(391g) Coupling Flow Synthesis and Formulation By Electrospinning | AIChE

(391g) Coupling Flow Synthesis and Formulation By Electrospinning


Domokos, A. - Presenter, Budapest University of Technology and Economics
Balogh, A., Budapest University of Technology and Economics
Farkas, B., Budapest University of Technology and Economics
Nagy, Z. K., Budapest University of Technology and Economics
Marosi, G., Budapest University of Technology and Economics
Pataki, H., Budapest University of Technology and Economics
Démuth, B., Budapest University of Technology and Economics

In the recent decades continuous manufacturing spread in almost every industrial sector while pharmaceutical technology still relies on traditional batch methods. Albeit batch manufacturing results in slower and more expensive production and deviations in product quality over time, strict regulations restrain any technological improvements. In contrast, real time analysis of the steady state flow coupled with immediate feedback in a continuous system ensures constant product quality. Moreover, the investment and operating costs of continuous pharmaceutical devices are lower and these systems require less inventories for the storage of intermediates while the entire process is accelerated.

There have been many studies of drug syntheses using continuous flow reactors, however, the direct formulation of the drug coming from the synthesis was found to be rather challenging. The only exemplary research on such an integrated system producing a solid dosage form was conducted in the laboratory of the Massachusetts Institute of Technology (MIT) [1]. Nevertheless, the connection of synthesis and formulation was resolved by a melting process unfavorable for thermosensitive drug compounds.

Electrospinning provides a unique opportunity to convert the final liquid flow of the synthesis into solid product immediately. During the process micro- and nanofibers are formed by applying high voltage and even non-volatile solvents can be removed in a gentle way under ordinary circumstances. The release rate of the drug can be adjusted by selecting the appropriate polymeric matrix for the fibers. Furthermore, ES can also be a suitable continuous formulation method of choice when coupling it with flow operations due to its scalable productivity in the range of 0.1-100 g h-1. Despite all these considerations, ES has not been applied as a part of a continuous-flow system to process liquid API streams into dry fibers serving as a base to produce solid dosage forms.

Thus, in this work we developed an end-to-end continuous model system (CMS) using ES as the key technology to turn the synthesized API solution into a fibrous solid product with the incorporation of a polymer [2]. Both synthesis and formulation were monitored by PAT tools with chemometric analyses combined with overall process control. The synthesis of acetylsalicylic acid (ASA) was chosen as model reaction using excess amount of acetic anhydride as reagent, and the side product acetic acid with high boiling point as well as the solvents of the reaction mixture had to be removed during the simultaneous formulation of the product.


Optimization of ASA synthesis:

ASA was synthesized using salicylic acid (SA) as starting material, acetic anhydride as reagent and phosphoric acid as catalyst. Following acetylation a quenching step was also required to get rid of the excess acetic anhydride and the quenchable byproducts. The optimal composition of the reaction mixture was chosen based on batch pre-experiments. Applying flow conditions, design of experiment studies were carried out for the discovery of the design space and for the identification of optimal reaction temperature and residence time in the acetylation and in the quenching step as well. At last, >99% conversion and >95% purity was achieved meeting the 3% regulatory limit for SA.

Connecting electrospinning to the flow reactors:

Polyvynilpyrrolidone K30 (PVPK30), a water-soluble polymer was introduced to the liquid stream of ASA synthesis after acetylation. Thus, after quenching the reaction mixture could be readily electrospun into fast-dissolving solid nanofibers with high purity applying high voltage. The fibers were collected on a water-soluble carrier film made of pullulan, forming a double-layered solid dosage form for peroral administration. The carrier film was continuously moved in front of the electrospinning needle, and the created double-layered product was conveyed further after the deposition of the fibers. An automated cutting mechanism cut the strip into single dosage units suitable for peroral administration.

Product characterization and CMS testing:

The physical state of ASA was investigated in the nanofibrous product with DSC and XRPD. Both analytical techniques showed that ASA turned into an amorphous form during ES.

Dissolution tests were carried out with different doses of layered PVPK30-ASA nanofibers on pullulan carrier. The ODWs were dissolved in 10 mL purified water without additional stirring at 25°C. Between the range of 1 and 25 mg ASA doses the dissolution of the fibers was instantaneous, the nanofibers disappeared in less than 2-3 seconds.

Residual solvent content measurements were conducted in steady state of the CMS for 4 hours. The results revealed satisfactorily low values in the fibrous product. The quantities of EtOH, EtOAc and AcOH were below the regulatory limit (5000 ppm) in all cases.

Repeated content uniformity measurements were conducted for 8 hours after the synthesis unit had reached steady state conditions. The settings of the formulation unit (i.e., film speed and cutting frequency) were determined earlier for 5 mg ASA dose. The collected layered ODWs showed mean contents close to the original target dose of 5 mg with satisfactorily low fluctuations.

The CMS was successfully operated for 24 hours, i.e., approximately 7 times of the residence time of the whole system including formulation. The purity of ASA in the nanofibers produced from the reaction mixture reached the >95% level not long after passing the nominal residence time. The SA content converged below the regulatory limit of 3% complementary with ASA purity. The purity of the ODWs produced by the CMS was comparable to a marketed ASA tablet formulation and both met the regulatory requirements for SA content.

Integration of PAT-based control strategies:

Real-time monitoring of quality was integrated into the CMS with spectroscopic PAT tools. The CMS was also equipped with PAT-based control loops to ensure quality. A Bruker Alpha FTIR spectrometer was used with an ATR flow cell to analyze the purity of ASA in the synthetized reaction stream. The flow cell was placed after the BPR and directly before the ES unit. Purity was calculated from the spectra by a quantitative model based on partial least squares (PLS) regression built with different ASA-SA ratios.

A Raman probe was applied for the inspection of the fibers on the pullulan strip placed before the cutting mechanism. The probe was motorized providing transversal movement of the laser beam patrolling on the surface of the nanofibrous film.


A novel approach is presented based on ES for the continuous production of a solid dosage form from the synthesis of the API to the final formulation of layered ODWs with integrated PAT quality assurance. As for productivity, at 5 mg dosage strength ~1016 doses per day can be reached. Hence, a continuous benchtop device such as the one presented is able to produce considerable amounts of dosage units with ES especially when formulating high potency APIs.

Besides the optimization of ASA synthesis together with ES for purity and fiber morphology, solid phase analyses were conducted on the nanofibers verifying the amorphous form of the drug. Ultrafast dissolution could be observed with the pullulan-based nanofibrous composites at 1-25 mg ASA dose levels. The CMS was operated for 24 hours covering several cycles of the mean residence time; detailed measurements showed excellent stability of drug purity over time in addition to content uniformity and residual solvent content. Real time control of both synthesis and formulation was developed using ATR-FTIR and Raman tools combined with chemometric analyses.


[1] S. Mascia et al., Angew. Chem. Int. Ed., 52, 12359–12363 (2013)

[2] A. Balogh et al., Chem. Eng. J., 350, 290-299 (2018)