to continuous manufacturing, citing continuous drug manufacturing as a new process that could yield higher quality and more cost-effective pharmaceutical products. 

Overcoming the Disadvantages of Conventional Continuous Reactors

Nevertheless, conventional continuous reactors such as continuous stirred tank reactors (CSTRs), mixed-suspension mixed-product-removal (MSMPR) crystallizers, and tubular plug flow crystallizers (PFCs)/ plug flow reactors (PFRs) still face challenges such as non-uniform mixing, differential residence time, as well as fouling, clogging, encrustation and formation of dead zones during scale-up from lab or pilot-scale production to mass production. 

Taylor Vortex Reactor offered by LPR Global is a new generation of continuous flow reactor which addresses these challenges commonly seen in conventional continuous reactors with its patented design and unique fluid dynamics that allows for uniform micro-mixing, highly uniform residence time distribution, precise reaction parameter control, real-time monitoring and data gathering, efficient and easy scale-up, as well as easy cleaning and maintenance between processes. 

With more than 26  patents worldwide, our reactors are the first commercial reactors to successfully utilize the Taylor-Couette fluid dynamics in various chemical applications such as drowning-out crystallization, deracemization, co-precipitation, dissolution, exfoliation, liquid-liquid extraction, emulsion polymerization, enzymatic reactions, core-shell particle formation and more.  

Taylor Vortex Reactor Significantly reduces polymorphic crystallization time of Sulfamerazine

Park et al. (2015) compares the influence of periodic Taylor vortex flow generated by a Taylor vortex reactor (mentioned in the paper as Couette-Taylor crystallizer) and the random turbulent flow from a mixing tank crystallizer on the polymorphic crystallization of sulfamerazine (SMZ).

By significantly reducing the reaction time of SMZ- which has pharmaceutical polymorphs that require a long phase transformation period, Taylor Vortex reactor demonstrates itself as a more efficient and effective reactor system compared to conventional mixing tank crystallizer. 

The Taylor vortex reactor was composed of two annular cylinders, where the inner cylinder was rotated to induce a Taylor vortex fluid motion in the gap between the two annular cylinders, while the outer cylinder remained stationary, while in the mixing tank crystallizer, random turbulent fluid motion is generated by a single impeller. 

In the mixing tank crystallizer, the induction of the stable phase occurred 10-85 hours after the induction of the metastable phase, while the entire process was significantly reduced to 30 minutes in the Taylor vortex reactor. The drastic reduction in reaction time in the polymorphic crystallization of SMZ demonstrates the highly effective unique periodic toroidal fluid motion of the Taylor vortex flow. 

Reduced Phase Transformation Time of Sulfamerazine in a Taylor Vortex Continuous Reactor 

Lee et al. (2011) used a Taylor vortex continuous reactor to demonstrate the unique fluid dynamics of the Taylor vortex for the phase transformation of sulfamerazine (SMZ). With a conventional mixing tank (MT) crystallizer, the phase transformation from a metastable crystalline phase to the stable crystalline phase took more than 60 hours with acetonitrile (ACN) as the solvent and an agitation rate of 3000 rpm.

Using a Taylor vortex reactor, this phase transformation occurred within 3-7 hours with inner cylinder rotation speeds of 300-1000 rpm.

The phase transformation in the Taylor vortex flow reactor was always many times faster than that in the conventional mixing tank crystallizer.

Please visit our Taylor Vortex Reactor page to learn more about our different reactor models, customizable parameters & specifications and capabilities for different applications. If you would like to speak with a specialist, please contact us.