RESEARCH
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benzophenone in NMP (18) with neat bromoacetyl
chloride (19) premixed inline with a stream of
NMP (20). Bromine displacement, followed by
an intramolecular cyclization reaction upon addi-
the fluoxetine solution merged with a stream of
water to prevent the precipitation of the KF salt.
Extraction and separation produced a solution of
fluoxetine in tert-butyl methyl ether (TBME) (36)
in 43% yield and at a production rate corresponding
to 1100 doses per day (one dose is 5 ml at 4 mg/ml)
prior to downstream processing. Similar to the
other three APIs, the downstream processing
involved a precipitation and recrystallization
sequence to provide fluoxetine hydrochloride
crystals that met USP standards (fig. S25) (36).
Redissolution in water yielded the final concen-
trate in 100 to 200 doses.
Overall, the total cycle times for the production
and formulation of the APIs varied from 12.2 hours
in the case of lidocaine hydrochloride to 47.7 hours
for fluoxetine hydrochloride (table S3). Whereas
the upsteam syntheses required three residence
times (total of 0.7 to 1.3 hours) of the sequential
reactions to achieve steady state, the downstream
processes took much longer and were mainly
dominated by the precipitation step. Because the
system featured valves, convenient feed swaps
cal drugs demonstrates the concept of continuous,
small-scale, on-demand production of pharma-
ceuticals. Already-demonstrated advances in flow
chemistry (11–20) could be realized on similar
platforms, and with additional research, ultimately
enable the continuous synthesis of modern small-
molecule pharmaceuticals, including enantiopure
APIs. The current system focused on liquid oral
and topical dosage formulations commensurate
with the on-demand approach. A complete alter-
native platform to current batch manufacturing
would inevitably have to produce pharmaceuti-
cals in the common dosage forms of tablets and
capsules as well as sterile injectable solutions,
which would require advances in downstream
processing. Specifically, classical unit operations
of crystallization, drying, powder transport, solids
blending, and tableting would have to be mini-
aturized and integrated. New approaches such as
three-dimensional printing of tablets could facili-
tate these developments. Realization and dem-
onstration of good manufacturing practices and
ultimately FDA approval will be critical to future ap-
plications of this technology, including production
units for hospitals, health care organizations, phar-
maceutical development, and humanitarian aid.
3 2
tion of a stream of NH in MeOH/H O (21), then
furnished the target molecule. Similar to lidocaine,
the application of elevated pressure (1.7 MPa)
and temperatures (90°C and 130°C) in this sequence
enabled liquid flow and complete conversion of
the starting materials in only 13 min compared
to 24 hours of batch operation at room tempera-
ture (32). After a continuous extraction, the organ-
ic stream was then passed through the activated
charcoal cartridge to remove the dark colored di-
mer and trimer side-products. After precipitation
and recrystallization in the downstream section,
the dried diazepam crystals (3) (94% yield) had
a purity level that met USP standards (fig. S22)
(33). Resuspending in ethanol in the formulation
tank then provided a concentrate. At a dosage con-
centration of 1 mg/ml (one dose is 5 ml at 1 mg/ml),
this system can produce ~3000 doses per day.
Synthesis and formulation of
fluoxetine hydrochloride
(
from reagents to solvents) and fast cleaning
procedures between each API production were
achieved. Appropriate solvent combinations were
added to the reactor lines to flush the up- and
downstream units. At the shortest, switching
the production of lidocaine hydrochloride to di-
azepam required a total of 15 min for a complete
flush of the internal lines in the upstream section.
A switchover from the simplest to the most com-
plex synthesis (diphenhydramine hydrochloride
to fluoxetine hydrochloride) would take 2 hours.
No cross-contamination was detected from run to
run, and the results were reproducible within a
standard deviation of 0.6% (diphenhydramine
hydrochloride) to 4.7% (fluoxetine hydrochloride)
yield for each API production within a single run.
The downstream purification and formulation
units required no reconfiguration—only the afore-
mentioned flushing. Thus, all transitions between
production runs could be completed in less than
4 hours. To meet current good manufacturing
practices, one could consider replacing the per-
fluorinated tubing and membranes in the reactors,
BPRs, and separators. The units were designed to
facilitate such a replacement.
The last of the APIs produced, fluoxetine hydro-
chloride (4), was specifically chosen to demonstrate
the versatility and capacity of this system to carry
out a complex, fully integrated, telescoped, multi-
step, biphasic synthesis (Fig. 5; see also Fig. 2D).
A series of individual reactions carried out in flow,
with purification and isolation of each interme-
diate in batch, has been previously demonstrated
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1
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1
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Outlook
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