Advanced Continuous Flow Platform for On-Demand Pharmaceutical Manufacturing

Article abstract of DOI:10.1002/chem.201706004

As a demonstration of an alternative to the challenges faced with batch pharmaceutical manufacturing including the large production footprint and lengthy time-scale, we previously reported a refrigerator-sized continuous flow system for the on-demand production of essential medicines. Building on this technology, herein we report a second-generation, reconfigurable and 25 % smaller (by volume) continuous flow pharmaceutical manufacturing platform featuring advances in reaction and purification equipment. Consisting of two compact [0.7 (L)×0.5 (D)×1.3 m (H)] stand-alone units for synthesis and purification/formulation processes, the capabilities of this automated system are demonstrated with the synthesis of nicardipine hydrochloride and the production of concentrated liquid doses of ciprofloxacin hydrochloride, neostigmine methylsulfate and rufinamide that meet US Pharmacopeia standards.

Full text of DOI:10.1002/chem.201706004

DOI: 10.1002/chem.201706004
Full Paper
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Flow Methods
Advanced Continuous Flow Platform for On-Demand
Pharmaceutical Manufacturing
Ping Zhang,[a] Nopphon Weeranoppanant,[b] Dale A. Thomas,[c] Kohei Tahara,[d]
Torsten Stelzer,[e] Mary Grace Russell,[c] Marcus O’Mahony,[f] Allan S. Myerson,*[c]
Hongkun Lin,[c] Liam P. Kelly,[c] Klavs F. Jensen,*[c] Timothy F. Jamison,*[c] Chunhui Dai,[c]
Yuqing Cui,[c] Naomi Briggs,[c] Rachel L. Beingessner,[c] and Andrea Adamo[c]
Abstract: As a demonstration of an alternative to the chal-
lenges faced with batch pharmaceutical manufacturing in-
cluding the large production footprint and lengthy time-
scale, we previously reported a refrigerator-sized continuous
flow system for the on-demand production of essential med-
icines. Building on this technology, herein we report a
second-generation, reconfigurable and 25% smaller (by
volume) continuous flow pharmaceutical manufacturing
platform featuring advances in reaction and purification
equipment. Consisting of two compact [0.7(L)ꢀ0.5(D)ꢀ
1.3 m (H)] stand-alone units for synthesis and purification/
formulation processes, the capabilities of this automated
system are demonstrated with the synthesis of nicardipine
hydrochloride and the production of concentrated liquid
doses of ciprofloxacin hydrochloride, neostigmine methylsul-
fate and rufinamide that meet US Pharmacopeia standards.
Introduction
[a] Dr. P. Zhang
Novartis Institute of Biomedical Research
250 Massachusetts Avenue
Cambridge, MA, 02139 (USA)
Unlike commodity chemical and petrochemical industries,
which operate using an efficient continuous mode of produc-
tion, pharmaceutical manufacturing has traditionally operated
using a batch approach, despite the enormous space-time
demand and quality-control related challenges.[1] This has been
due in part to the technical complexity of active pharmaceuti-
cal ingredient (API) syntheses, coupled with the need for multi-
ple rounds of isolation and purification to meet purity stand-
ards. Recent advancements in continuous flow technology
however, have made this strategy a more practical alternative,
fueling the development of highly streamlined laboratory-scale
syntheses of APIs,[2] and initiating the realization of integrated,
automated processes for manufacturing drug and potential
drug products.[3]
[b] Dr. N. Weeranoppanant
Department of Chemical Engineering
Faculty of Engineering
Burapha University
169 Long-Hard Bangsaen Road
Chonburi 20131 (Thailand)
[c] D. A. Thomas, M. G. Russell, Prof. Dr. A. S. Myerson, Dr. H. Lin, L. P. Kelly,
Prof. Dr. K. F. Jensen, Prof. Dr. T. F. Jamison, Dr. C. Dai, Dr. Y. Cui,
Dr. N. Briggs, Dr. R. L. Beingessner, Dr. A. Adamo
Department of Chemical Engineering or Department of Chemistry
Massachusetts Institute of Technology
77 Massachusetts Avenue
Cambridge, MA, 02139 (USA)
E-mail: myerson@mit.edu
kfjensen@mit.edu
tfj@mit.edu
In general, the benefits of continuous flow for improved
chemical reaction efficiency[4] are numerous, offering the po-
tential for decreased production times through process intensi-
fication,[5] enabling facile scale-up, and improving environmen-
tal and safety profiles and quality and consistency in produc-
tion. Driven by some of these factors, Eli Lilly and Company re-
cently developed a continuous CGMP production process for
prexasertib monolactate monohydrate to be used in human
clinical trials.[6] Eight continuous unit operations configured
within laboratory fume hoods, enabled 3 kg of the material to
be produced per day.
[d] Prof. Dr. K. Tahara
Laboratory of Pharmaceutical Engineering
Gifu Pharmaceutical University
1-25-4 Daigaku-Nishi
Gifu 501-1196 (Japan)
[e] Prof. Dr. T. Stelzer
Department of Pharmaceutical Sciences
University of Puerto Rico, Medical Sciences Campus
San Juan, PR 00936 (USA)
[f] Dr. M. O’Mahony
Pharmaceutical & Preclinical Sciences
Vertex Pharmaceuticals Inc.
50 Northern Avenue
Previous work with colleagues at the Massachusetts Institute
of Technology led to the development of a continuous auto-
mated platform for manufacturing the pharmaceutical drug
aliskiren hemifumarate.[3a] The shipping container-sized unit
was capable of the multi-step chemical reactions, separations,
Boston, MA 02210 (USA)
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under https://doi.org/10.1002/
chem.201706004.
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crystallizations, drying and formulation steps needed for the
end-to-end production of tablets of this API. This work enabled
us to recognize and pursue further advances in continuous
manufacturing that culminated in the design of a reconfigura-
ble system, ~1/40th the size [0.7(L)ꢀ1.0(D)ꢀ1.8 m (H)], for the
on-demand synthesis and final drug product formulation of
not just one, but multiple APIs.[3b] At the size of a standard
North American refrigerator, this plug-and-play, first-generation
reconfigurable platform succeeded in producing hundreds to
thousands of liquid doses per day of diphenhydramine hydro-
chloride, diazepam, lidocaine hydrochloride and fluoxetine hy-
drochloride, each from simple starting materials. While only a
proof-of-principle at this stage, an on-demand pharmaceutical
manufacturing system that can be easily replicated and operat-
ed by a single end-user, offers a potential solution to the criti-
cal drug shortages[7] that often result from the challenges with
batch manufacturing. Such a system could also help meet the
needs of small patient populations, and provide a strategy to
replace medicines with a short-shelf life, among other applica-
tions.
compact Milligat pumps, and a custom-built in-line evaporator.
Furthermore, whereas the first generation downstream unit[3b]
operated purely in batch mode for isolations and purifications,
this next generation system includes continuous processing for
crystallization[8] and semi-continuous filtration, washing, dis-
pensing and drying.
To showcase the capabilities of this platform by highlighting
a variety of unit operations, the continuous synthesis of nicar-
dipine hydrochloride (1) (antihypertensive drug) and the manu-
facturing of concentrated liquid doses of ciprofloxacin hydro-
chloride (2) (antibiotic), neostigmine methylsulfate (3) (muscle
strengthener) and rufinamide (4) (anticonvulsant) that meet
United States Pharmacopeia (USP) standards are demonstrated
(Figure 1c). While we have previously developed flow strat-
egies to synthesize two of these APIs, namely ciprofloxacin hy-
drochloride[9] and rufinamide[10] in their crude forms and on
the milligram scale, this is the first demonstration of their end-
to-end manufacturing into oral liquid doses that meet USP
standards within such a platform.
In seeking to further this technology, herein we present a
second-generation, reconfigurable, continuous flow pharma-
ceutical manufacturing platform. As shown in Figures 1a,b, this
new system features stand-alone upstream and downstream
units for the synthesis and the purification and formulation of
APIs, respectively. It features many advances that enhance the
manufacturing capabilities and also reduce the total volume of
the system by more than 25% relative to the first-generation
platform.[3b] These advances include a streamlined room tem-
perature and heated reactor design and holding bay, modified
Results and Discussion
Upstream unit
The self-contained upstream unit has a frame dimension of
0.7(L)ꢀ0.5(D)ꢀ1.3 m (H) and consists of three compact mod-
ules housing the operations required for the synthesis of the
APIs including the reaction-based equipment and controls (i.e.
reaction module), the pumps (i.e. pump module) and reaction
solvents (i.e. solvent module) (Figure 1a). A custom LabVIEW
Figure 1. Labelled photographs of the a) upstream unit for the synthesis and b) downstream unit for the purification and formulation of the APIs. c) Four APIs
synthesized in the platform.
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interface is used to coordinate the pumps and temperature
control as well as monitor the pressure and temperature
throughout the synthesis and capture in a data file.
evaporator shown in Figure 2c, was designed with operating
principles similar to those previously described[11] and is suita-
ble for a liquid flow rate up to 5 mLminÀ1. It combines a heat
exchanger, back pressure regulator (BPR) and membrane-
based separator[3b] into one device and operates by heating
the incoming fluid stream under pressure to a temperature
above the boiling point of the solvent to be removed. The
stream experiences a pressure drop as it passes through the
BPR and flash evaporates to a gas-liquid mixture. The vapor is
then separated from the fluid stream with the use of the in-
line gas-liquid separator.
The reaction module shown in Figure 1a contains ten bays
for holding process reactors capable of operating at room tem-
perature or under thermal conditions. The custom-designed re-
actors use disposable perfluoroalkoxy alkane (PFA) tubing that
can be readily replaced to prevent cross-contamination be-
tween API production runs. Figure 2a shows the 3D printed
Along with the reactor module, the upstream unit also fea-
tures a pump module for operating 21 modified Milligat
pumps capable of withstanding high pressures and continuous
operation (Figure 1a). Lastly, a ventilated solvent module is in-
corporated in the upstream unit for holding 10ꢀ1 L and 13ꢀ
500 mL solvent bottles.
Downstream unit
The downstream unit shown in Figure 1b and Figure S3, con-
sists of a processing module (top) along with utilities and stor-
age (bottom) within a frame having dimensions of 0.7(L)ꢀ
0.5(D)ꢀ1.3 m (H). Within the processing module, separation
and purification operations are performed on the crude API
liquid stream delivered from upstream, to generate the solid
drug substance, which is then formulated into liquid doses.
The system achieves these operations using a number of
custom-designed units including a precipitation unit (Fig-
ure 3a), batch and continuous crystallization units (Figure 3b),
formulation/feed tank units (Figure 3c) and a filter-washing
drying unit (FWD) (Figure 3d). Automation is achieved using a
LabVIEW interface with the exception of liquid coolers and
magnetic stirrers which are hardware controlled.
Notably, continuous crystallization is realized in this second
generation system using the pressure driven flow crystalliza-
tion (PDFC) unit shown in Figure 3b. It is designed to perform
a single or two-stage crystallization process using jacketed
temperature-controlled continuous stirred tank reactors
(CSTRs) with 30–180 mL working volumes. Feed and antisol-
vent streams are continuously fed into these units and the re-
sulting product stream is intermittently withdrawn and
pumped into the FWD unit shown in Figure 3d. The FWD unit
vacuum filters the solid product from the mother liquor,
washes the product over the filter and then pneumatically
transfers and dispenses the product to a collection chamber
for additional drying. Once a batch has been collected and
dried in the collection chamber, formulation solvent can be
added to dissolve or suspend (in the case of a suspension for-
mulation) the product prior to transfer to the formulation tank
(Figure 3c) for further concentration adjustment if needed. The
formulation unit consists of a jacketed temperature controlled
vessel with a level sensor, a suspended magnetic stirrer for
mixing and a single frequency ultrasound (SFU) probe in place
for determining solution concentration.
Figure 2. Photographs of the a) room temperature reactor, b) heated reactor
and c) in-line evaporator. The heat exchanger, BPR and membrane-based
separator in the in-line evaporator are indicated in (c) by 1–3, respectively.
reel of the room temperature reactor whereby the PFA tubing
(volume from 500 mL–10 mL) is coiled onto an aluminum back-
ing plate. The heated reactors (5 and 10 mL) alternatively, con-
sist of an aluminum shell, silicone insulation and a thin-walled
PFA tubular liner to improve heat transfer into the process
stream (Figure 2b). The aluminum shell not only provides uni-
form heating, but also supports the tubing at high tempera-
tures and pressures as the yield strength of PFA exponentially
declines with increasing temperature. Reactor heating is ac-
complished through the use of embedded cartridge heaters.
In addition to the reactors, the reactor module also holds
20 auxiliary devices such as the custom-built in-line evaporator,
flow meter, pressure sensors and separators.[3b] The in-line
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Figure 3. Overview of the custom-designed downstream system components. a) Precipitation unit with filter in base. b) Pressure-driven flow crystallizer.
c) Feed tank/formulation tank design. d) FWD unit with collection chamber.
API synthesis
followed by a purification/extraction process with the aid of
As shown in Figure 4, the capabilities of the upstream unit
were first demonstrated with the synthesis of a crude solution
of nicardipine hydrochloride (1). Neat N-benzyl-N-methyletha-
nolamine (5) was reacted with neat 2,2,6-trimethyl-4H-1,3-
dioxin-4-one (6)[12] in Reactor I at 1208C at a pressure of
0.97 MPa via the use of a BPR.[3b] After a residence time of
60 min, the resulting intermediate 7 was then mixed with a
stream of 3-nitrobenzaldehyde (8) and methyl 3-amino-2-bute-
noate (9) in the presence of 10% piperidine and 10% acetic
acid in a mixture of iPrOH and CH2Cl2. After flowing through
Reactor II for 20 min at 1208C to promote the condensation re-
action, the crude nicardipine underwent in-line acidification
two separate mixing tubes to increase mass transfer and two
membrane-based liquid-liquid separators. The resulting nicardi-
pine hydrochloride (1) was provided in 43% yield as a solution
in DMSO and H2O and at a production capacity of 3150 doses
per day. Due to the tendency of the API to oil-out and form
amorphous solids during the batch precipitation and recrystal-
lization studies,[13] downstream processing in the frame was
not carried out in the interest of time. Regardless, this work
demonstrated the use of elevated pressure (0.97 MPa) and
temperature (1208C) in the frame, enabling complete conver-
sion of the starting materials to the crude API in just 80 min.
Figure 4. Upstream synthesis of nicardipine hydrochloride (1).
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Figure 5. Upstream and downstream manufacturing of ciprofloxacin hydrochloride (2) starting from intermediate 10.[14]
Following the upstream synthesis of 1, we next transitioned
to the end-to-end manufacturing of ciprofloxacin hydrochlo-
ride (2). As shown in Figure 5, the upstream synthesis com-
probe provided a final concentration of 1.5 mgmLÀ1. HPLC
analysis (Figure S6) resulted in a 98.2% purity for 2 and thus
conformed to USP standards.[16] Overall, 2700 doses of 2 were
produced (3.5 mgmLÀ1 solution, 1 drop per eye, 0.6 mg per
dose). After start-up and reaching steady state (6.8 h) this cor-
responds to a production rate of 9600 doses per day.
menced by merging
a
stream of excess 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) with intermediate 10.[14] After
flowing through Reactor I for 1.7 min at 1508C, a solution of
piperazine (11) in DMSO was added and the combined mixture
was heated to 1508C in a 30 mL reactor constructed using
three sequential 10 mL reactors. After a residence time of
6.7 min, an aqueous NaOH solution was added and the com-
bined mixture was flowed through Reactor III for 0.9 min at
808C. The sodium carboxylate salt of ciprofloxacin was provid-
ed in 86% yield as a solution in DMSO and H2O. Overall, this
crude material was produced from 10 in only 9.3 min com-
pared to other reported protocols which require many hours
starting from similar intermediates.[15]
The third API manufactured was neostigmine methylsulfate
(3) (Figure 6). The upstream synthesis of 3 began by mixing a
solution of 3-(dimethylamino)phenol (12) and 18-crown-6 in
DMF with a stream of KOtBu in THF. After a residence time of
3.5 min at 408C in Reactor I, a solution of dimethylcarbamoyl
chloride (13) in THF was added and the mixture was heated in
Reactor II (spiral-type[3b]) for 30 s at 408C to facilitate the acyla-
tion reaction. Two in-line extraction and separation steps with
the aid of membrane-based separators[3b] provided the acylat-
ed adduct as a solution in toluene. Subsequent solvent evapo-
ration via the in-line evaporator, yielded a ꢀ30% more con-
centrated solution that was then treated with a stream of di-
methyl sulfate as a 5m solution in toluene. After heating in Re-
actor III at 958C for 5.5 min, 3 was provided as a crude solution
in toluene in 54% yield.
For the downstream processing, the API was first precipitat-
ed with 0.1m HCl, filtered, washed and then redissolved in
0.25m HCl prior to a continuous antisolvent crystallization
using acetone. The crystal suspensions were then processed in
the FWD unit, and transferred into a collection chamber and
held for 1 h at 608C prior to dissolving in the water formula-
tion solvent (Table S5). Real-time monitoring using an SFU
For the downstream processing, ethanol was first added to
the crude suspension of 3 to generate a homogeneous solu-
Figure 6. Upstream and downstream synthesis of neostigmine methylsulfate (3).
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tion. The API was then precipitated with methyl tert-butyl
ether (MTBE), filtered and dissolved in ethanol under batch
conditions to remove the residual dimethyl sulfate. The result-
ing feed solution was next precipitated, filtered, washed and
dried in the downstream unit prior to a continuous antisolvent
crystallization using MTBE. After repeating the batch precipita-
tion and continuous crystallization process, crystal suspensions
of sufficient purity were provided, which were then processed
through the FWD unit. The dried solids, which met USP stand-
ards (Figure S10),[17] were dissolved in the water formulation
solvent to provide a final concentration of 3 of 1.1 mgmLÀ1 as
determined using a SFU probe (Table S5). To accommodate the
batch processing of 3 in the downstream process, further opti-
mization is required. Although a production rate cannot be ac-
curately determined, 9450 liquid doses (0.5 mg/dose) of 3
were successfully produced.
sions were then filtered and washed with a mixture of acetone
and water prior to being held in the collection chamber at
608C for 24 h. HPLC analysis revealed the resulting rufinamide
crystals had a 99.4% purity and thus met USP standards (Fig-
ure S13).[16] Redissolution in the formulation solvent (0.1% po-
loxamer) provided a final concentration of 40.4 mgmLÀ1
(Table S5). In total, 20 doses of rufinamide (4), each dose corre-
sponding to 200 mg (5 mL of 40 mgmLÀ1 suspension/dose)
were manufactured. After start-up and reaching steady state
(4.5 h) this corresponds to a production rate of 75 doses per
day.
Conclusion
In summary, a reconfigurable, continuous flow platform featur-
ing custom-designed unit operations has been developed for
on-demand manufacturing of liquid formulations of APIs.
Among the advancements in this second-generation system is
an in-line evaporator, which was implemented in the upstream
synthesis of neostigmine methylsulfate (3). Streamlined room
temperature and heated reactors have also been developed
that fit within standardized bays within the reactor module in
the upstream unit. In addition to having a more compact
design, the PFA tubing within these reactors can be readily re-
placed as part of the facile switching process between API pro-
duction runs. Other innovations in this system include the in-
corporation of continuous processing operations for crystalliza-
tion[8] and semi-continuous filtration, washing, dispensing and
drying.
The final API manufactured was rufinamide (4). As detailed
in Figure 7, a convergent strategy was implemented whereby
energetic benzyl azide 15 was produced in situ to avoid han-
dling. It was then consumed in a [3+2] cycloaddition reaction
with propiolamide (17), a polymerization-prone[18] intermediate
also generated in situ. The synthesis of the requisite azide 15
was accomplished by merging a solution of 14 in DMSO with
excess sodium azide in DMSO in Reactor I for 7 s at room tem-
perature. Propriolamide (17) was separately generated by re-
acting neat methyl priopiolate (16) with an aqueous solution
of ammonia in Reactor II at room temperature for 5.9 min.
After merging the two solutions, the mixture was treated with
an aqueous solution of sodium ascorbate followed by a pre-
mixed aqueous solution of Cu(OAc)2 and 1,10-phenanthroline
in catalytic quantities. Heating in Reactor III for 6.8 min at 808C
under elevated pressure (0.69 MPa) provided 4 in 77% yield as
a crude solution in DMSO and water.
To increase the throughput of APIs such as rufinamide which
have large prescribed doses (200 mg), future considerations
may include the scale-up of custom vessels or operating multi-
ple units in parallel. For example, based on the current crystal-
lization process, increasing the working volume from 60 mL to
350 mL per crystallizer would deliver approximately 1200
doses of 4 per day. Crystallizers with this larger volume are
projected to fit within the current downstream module.
The downstream processing commenced by precipitating 4
using an aqueous solution of ethylenediaminetetraacetic acid
(EDTA) and NaOH at 508C. Following filtration and washing,
the solids were re-dissolved in DMSO prior to a continuous an-
tisolvent crystallization using EDTA/NaOH. The crystal suspen-
Figure 7. Convergent upstream synthesis and downstream processing of rufinamide (4).
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assembled from three 10 mL reactors connected sequentially) at
1508C. After a residence time of 6.7 min, the outflow was mixed
with a stream of aqueous NaOH (2m, 4 equiv.) (0.84 mLminÀ1) and
flowed through Reactor III (5 mL reactor) at 808C for a residence
time of 0.9 min. The sodium carboxylate salt of ciprofloxacin was
collected and provided in 86% yield as a solution in DMSO and
H2O.
Experimental Section
Additional details of the platform and synthesis and characteriza-
tion (NMR, XRPD and HPLC) data can be found in the Supporting
Information.
General methods: All reagents and solvents were purchased from
commercial suppliers and used as received, unless otherwise
noted. Deionized (DI) water was obtained from a Milli-Q, Millipore
system. NMR analysis was performed on
a JEOL JNM-ECZR
Downstream processing of 2
500 MHz spectrometer in the specified deuterated solvent. The
1H NMR data is reported as follows: chemical shift in parts per mil-
lion (ppm), multiplicity (s=singlet, d=doublet, t=triplet, q=quar-
tet, m=multiplet), coupling constant in hertz (Hz) and integration.
X-ray powder diffraction was performed on all samples using a
PANalytical X’Pert PRO diffractometer at 45 kV with an anode cur-
rent of 40 mA. The instrument has a PW3050/60 standard resolu-
tion goniometer and a PW3373/10 Cu LFF DK241245 X-ray tube.
Samples were placed on a spinner stage in reflection mode. Set-
tings on the incident beam path included soller slit 0.04 rad, mask
fixed 10 mm, programmable divergence slit and fixed 18 anti-scat-
ter slit. Settings on the diffracted beam path include: soller slit 0.04
rad and programmable anti-scatter slit. The scan was set as a con-
tinuous scan: 2q angle between 48 and 408.
Precipitation: The crude solution from the upstream synthesis was
neutralized using HCl (0.1m) at a ratio of crude solution:0.1m HCl
of 1:4.5. The crude solution (29.3 mgmLÀ1) was pumped into the
buffer tank until the desired volume was reached (400 mL) and to
this, HCl (0.1m, 600 mL) was added. The diluted crude was then
processed in 3 batches through the precipitation tank with the ad-
dition of HCl (0.1m) to complete the neutralization. Each batch
was aged for 20 min before pumping into the precipitation unit
for filtration and washing. Solids were washed with water before
holding the system under vacuum for 10 min. The washed solid
was dissolved in HCl (0.25m) under agitation for 20 min before
pulling the generated API salt solution into the crystallization feed
tank. Details of the solvent volumes are provided in the Supporting
Information in Table S1. A sample of the API solution was removed
from the feed tank to assess the concentration. HPLC analysis (data
not shown) provided a concentration of 35.2 mgmLÀ1. The result-
ing yield of this process was 67%.
Continuous crystallization: The continuous antisolvent crystallization
was carried out using acetone at a solvent:antisolvent ratio of
about 10:90. The feed solution and acetone were pumped into the
first stage CSTR at 0.49 and 4.6 mLminÀ1, respectively. Details re-
garding the crystallization volumes and process parameters are
provided in the Supporting Information in Table S2. The agitation
rate at each stage was 600 rpm. The resulting yield of ciprofloxacin
hydrochloride (2) from this process was 32%.
Nicardipine hydrochloride (1)
Upstream synthesis of 1: Premixed N-benzyl-N-methylethanola-
mine (5) (neat, 0.9 equiv.) and 2,2,6-trimethyl-4H-1,3-dioxin-4-
one (6) (neat, 1.0 equiv.) were pumped (0.08 mLminÀ1) through Re-
actor I (5 mL reactor, 2 mm inner diameter) for a residence time of
60 min at 1208C. The resulting ester was then treated with a
stream (0.42 mLminÀ1
)
of 3-nitrobenzaldehyde (8) (0.48m,
0.8 equiv.), methyl 3-amino-2-butenoate (9) (0.8 equiv.), 10% piperi-
dine and 10% acetic acid in a 5:1 mixture of isopropanol and di-
chloromethane. The combined reaction stream was heated to
1208C in Reactor II (10 mL reactor) for 20 min and passed through
a 0.97 MPa back pressure regulator. A solution of HCl (3m,
1.4 mLminÀ1) and dichloromethane (0.29 mLminÀ1) was subse-
quently introduced and the resulting mixture was flowed through
a 2.5 mL mixing tube, followed by a membrane based liquid-liquid
separator. The product was treated with a 1:1 stream of dimethyl
sulfoxide (0.86 mLminÀ1) and water (0.29 mLminÀ1) and passed
through a second 2.5 mL mixing tube, followed by a membrane
based liquid–liquid separator to provide nicardipine hydrochlo-
ride (1) in 43% yield as a solution in dimethyl sulfoxide and water.
1H NMR of the crude free base (500 MHz, CD3CN): d=8.07 (t, J=
2 Hz, 1H), 7.95 (ddd, J=8.3, 2.4, 1.1 Hz 1H), 7.70–7.68 (dt, J=7.8,
1.4 Hz, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.29–7.20 (m, 5H), 5.07 (s, 1H),
4.12 (t, J=5 Hz, 2H), 3.57 (s, 3H), 3.53–3.43 (m, 2H), 2.63–2.54 (m,
2H), 2.30 (s, 3H), 2.29 (s, 3H), 2.13 ppm (s, 3H). 13C NMR of the
crude free base (125 MHz, CDCl3) d=167.6, 167.1, 149.7, 148.4,
145.3, 145.2, 138.7, 134.5, 129.0, 128.8, 128.3, 127.2, 122.9, 121.5,
103.2, 62.6, 61.8, 55.6, 51.2, 42.3, 39.7, 19.73, 19.67 ppm. HRMS
(ESI+) m/z calcd for C26H29N3O6H+ [M+H]+: 480.2129; found:
480.2127.
Filtration, washing, drying and formulation: Crystal suspensions
were processed in the FWD at 2 mLminÀ1 (30 mL aliquots per
15 min FWD cycle). The filtered material was washed with acetone
(10 mL) before vacuum drying for 10 min. Solids were then trans-
ferred into the collection chamber for further drying. In total, 7 ali-
quots were filtered, washed, dried and dispensed from the FWD
unit. A manual sample taken from the collection chamber before
further drying resulted in a TGA analysis of 93.7% solids. Solids
were held in the collection chamber for 60 min with the heating
tape set to 608C (note that the heating tape applied to the outside
of the FWD collection chamber is not shown in Figure 3 or Fig-
ure S3). Formulation solvent (300 mL of water) was pumped into
the collection chamber with agitation before transferring into the
formulation tank. The resulting concentration of the ciprofloxacin
hydrochloride (1) solution was 1.5 mgmLÀ1. In total, 1.62 g of cipro-
floxacin hydrochloride was produced corresponding to 2700 doses
(3.5 mgmLÀ1 solution, 1 drop for each eye, 0.6 mg per dose). After
start-up and reaching steady state, this corresponds to a produc-
1
tion rate of 9600 doses per day. H NMR (500 MHz, [D6]DMSO): d=
15.11 (s, 1H), 9.38 (s, 2H), 8.67 (s, 1H), 7.94 (d, J=13.0 Hz, 1H), 7.59
(d, J=7.3 Hz, 1H), 3.85 (m, 1H), 3.55 (t, J=4.8 Hz, 4H), 3.28 (over-
lap with solvent, 4H), 1.30 (t, J=6.5 Hz, 2H), 1.18 ppm (t, J=
5.1 Hz, 2H). 1H NMR (500 MHz, D2O) d=8.43 (s, 1H), 7.36 (d, J=
7.0 Hz, 1H), 7.19 (d, J=12.7 Hz, 1H), 3.68–3.53 (m, 5H), 3.49 (t, J=
4.8 Hz, 4H), 1.39 (d, J=7.0 Hz, 2H), 1.12 ppm (bs, 2H). 13C NMR
(126 MHz, D2O): d=175.5, 168.6, 154.2, 152.2, 148.0, 144.5 (d, J=
10.0 Hz), 138.7, 118.4 (d, J=8.4 Hz), 110.4 (d, J=23.6 Hz), 106.0 (d,
J=111.5 Hz), 46.3 (d, J=4.7 Hz), 43.2, 36.1, 7.5 ppm. HRMS (ESI+)
Ciprofloxacin hydrochloride (2)
Upstream synthesis of 2: Ester 10 (0.15m in DMSO, 1 equiv.)
(2.8 mLminÀ1
) was mixed with excess DBU (neat, 2 equiv.)
(118 mLminÀ1) and flowed through Reactor I (5 mL reactor) at
1508C for a residence time of 1.7 min. The outflow was then treat-
ed with a stream of piperazine (11) (0.8m in DMSO, 3 equiv.)
(1.58 mLminÀ1) and pumped through Reactor II (a 30 mL reactor
m/z calcd for C17H19FN3O3 [M+H]+: 332.1405; found: 332.1421.
+
Chem. Eur. J. 2018, 24, 1 – 10
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See Figure S5 and Figure S6 in the Supporting Information for the
XRPD and HPLC analysis, respectively.
8 min FWD cycle). The filtered material was washed with MTBE:
EtOH 90:10 (20 mL) before transfer. Solids were then transferred
into the collection chamber and held for 12 h with the heating
tape set to 608C. Formulation solvent (water) was pumped into
the collection chamber with agitation before transferring into the
formulation tank. The resulting concentration of the solution was
1.1 mgmLÀ1. In total, 4.75 g of neostigmine methylsulfate was pro-
duced corresponding to 9450 doses (0.5 mg per dose). Given that
neostigmine methylsulfate required isolation offline prior to precip-
itation and a further purification after processing in the down-
stream unit continuous crystallizers, a production rate cannot be
Neostigmine methylsulfate (3)
Upstream synthesis of 3: A solution of 3-dimethylaminophe-
nol (12) (0.15m, 1 equiv.) and 18-crown-6 (0.01m, 0.07 equiv.) in
DMF (500 mL) was pumped at a rate of 1.2 mLminÀ1 and com-
bined with a solution of potassium tert-butoxide (1m in THF,
1.3 equiv.) (0.23 mLminÀ1). After flowing through Reactor I (5 mL
reactor) at 408C for a residence time of 3.5 min, the resultant
stream was mixed with a solution of dimethylcarbamoyl chlo-
ride (13) (1.5m in THF, 1.5 equiv.) (0.18 mLminÀ1) in Reactor II[3b] for
30 s at 408C. This stream was then met with an aqueous solution
1
accurately determined. H NMR (500 MHz, CDCl3): d=7.80 (dd, J=
8.5, 2.6 Hz, 1H), 7.63 (t, J=2.3 Hz, 1H), 7.56 (dt, J=8.4, 12.7 Hz,
1H), 7.27 (dd, J=8.1, 1.8 Hz, 1H), 3.75 (s, 9H), 3.67 (s, 3H), 3.11 (s,
3H), 2.98 ppm (s, 3H).13C NMR (126 MHz, CDCl3): d=154.0, 152.6,
147.7, 131.4, 124.3, 117.0, 114.2, 57.3, 54.5, 36.9, 36.7 ppm. HRMS
(ESI+) m/z calcd for C12H19N2O2 [M]+: 223.1441; found: 223.1432.
See Figure S9 and Figure S10 in the Supporting Information for the
XRPD and HPLC analysis, respectively.
of K3PO4 (0.4m) (2.4 mLminÀ1
) and a stream of toluene
(1.6 mLminÀ1) in a cross mixer to form a triphasic mixture. The mix-
ture was then passed through a membrane separator and the
aqueous phase was flowed through a 0.34 MPa BPR and then to
waste. The organic stream was next mixed with a stream of deion-
ized water at a T-mixer and passed through another membrane
separator, also connected to a 0.34 MPa BPR. This solution was
passed through an in-line evaporator at a temperature of 1128C at
a backpressure of 0.41 MPa. Once concentrated (approximately
30% under these conditions), it was mixed with a solution of
Rufinamide (4)
Upstream synthesis of 4: Streams of 2,6-difluorobenzyl bro-
mide (14) (1.0m in DMSO, 1.0 equiv.) and sodium azide (0.5m in
DMSO, 1.25 equiv.) at flow rates of 1.17 mLminÀ1 and
2.92 mLminÀ1 respectively, were combined and flowed through Re-
actor I (500 mL reactor, 0.03“ id) at ambient temperature for a resi-
dence time of 7 s. Neat methyl propiolate (16) (1.5 equiv.)
Me2SO4 (5m in toluene, 3 equiv.) (0.11 mLminÀ1
) and passed
through Reactor III (5 mL reactor) at 958C, achieving full conversion
in 5.5 min and providing the crude neostigmine methylsulfate in
54% yield.
(0.16 mLminÀ1
)
and
ammonia
hydroxide
(2.25 equiv.)
(0.18 mLminÀ1) were combined and flowed through Reactor II
(2 mL reactor, 1/16” id) at ambient temperature for a residence
time of 5.9 min. The outcoming streams from Reactors I and II
were then mixed with an aqueous solution of sodium ascorbate
(3m, 0.3 equiv.) (0.18 mLminÀ1). An aqueous solution (0.5m) of pre-
mixed Cu(OAc)2(phen)2 (phen=1,10-phenanthroline, 0.05 equiv.)
(0.18 mLminÀ1) was next introduced at a T-mixer using a tube-in-
tube reactor and then passed through two static mixers. The final
stream was passed through Reactor III (3ꢀ10 mL reactors) at 808C
for a residence time of 6.8 min. A back pressure regulator set at
0.69 MPa was used after the reactor. Steady state was reached
after 20 min. Rufinamide was obtained in 77% yield as a solution
in DMSO and water.
Downstream processing of 3
Precipitation: Ethanol was added to the crude neostigmine methyl-
sulfate suspension obtained from the upstream synthesis (1:2,
ethanol:crude) to generate a homogeneous solution, which was
then processed in 4 batches offline. Solids were precipitated via
the addition of methyl tert-butyl ether (MTBE) at a flow rate of
10 mLminÀ1 and a ratio about 50:50, resulting in 38% yield. The
solids were then dissolved in ethanol (250 mL) to generate a
39.7 mgmLÀ1 feed solution of neostigmine methylsulfate. This feed
solution was processed in the frame through the precipitation tank
in 3 batches of 80 mL with 720 mL of MTBE added at a flow rate of
24 mLminÀ1. Each batch was aged for 20 min prior to pumping
into the precipitation unit for filtration. All 3 batches of solids were
collected in the precipitation unit before washing with MTBE
(200 mL). The slurry was filtered and held under vacuum for
10 min. The solids were dissolved in ethanol (210 mL) under addi-
tion for 10 min before pulling the API solution into the crystalliza-
tion feed tank. The process yield was 82%.
Continuous crystallization: The continuous antisolvent crystallization
was carried out using MTBE as the antisolvent at a ratio of solven-
t:antisolvent of about 10:90. The feed solution and antisolvent
were pumped into the first stage CSTR at 0.7 and 4.7 mLminÀ1 re-
spectively. Details of crystallizer volumes and process parameters
can be found in the Supporting Information in Table S3. The agita-
tion rate in each stage was 600 rpm. The yield for this process was
85%. Since the resulting solids did not meet purity specifications,
the material was processed offline in batch mode following the
aforementioned batch precipitation procedure (solids dissolved in
ethanol to generate a 40 mgmLÀ1 solution prior to precipitation
via the addition of MTBE at a flow rate of 10 mLminÀ1 and a ratio
ca. 50:50). The resulting yield was 90%. The slurry was then pro-
cessed through filtration, washing, and drying steps in frame.
Filtration, washing, drying and formulation: Crystal suspensions
were processed in the FWD at 3 mLminÀ1 (25 mL aliquots per
Downstream processing of 4
Precipitation: The crude rufinamide solution (49.5 mgmLÀ1) from
the upstream synthesis was heated to 508C and then processed in
the precipitation tank in 3 batches containing 150 mL of the crude
and 350 mL of an aqueous solution prepared from ethylenediami-
netetraacetic acid (EDTA) (60 mgmLÀ1) and NaOH (27.3 mgmLÀ1).
Each batch was aged for 20 min before pumping into the precipi-
tation unit for filtration and washing. Solids were washed with
water (100 mL) followed by a second wash using water:acetone
(50:50, 100 mL). Vacuum was applied for 10 min before dissolving
the resulting solids. The washed solid was dissolved in DMSO
(175 mL) under agitation for 20 min before pulling the generated
API solution into the crystallization feed tank.
Continuous crystallization: The continuous antisolvent crystallization
was performed using an aqueous solution prepared from ethylene-
diaminetetraacetic acid (EDTA) (60 mgmLÀ1
)
and NaOH
(27.3 mgmLÀ1). The feed solution and antisolvent (ratio of ca.
30:70) were pumped into the first stage CSTR at 1.3 and
2.6 mLminÀ1 respectively. Details of crystallizer volumes and pro-
cess parameters can be found in the Supporting Information in
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McQuade, P. H. Seeberger, Angew. Chem. Int. Ed. 2015, 54, 4945–4948;
Angew. Chem. 2015, 127, 5028–5032; e) M. Viviano, T. N. Glasnov, B.
Reichart, G. Tekautz, C. O. Kappe, Org. Process Res. Dev. 2011, 15, 858–
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Filtration, washing, drying and formulation: Crystal suspensions
were processed in the FWD at 1 mLminÀ1 (20 mL aliquots per
20 min FWD cycle). The filtered material was washed with a 50:50
mixture of acetone:water (50 mL). Solids were then transferred into
the collection chamber and held for 24 h with the heating tape set
to 608C. Formulation solvent (50 mL 0.1% poloxamer) was
pumped into the collection chamber with agitation before transfer-
ring into the formulation tank. The resulting suspension had a con-
centration of 40.4 mgmLÀ1. In total 4.75 g of rufinamide was pro-
duced corresponding to 20 doses (5 mL of 40 mgmLÀ1 suspension
for 1 dose). After start-up and reaching steady state this corre-
sponds to a production rate of 75 doses per day. Given the rufina-
mide oral suspension has a dose strength (200 mg) over 2 orders
of magnitude larger than the oral and ophthalmic dose strengths
of neostigmine methylsulfate and ciprofloxacin hydrochloride (0.6
and 0.5 mg, respectively), the doses produced and daily through-
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1
put are significantly lower. H NMR (500 MHz, [D6]DMSO): d=8.55
(s, 1H), 7.85 (s, 1H), 7.52 (quint, J=7.5 Hz, 1H), 7.48 (s, 1H), 7.19 (t,
J=8.1 Hz, 2H), 5.72 ppm (s, 2H). 13C NMR (126 MHz, [D6]DMSO) d=
161.8 (d, J=7.1 Hz), 161.3, 159.8 (d, J=7.2 Hz), 142.8, 131.8 (t, J=
10.1 Hz), 126.8, 112.2–111.2 (m), 111.1, 41.2 ppm. HRMS (ESI+) m/z
calcd for C10H8F2N4ONa+ [M+Na]+: 261.0558; found: 261.0562. See
Figure S12 and Figure S13 in the Supporting Information for the
XRPD and HPLC analysis, respectively.
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Acknowledgements
The authors thank Charles Ocampo, Jie Wu and Shogo Oku-
mura for assistance with the development of chemistry and
Norman Horn for help with the organization. This work was
supported by the Defense Advanced Research Project Agency
(DARPA) and Space and Naval Warfare Systems Center Pacific
(SSC Pacific) under Contract No. N66001-16-C-4005.
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Conflict of interest
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The authors declare no conflict of interest.
Keywords: active pharmaceutical ingredients · continuous
flow chemistry · industrial chemistry · synthetic methods
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endale, R. D. Braatz, B. K. Hodnett, K. F. Jensen, M. D. Johnson, P. Shar-
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Seeberger, Angew. Chem. Int. Ed. 2012, 51, 1706–1709; Angew. Chem.
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Biomol. Chem. 2013, 11, 1822–1839; d) C. A. Correia, K. Gilmore, D. T.
Manuscript received: December 19, 2017
Version of record online: && &&, 0000
Chem. Eur. J. 2018, 24, 1 – 10
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FULL PAPER
On-demand pharmaceutical produc-
tion: The capabilities of a second-gener-
ation, compact, continuous flow plat-
form for on-demand pharmaceutical
manufacturing are demonstrated with
the synthesis of nicardipine hydrochlo-
ride and the production of concentrated
liquid doses of ciprofloxacin hydrochlo-
ride, neostigmine methylsulfate and ru-
finamide that meet US Pharmacopeia
standards.
&
Flow Methods
P. Zhang, N. Weeranoppanant,
D. A. Thomas, K. Tahara, T. Stelzer,
M. G. Russell, M. O’Mahony,
A. S. Myerson,* H. Lin, L. P. Kelly,
K. F. Jensen,* T. F. Jamison,* C. Dai, Y. Cui,
N. Briggs, R. L. Beingessner, A. Adamo
&& – &&
Advanced Continuous Flow Platform
for On-Demand Pharmaceutical
Manufacturing
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ꢁ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!