Post on 17-Feb-2018
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 1/20
Research paper
Active pharmaceutical ingredient (API) production involving continuous
processes – A process systems engineering (PSE)-assisted design framework
Albert E. Cervera-Padrell a, Tommy Skovby b, Søren Kiil a, Rafiqul Gani a, Krist V. Gernaey a,⇑
a Department of Chemical and Biochemical Engineering, Technical University of Denmark (DTU), Building 229, DK-2800 Kgs. Lyngby, Denmarkb Chemical Production Development, H. Lundbeck A/S, Oddenvej 182, DK-4500 Nykoebing Sj., Denmark
a r t i c l e i n f o
Article history:
Received 25 April 2012
Accepted in revised form 3 July 2012
Available online 20 July 2012
Keywords:
Design framework
Methodology
Continuous pharmaceutical manufacturing
Continuous processes
Microfluidic
Active pharmaceutical ingredient
a b s t r a c t
A systematic framework is proposed for the design of continuous pharmaceutical manufacturing pro-
cesses. Specifically, the design framework focuses on organic chemistry based, active pharmaceutical
ingredient (API) synthetic processes, but could potentially be extended to biocatalytic and fermenta-
tion-based products. The method exploits the synergic combination of continuous flow technologies
(e.g., microfluidic techniques) and process systems engineering (PSE) methods and tools for faster process
design and increased process understanding throughout the whole drug product and process develop-
ment cycle. The design framework structures the many different and challenging design problems
(e.g., solvent selection, reactor design, and design of separation and purification operations), driving
the user from the initial drug discovery steps – where process knowledge is very limited – toward the
detailed design and analysis. Examples from the literature of PSE methods and tools applied to pharma-
ceutical process design and novel pharmaceutical production technologies are provided along the text,
assisting in the accumulation and interpretation of process knowledge. Different criteria are suggested
for the selection of batch and continuous processes so that the whole design results in low capital and
operational costs as well as low environmental footprint. The design framework has been applied to
the retrofit of an existing batch-wise process used by H. Lundbeck A/S to produce an API: zuclopenthixol.
Some of its batch operations were successfully converted into continuous mode, obtaining higher yieldsthat allowed a significant simplification of the whole process. The material and environmental footprint
of the process – evaluated through the process mass intensity index, that is, kg of material used per kg of
product – was reduced to half of its initial value, with potential for further reduction. The case-study
includes reaction steps typically used by the pharmaceutical industry featuring different characteristic
reaction times, as well as L–L separation and distillation-based solvent exchange steps, and thus consti-
tutes a good example of how the design framework can be useful to efficiently design novel or already
existing API manufacturing processes taking advantage of continuous processes.
2012 Elsevier B.V. All rights reserved.
1. Introduction
Pharmaceutical companies have traditionally invested their re-search and development efforts in bringing new products to the
market in the shortest time [1]. Limited patent lifetime and strin-
gent regulations practically meant that focus was on drug discov-
ery rather than on optimal process design [2]. The advent of globalization, the growing importance of generic manufacturers,
the ever increasing awareness of environmental impact, and the
encouragement by the regulatory authorities to increase process
understanding and improve quality and efficiency while minimiz-
ing risk have led the pharmaceutical industry to reconsider the
way drug products are manufactured and process development is
approached [3]. This self-reflection has resulted in the promotion
of continuous pharmaceutical manufacturing (CPM) [2] and pro-
cess analytical technology (PAT) [4] in order to significantly
increase the efficiency and sustainability of production processes.
Concomitantly, microfluidic technologies have emerged [5],
demonstrating enhanced mass and heat transfer compared to
0939-6411/$ - see front matter 2012 Elsevier B.V. All rights reserved.http://dx.doi.org/10.1016/j.ejpb.2012.07.001
Abbreviations: API, active pharmaceutical ingredient; CFD, Computational Fluid
Dynamics; CPM, continuous pharmaceutical manufacturing; CPME, cyclopenthyl-
methyl-ether; DOE, design of experiments; FDA, Food and Drug Administration, US;
ICH, International Conference on Harmonization; IND, investigational new drug
(application); LCA, life cycle assessment; Me-THF, 2-methyl-tetrahydrofuran; NDA,
new drug application; NIR, near-infrared; OED, optimal experimental design; PAT,
process analytical technology; PMI, process mass intensity; PSE, process systems
engineering; QbD, quality by design.⇑ Corresponding author. Department of Chemical and Biochemical Engineering,
Technical University of Denmark (DTU), Building 229, DK-2800 Kgs. Lyngby,
Denmark. Tel.: +45 45252970; fax: +45 45932906.
E-mail address: kvg@kt.dtu.dk (K.V. Gernaey).
European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456
Contents lists available at SciVerse ScienceDirect
European Journal of Pharmaceutics and Biopharmaceutics
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / e j p b
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 2/20
batch reactors, resulting in higher yield, increased safety, improved
product quality, and shorter development time.
The use of microfluidic techniques and other continuous flow
processes, optimally combined with PAT, can very effectively con-
tribute to improved and faster process understanding [6]. Process
knowledge can optimally be stored as mechanistic models [7]
and used by process systems engineering (PSE) methods and tools
in order to tackle the process design problem. However, few stud-
ies (e.g., [8]) have focused on the effective use of continuous flow
techniques in order to facilitate process design and vice versa,
exploiting the structured and systematic way of solving problems
of PSE in order to assist in the planning and effective design of
experiments. Furthermore, although very significant contributions
have been made for the development of continuous processes [5],
it is still not clear when batch-wise production and/or continuous
manufacturing should be selected. In this contribution, a PSE-as-
sisted design framework for the development of continuous phar-
maceutical manufacturing processes is proposed. The objective of
the design framework is to identify PSE methods and tools that
can assist in the efficient acquisition of process knowledge and
the systematic application to the different process design problems
that arise throughout the drug product and process development
cycle. This manuscript presents the structure of the design frame-
work step by step, using information from the literature about con-
tinuous flow technologies and PSE methods and tools for process
design applied to pharmaceutical process development. Next, the
design framework is applied to a case study: the conversion of a
batch-wise process used for the production of an active pharma-
ceutical ingredient (API) developed by H. Lundbeck A/S (zuc-
lopenthixol). It is shown that the application of the design
framework and the development of continuous flow technologies
resulted in a significant simplification of the manufacturing pro-
cess, implying capital and operational costs savings, and lower pro-
cess environmental footprint.
2. Design framework
2.1. Scope
From medicinal chemists to chemical engineers, a considerable
number of cross-disciplinary professionals are involved in the
development of a pharmaceutical product. Experience has demon-
strated that decisions taken in the early development stages of a
drug (e.g., finding a suitable synthesis route to an API) establish
the core features of the industrial scale process [9]. Hence, it is
hypothesized that the whole pharmaceutical product-process
development cycle (Fig. 1) must be involved – perhaps in different
degrees – in the frame of a strategic evolution toward more sus-
tainable discovery, development, and operation activities [9,10].
The very large attrition rate through the drug development cycle
practically means that generic approaches toward process devel-
opment are required [11]. Due to the very short time frame avail-
able for process development, a cross-disciplinary strategic
approach toward development must be coordinated.
2.2. Aim
The aim of the proposed design framework is to assist in the de-
sign of continuous pharmaceutical manufacturing (CPM) pro-
cesses, that is, processes taking advantage of continuous flow
when relevant. The workflow of design activities should follow
the drug product-process development cycle (Fig. 1). The design
framework should identify already existing process systems engi-
neering (PSE) methods and tools that can assist in each design
problem. While these PSE methods and tools are well established
in other chemical industries, they may require further develop-
ment in the context of pharmaceutical production [11].
2.3. Structure of the design framework
In each step of the proposed design framework (Fig. 2), a model-
centric approach [7] – complemented by relevant PSE methods and
tools – is used to assist experimental studies for the most efficient
acquisition and storage of process knowledge. A cross-disciplinary
strategy is established, where a sustainability mindset [9] and a
commitment to the application and development of novel process
technologies (e.g., process intensification and continuous pro-
cesses) are communicated throughout the workflow. From the de-
sign problem point of view, the proposed design framework is
generic, that is, both ‘‘new process designs’’ and ‘‘retrofit of old pro-
cesses’’ are treated in a similar manner. The main difference is to be
found in the initial step in the methodology – it is assumed that a
retrofit problem (for example, converting an already existingbatch-wise process into a continuous one) is based on a substantial
amount of previously acquired process experience/knowledge.
However, since continuous processing opens the gate to ‘‘novel
process windows’’ [12], acquisition of novel process knowledge
outside conventional process conditions will be a requirement.
The design framework makes use of the knowledge that is initially
available and extends it with novel methods based on continuous
flow experiments when relevant.
2.3.1. Step 1: Drug discovery and development
This step is typically carried out by medicinal chemists and bio-
chemists and should – at least in our opinion – be optimally com-
plemented by a ‘‘chemical engineering perspective’’, introducing
novel technologies and simplified PSE methods and tools. Microflu-idic techniques can be used to perform high throughput experi-
mentation throughout the drug discovery and development
phases, using lower amounts of reagents and achieving faster reac-
tion times [13]. In this way, a flow chemistry mindset can be pro-
moted, where chemistries that are not feasible in batch mode (e.g.,
involving unstable reaction intermediates), or which are advanta-
geous under non-conventional process conditions, may provide
new opportunities for simpler processes [12,14]. Introducing sim-
plified versions of solvent selection methodologies and promoting
sustainability awareness in research laboratories [9] may also
simplify process development activities. Furthermore, the
development of generic methodologies for substrate adoption
[15] – that is, using a generic plant/microfluidic platform to per-
form one type of reaction with different substrates – could contrib-ute to faster and more efficient compound library generation for
Fig. 1. Phases of the drug development cycle [79]. (For interpretation of the
references to color in this figure legend, the reader is referred to the web version of this article.)
438 A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 3/20
Fig. 2. Design framework for the development of API manufacturing processes involving continuous processes – workflow of design activities.
A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456 439
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 4/20
high throughput screening (HTS). The use of real-time, in-line
monitoring techniques [6], leads to information-rich experiments
that could be automatically driven by optimal experimental design
(OED) algorithms [8]. The use of well-structured ontologies should
be encouraged to organize the large amounts of information gener-
ated in process databases (e.g., [16,17]).
2.3.2. Step 2: Preliminary data collection for process designIn this step, all information obtained during the drug discovery
phase and preclinical tests relevant for process design is collected.
This could include API and intermediate product molecular
weights, chemical structures, solubility data, degradation profiles,
boiling and melting points, synthetic route, by-product formation,
reaction enthalpies, potential hazards, etc. If some of these data are
missing, additional data may be obtained by using property predic-
tion tools (e.g., ICAS ProPred [18]) and by performing experiments
as discussed in step 1.
2.3.3. Step 3: Generate/retrieve base-case design: preliminary process
flowsheet
A preliminary process flowsheet must be found before the clin-
ical trials begin (Fig. 2), since significant amounts of the drug prod-
uct (with different formulations) are to be administered to humans
involved in the studies. The drug product will then gradually be
fine-tuned to accomplish the desired bioavailability and pharma-
cokinetic and pharmacodynamic behavior until a final formulation
is found [13]. The preliminary process flowsheet may be quickly
generated by the process development team using simplified ver-
sions of the design methods and tools explained throughout step
4 or simply retrieved from the chemical development team who
found the synthetic route to the API. The preliminary process flow-
sheet (base-case design) may include somewhat redundant,
unnecessary or inefficient washing, isolation, and purification
steps, since at this point, the priority is to ensure that the drug
product complies with the required quality specifications, and pro-
cess knowledge may still be rather limited.
2.3.4. Step 4: Retrofit analysis
In this step, either a preliminary process flowsheet from step 3
or a traditional batch-wise process from an already existing phar-
maceutical product is retrofitted to remove unnecessary separation
or purification steps and optimize solvent use, reaction yields, and
selectivities.
2.3.4.1. Step 4.1 Solvent selection and solvent exchange. Solvents may
account for about 80–90% of the mass utilization in a typical phar-
maceutical process [19]. Solvent selectionmust be considered in an
early phase of the process design, since solvents might strongly
influence reactivity [20,21], and work-up operations obviously de-
pend on the solvent(s) choice [22]. Regardless of the selection
strategy, for example, [18,20,23–25], two main objectives shouldbe sought. Firstly, the solvent or combination of solvents should
perform its/their intended function at the lowest economic and
environmental costs while avoiding health and safety issues. Sec-
ondly, solvent exchange [26,27] between different operations
should be enabled and if possible minimized, pursuing similar
aims in terms of costs and safety. Alternatively, solvent mixtures
leading to improved performance [25], and potential reaction yield
improvements obtained through telescoping reactions can be
investigated [14,28]. A holistic selection approach thus becomes
necessary. Fig. 3 shows the workflow followed for solvent selection
in this design framework, together with the required methods and
tools and the data-flow (input/output).
2.3.4.2. Step 4.2 Reaction analysis and reactor design. Guidelines areneeded to decide whether a certain reaction should be operated in
batch or in continuous mode, or if the reaction has the potential to
be intensified to a point where it can be performed in continuous
mode. Subsequently, reactions can be optimized according to dif-
ferent criteria. Process knowledge must be progressively added in
order to solve these design questions (Fig. 4).
Steps 4.2.1–4.2.3 in the design framework are used to charac-
terize the different reactions. Heterogeneity – and in particular, so-
lid handling – is a major challenge that hinders widespread use of
microreactor technology [29,30]. However, other continuous flow
applications have been developed to deal with solids and need to
be identified accordingly [31]. Calorimetric studies, preliminary ki-
netic analysis, and safety assessment should be performed [32] –
preferably using in situ monitoring techniques [6,33] – in order
to get familiar with the reaction and identify potential challenges.
An exploratory design of experiments (DOE) may be particularly
useful to find out (at least qualitatively) the influence of process
variables on the reaction yield, product selectivity and kinetics
[32], while optimal experimental design (OED) [34] can be used
to minimize the number of experiments to be performed.
In Step 4.2.4, the reaction is classified in terms of kinetics and
mass and heat transfer demands, for example, according to types
A–C as proposed by Roberge et al. [29]. In this way, a suitable reac-
tor design (e.g., microstructured vs. mesoflow) may be suggested
[29,35]. Alternatively, the classification criteria proposed by Hart-
man et al. [36] in the context of laboratory-scale process develop-
ment could be extended to large-scale processes. In this case, non-
dimensional numbers are used to identify the relative importance
of kinetics to mixing, heat exchange, and axial dispersion.
Step 4.2.5 is used to find a ‘‘business case’’ based on economic
and/or environmental cost factors (e.g., sustainability indicators)
and thereby compare batch and continuous flow strategies. Note
that the cost drivers (e.g., quality, speed to market, throughput,
operational and capital costs) may change along the drug develop-
ment cycle [37] and may thus be difficult to identify. Regarding
sustainability, the process mass intensity – defined as total mass
of materials used to produce a specified mass of product – can be
used as the key metric for fast evaluation and benchmarking of whole processes or single units [38]. For a detailed analysis, other
methodologies and software tools could be used, e.g., SustainPro
[39].
Finally, in step 4.2.6, the information obtained throughout steps
4.2.1 to 4.2.4, combined with the objectives arising from step 4.2.5,
is used to select a batch or a continuous flow configuration. This
subject is too broad to be covered in detail in this text. However,
this step consumes a large amount of the process development
time, and in many scenarios, highly customized equipment is re-
quired. Hence, considering the multiproduct/multipurpose nature
of pharmaceutical plants, generic approaches toward substrate
adoption are highly desired [15,35,40]. Finding the optimal reactor
network has been the subject of intense study [41–43], while system-
atically identifying opportunities for process intensification – forexample, combining reaction and separation phenomena – could
be considered at this point [44,45]. To find a solution to the reactor
configuration and/or network problem, solving an optimization
problem may be needed (step 4.2.7), either rigorously (mathemat-
ically) or approximately (using heuristics and expertise). The prac-
tical application of the methodology needs to take into account
time and equipment or space constraints, which will depend on
the infrastructures and resources available. Ultimately, an eco-
nomic analysis will evaluate the feasibility of the project (step 7).
An approximate economic evaluation of the reactor proposed could
however be advanced at this point (see Fig. 4).
2.3.4.3. Step 4.3 Separation and purification operations. While al-
ready in step 4.1 solvents and solvent exchange operations wereproposed, separation and purification operations (Fig. 5) should
440 A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 5/20
be designed after assessment of the reaction products obtained. In
steps 4.3.1–4.3.5, the intermediate products obtained after each
reaction step are analyzed, and the washing, isolation, and solvent
exchange operations proposed in steps 3 and 4.1 are tested exper-
imentally in order to understand the distribution of the com-
pounds of interest in the resulting streams. Subsequently,
degradation profiles and cross-interactions between API interme-
diates and impurities are studied, in order to find incompatible
compounds/reactions. Very unstable compounds will require
immediate downstream processing upon formation, which can
either be accomplished by cascade reactions [12,14,28] or by con-
tinuous downstream processing [5]. If a full (quantitative) chemi-
cal and physical characterization of by- and side-products is
available, thermodynamic models could be employed to predict
the distribution of API intermediates and impurities in different
streams. An attempt is made to streamline the process – eliminat-
ing unnecessary separation and purification steps – through en-
hanced reaction selectivity obtained in flow mode [37,46].
Designing the separation and purification operations (step
4.3.6) completes the basic features of the simplified process flow-
sheet. As with reactor design, this step involves much of the design
efforts. The optimal flowsheet generation for the separation of
multi-component mixtures has been a subject of wide interest
for the PSE community [47–51]. Computer-aided methods and
tools and simulation software based on thermodynamic models
(with predictive ability) and experimental data are essential for
efficient design and sequencing of separation operations (e.g.,
[25]).
PSE methods and tools for flowsheet synthesis and design are
therefore well established. However, in order to sequence the sep-
aration and purification operations and establish the basic operat-
ing conditions, the first decision to make is whether the
separation/purification operation(s) should be performed batch-
wise or continuously. This is a more difficult question to answer
compared to reactor design, since batch stirred vessels have the
advantage of being multipurpose (reaction + separation), and re-
search on small-scale (micro/meso-scale) continuous separation
units [5,27,52–54] lags to some degree behind the development
of micro- and microstructured reactors. Hence, in our opinion,
deciding whether a separation operation should be carried out in
batch mode or in continuous mode is largely dependent on the
operating mode of the reactions immediately before and immedi-
ately after the separation operation, which requires a holistic pro-
cess design approach. Flow technology specific advantages are
subject of current research and development.
2.3.4.4. Step 4.4 Process flowsheet simulation and/or experimentalvalidation. A process flowsheet should at this point be available,
whose actual feasibility must be verified. Using a model-centric
design approach [7] throughout process development will allow
Fig. 3. Workflow, methods and tools, and data-flow corresponding to step 4.1 of the design framework: solvent selection and solvent exchange.
A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456 441
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 6/20
Fig. 4. Workflow, methods and tools, and data-flow corresponding to step 4.2 of the design framework: reactor design.
442 A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 7/20
Fig. 5. Workflow, methods and tools, and data-flow corresponding to step 4.3 of the design framework: design of separation and purification operations.
A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456 443
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 8/20
deeper process understanding and will probably yield a larger de-
sign space [55]. However, in the last instance, an experimental val-
idation of the process will be required.
2.3.4.5. Step 4.5 Scale-up/out. If the simplified process flowsheet is
successfully validated, the next step is to demonstrate its scalabil-
ity, that is, propose the design of operation units able to meet the
desired industrial-scale throughput while being flexible to respond
to large variations of the demand. The pharmaceutical industry has
traditionally handled this uncertainty by using large multi-purpose
batch units and dividing the yearly production in a number of cam-
paigns as required. In contrast, for continuous operating units, a
modular concept (toolbox concept, [37]) has been proposed, where
parallel (small) units could be replicated as needed (scaling-out or
numbering-up approach) [2,29,56]. However, fluid distribution and
parallelization may be complex [57] and prohibitively costly.
According to Kockmann et al. [40], the numbering-up approach
should actually be kept as a last option. Furthermore, solids han-
dling is still a major limitation for microreaction technology
[29,30]. Hence, a scale-up approach may still be the most econom-
ical method to process large flow rates in challenging scenarios
while maintaining some of the advantages of operating at small
length scales (e.g., using meso-units). In order to accomplish these
objectives, Barthe et al. [58] and Kockmann et al. [40] have shown
that scaling-up should be driven by a thorough description of mass
and heat transfer characteristics. Computational Fluid Dynamics
(CFD) [59] could also be useful to investigate hownon-ideal mixing
influences reaction performance at larger scales [11].
2.3.5. Step 5: Process evaluation and intensification, integration, and
optimization
The process can be evaluated in order to find potential further
improvements, which should be communicated to the upper levels
of the design framework when relevant (Fig. 2). Software-assisted
methodologies have been proposed in order to find process
streams where significant improvements could be achieved in
terms of mass or energy use, for example, SustainPro [39]. One op-tion could be finding opportunities for further process intensifica-
tion [44,45] – for example, combining reaction and separation.
Another opportunity arising from the more extended use of contin-
uous operating units is to introduce solvent integration [46]. En-
ergy consumption has also been generally disregarded by the
pharmaceutical industry as a potential gate to cost and environ-
mental impact reduction [60]. Once all structural decisions form-
ing the process flowsheet have been taken, all process variables
that have not been fixed may be subject to a reduced optimization
problem. The objective could be single or multiple (cost, environ-
mental impact, energy use, etc.).
2.3.6. Step 6: Process monitoring and control tools
With the introduction of PAT and QbD in the pharmaceuticalindustry, the design and validation of processes in a range of pro-
cessing conditions – known as the design space – have been encour-
aged [4,55]. Implementing QbD practically means that the process
can be regulated to respond to disturbances or to meet a certain
optimization criterion, without the need to re-validate the whole
process. However, in order to do so, one must demonstrate suffi-
cient process knowledge, which can for example be stored using
a model-centric approach [7]. The use of data-driven models
(e.g., partial least squares regression) has also been proposed to
respond to, for example, variability in the raw materials via feed-
forward control [61]. Singh et al. [62] created a systematic
computer-aided framework to develop a software (ICAS-PAT) for
design, validation, and analysis of PAT systems. Operability and
flexibility considerations may also be integrated into the processsynthesis procedures themselves [63,64].
2.3.7. Step 7: Process assessment
The final step in the design framework is the economical and/or
environmental assessment of the final process. The environmental
impact related to the process can be evaluated using different
guidelines and software tools as reviewed by Linninger and Mal-
colm [65]. The use of a full LCA should also be encouraged to eval-
uate the origin and nature of the impacts and understand how they
can be reduced [38,60]. One example of an economical analysis of a
pharmaceutical production process including continuous opera-
tions has been given by Schaber et al. [66].
2.3.8. Step 8: Implementation
A verified simplified process including continuous operating
units can be implemented in this step. This step must be reached
at the same time as the regulatory agency approves manufacturing
of the pharmaceutical product. The implementation of continuous
operating units will require training of operators, where a transi-
tion from manual operation to supervision of automated process
regulation through PAT will be a key innovation factor.
3. Results and discussion
One possible application of the proposed design framework is
illustrated through a case study, where a batch-wise process used
by H. Lundbeck A/S to produce the API zuclopenthixol was retrofit-
ted by exploring the advantages of continuous processing. The pro-
duction of zuclopenthixol is a multistep process including
reactions in different solvents and with different reaction rates
and thus constitutes a good example of a typical organic-chemistry
based API production process. Since the original process was al-
ready known and previous experience was available, the design
procedure started from step 4 of the design framework (retrofit
analysis), taking as a base-case design (step 3) the known batch-
wise process. The text below describes the step-by-step applica-
tion of the design framework and summarizes the achievements
obtained throughout the process.
3.1. Case study – synthetic route – steps 1 and 2 of the design
framework
Zuclopenthixol (traded by H. Lundbeck A/S as clopixol) can be
isolated from a mixture of cis- and trans-clopenthixol (4-[3-(2-
Chlorothioxanthen-9-ylidene)propyl]-1-piperazineethanol), where
the trans-isomer is recycled and isomerized to a cis–trans mixture.
This case study focuses on the synthesis of cis- and trans-clope-
nthixol (compound 7) through 4 reaction steps (Scheme 1), result-
ing in an almost equimolar mixture of the two isomers. The first
reaction step is a Grignard alkylation, where allylmagnesiumchlo-
ride (AllylMgCl, compound 2) reacts with chlorothioxanthone
(CTX, compound 1) to produce an alkoxide product (compound3). In the second step, the alkoxide reacts with acidic water to pro-
duce 9-Allyl-2-Chlorothioxanthen-9-Ol (short name ‘‘allylcarbi-
nol’’, compound 4) and magnesium salts. The next step is a
dehydration of the ‘‘allylcarbinol’’ to 9H-Thioxanthene, 2-chloro-
9-(2-propenylidene)-(9CI) (short name ‘‘butadiene’’, compound
5). The last step is a hydroamination of the ‘‘butadiene’’ with 1-
(2-Hydroxyethyl)piperazine (short name ‘‘HEP’’, compound 6) to
produce clopenthixol (7).
3.2. Description of the base-case design (batch-wise process) – step 3
of the design framework
The original batch-wise process flowsheet is divided into two
stages (Fig. 6). The first stage involves the synthesis and isolationof the ‘‘allylcarbinol’’ intermediate. After alkylation of CTX and
444 A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 9/20
hydrolysis of the alkoxide product, the organic phase (containing a
mixture of THF, water, and ‘‘allylcarbinol’’) is separated from the
aqueous phase (containing a mixture of water, THF, Mg salts, and
polar impurities). Since a small amount of unknown impurities is
found after the batch alkylation, ‘‘allylcarbinol’’ is isolated by crys-
tallization before continuing the synthesis. Therefore, a solvent ex-
change step from THF to the antisolvents ethanol and water is
performed. The ‘‘allylcarbinol’’ crystals are separated by filtrationand subsequently dried and collected for storage.
In the second stage (Fig. 6), ‘‘allylcarbinol’’ is dissolved in tolu-
ene and dehydrated to the ‘‘butadiene’’ intermediate. Acetic acid
anhydride is used as dehydrating agent, while acetyl chloride is
used as acid catalyst. The final reaction step (hydroamination) is
a slow reaction (24 h batch). An excess of HEP is desired in order
to increase the reaction rate. Because of its solubility and reactivity
properties, HEP can act both as solvent and as reactant. In a solvent
exchange step, toluene is distilled off and HEP is gradually added.
When the solvent exchange is complete, the reaction proceeds un-
til all ‘‘butadiene’’ is converted. This step ends the process as stud-
ied in this case study. However, a final extraction of clopenthixol
with toluene and separation of HEP with water is performed after
the hydroamination reaction. It is so far assumed that these steps
will be carried out as in the original batch-wise process (cf. Tables
6 and 9).
3.3. Retrofit analysis – step 4 of the design framework
In this step, the original batch-wise process was streamlined as
much as possible, converting its unit operations to continuous
mode when favorable. The following text describes how the pro-
posed design framework was used to systematically resolve the
different design problems.
3.3.1. Solvent selection and exchange – step 4.1
The solvent selection procedure has been summarized in Ta-
ble 1, where for both the original batch-wise process and the ret-
rofit process, and for each synthetic or isolation step (the
crystallization of ‘‘allylcarbinol’’), plausible solvent candidateshave been marked with a cross. The different process options have
been indicated with arrows, where a dashed line represents a nec-
essary solvent exchange operation. In the base-case design, four
solvents are employed: THF is used in the alkylation reaction, eth-
anol and water are used for the controlled crystallization of ‘‘allyl-
carbinol’’, and toluene is used for the dehydration of ‘‘allylcarbinol’’
to ‘‘butadiene’’. The hydroamination is ‘‘solvent-free’’ after evapo-
ration of toluene, where the ‘‘butadiene’’ is mixed (and in fact, dis-
solved) in an excess of HEP.
For the retrofit design, different options were found. The selec-
tion procedure (a simplified version of the methodology by Gani
et al. [18]) began by identifying solvent candidates for each step.
The alkylation reaction requires the use of an ethereal solvent
[67]. Alternatives to THF have been claimed to be greener, forexample, 2-methyl-THF (Me-THF) [68] and cyclopenthyl-methyl-
ether (CPME) [69]. Some of their advantages compared to THF in-
clude low miscibility with water, enabling two-phase separation
in aqueous quench/extraction and thus facilitating wastewater
treatment [9], and a higher boiling point. The hydrolysis reaction
is a work-up step after the alkylation and only requires the use
of acidic water to solubilize Mg salts. The dehydration of ‘‘allyl-
carbinol’’ allows a large spectrum of solvents to be used, with basic
Fig. 6. Flowsheet representing the original batch-wise process used by H. Lundbeck A/S to produce clopenthixol.
Scheme 1. Synthetic route followed to produce clopenthixol from CTX.
A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456 445
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 10/20
requirements including a high boiling point in order to perform the
reaction at high temperature (increasing the reaction rate as dis-
cussed below) and a low miscibility with water in case work-up
washing steps are needed. Traditionally, toluene has been the sol-
vent of choice.
It was hypothesized that by changing the alkylation reaction to
continuous mode, the yield could be improved and a lower amount
of impurities would be formed [31,70]. This would make the crys-tallization step (used to isolate ‘‘allylcarbinol’’ crystals) unneces-
sary, as well as the solvent exchange step to ethanol/water.
Consequently, stages 1 and 2 in the original process could be inte-
grated in one stage. This could be achieved in two ways (see
Table 1):
Option 1: Perform the dehydration reaction in an ethereal sol-
vent (THF, Me-THF, or CPME), thereby streamlining the process.
Only a solvent evaporation prior to the hydroamination reaction
would in this case be needed. However, it would be necessary to
demonstrate the dehydration reaction in the ethereal solvent of
choice. Me-THF and CPME have the advantage of higher boiling
points (potentially enabling faster high temperature dehydra-
tions) and low miscibility with water (facilitating L–L separa-tion and washing steps).
Option 2: Perform the dehydration reaction in toluene as in the
traditional batch-wise process. A solvent exchange step from
the ethereal solvent chosen for the alkylation reaction would
in this case be needed, as well as toluene evaporation prior to
the hydroamination reaction.
Option 1 is clearly the simplest solution, and thus, it was chosen
as the priority. THF was kept as the preferred ethereal solvent due
to its availability and price compared to Me-THF and CPME, under
the condition that the dehydration reaction could be performed in
THF with high conversions in short time. A simplified process flow-
sheet was thereby proposed (Fig. 7). Interestingly, the same acid
used for Mg salt solubilization in the hydrolysis (HCl) could be
used for ‘‘allylcarbinol’’ dehydration after L–L separation, avoiding
the use of acetic acid anhydride and acetyl chloride.
3.3.2. Reaction analysis and reactor design – step 4.2
In this step, the feasibility of the simplified process flowsheet
shown in Fig. 7 was experimentally verified. The reactor analysis
and design procedure was repeated for each reaction step, that
is, alkylation, hydrolysis, dehydration, and hydroamination. For
illustration purposes, Tables 2–5 contain a summary of the infor-
mation collected and the design decisions taken throughout the
application of the design framework to the four reactions. A brief description of the reactor designs proposed is provided in the fol-
lowing subsections.
3.3.2.1. Alkylation (Grignard reaction). The alkylation of CTX is a fast
and exothermic Grignard reaction (reaction type A), most suitable
for microstructured flow reactors as long as homogeneous condi-
tions can be guaranteed [29,35,58,71]. In this particular case, CTX
has a low solubility in THF, while AllylMgCl and the alkoxide prod-
uct have high solubility. The suitability of a continuous filter reac-
tor followed by a tubular reactor with multiple injections has been
demonstrated elsewhere [31,70]. In short, the filter reactor pro-
vides solvent savings, while the multiple injection tubular reactor
provides accurate titration of CTX excess with low impurity forma-
tion. The reactor system can be monitored and potentially con-trolled by real-time in-line NIR spectroscopy measurements [70].
3.3.2.2. Hydrolysis of alkoxide product. According to the process
flowsheet in Fig. 7, HCl can be used to convert MgCl(OH) into more
soluble MgCl2. The reaction is very fast and exothermic (type A).
Four phases may be present in the reaction, a solid phase (poorly
soluble Mg salts and potentially CTX precipitated), two liquid
phases (organic and aqueous phase), and a gas phase, in case the
alkoxide product contains excess Grignard reagent (forming pro-
pene gas when reacting with water [67]). While the alkylation
reactor is operated and monitored such that a small amount of
CTX is always present in the product (the monitoring strategy used
to ensure this condition is described by Cervera-Padrell et al. [70]),
the hydrolysis reactor must be designed to handle the eventualityof propene formation (safe venting must be ensured) as well as the
high exothermicity of the Grignard reagent quench reaction. Right
Table 1
Solvent selection and solvent exchange strategies followed in the traditional batch-wise process and the simplified process containing continuous operation units. Plausible
solvent candidates have been marked with a cross. The different process options have been indicated with arrows, where a dashed line represents a necessary solvent exchange
operation. The followed selection procedure is a simplified version of the methodology developed by Gani et al. [18].
Alkylation Hydrolysis Crystallization Dehydration Hydroamination
Batch
THF x x
Ethanol/Water x
Toluene x
HEP x
Retrofit
Ethereal solv. x x ?
Ethanol/Water
Toluene x
HEP x
Fig. 7. Flowsheet representing the simplified process proposed for the production of clopenthixol using continuous flow operations.
446 A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 11/20
after the hydrolysis reaction, liquid–liquid separation should be
performed, since only the organic phase is used further on in the
process. Therefore, the reactor design may be integrated with the
subsequent phase separation. One option could be using a hydro-
cyclone [72] to perform mixing, reaction and separation in one de-
vice, properly adjusted to handle the solid and gas phases. A
different solution has been experimentally tested, using a small-
scale PTFE tubular reactor with segmented flow followed by a PTFE
membrane separator [73]. It is expected that the formation of li-
quid slugs with internal mixing [74] helps to avoid solid precipita-
tion on the reactor walls.
3.3.2.3. Dehydration of ‘‘allylcarbinol’’. The organic phase obtained
after L–L phase separation (Fig. 7) contains THF, water, and HCl
acid. Since this acid works as a catalyst for the dehydration of
‘‘allylcarbinol’’, the solution is ready for the reaction step, provided
that it is verified that the reaction is irreversible and thus water
does not affect the reaction equilibrium. A kinetic model was
developed based on batch experiments at normal pressure,
describing the effect of temperature and concluding that the reac-
tion is indeed irreversible. Due to the low boiling point of THF, the
maximum temperature achieved was 67.5 C, requiring more than
40 min for full conversion [75]. It was therefore decided to increase
the pressure so that the temperature could be increased above the
normal boiling point of the solution. At 120 C and 5 bar, it was
predicted that 99% conversion could be obtained in about 2 min,thereby simplifying the continuous flow reactor design. This was
confirmed experimentally using a small-scale tubular reactor,
where water was added to saturation as would occur after the
hydrolysis and L–L separation. Further discussion on the model
building procedure and experimental results can be found else-
where [75].
3.3.2.4. Hydroamination of ‘‘butadiene’’ with HEP. The hydroamina-
tion of ‘‘butadiene’’ with HEP is carried out in batch mode at
90 C for 24 h, obtaining a yield of around 70%. Unfortunately,
the acceleration of this reaction is not as obvious as in the dehydra-
tion, since at high temperatures, the conversion may be thermody-
namically limited [76]. The ‘‘butadiene’’ conversion rate could beincreased with temperature to a point where the time for almost
full conversion could be reduced to a few hours, while decreasing
the selectivity. Since the most important cost driver in this reaction
is yield and not throughput, reaction rate improvements implying
loss in yield cannot be justified. Hence, a different approach toward
reaction rate and selectivity improvements was explored using
catalysis.
Anti-markovnikov hydroamination of non-activated olefins has
been listed as one of the so-called ‘‘ten challenges for catalysis’’
[76]. Studies have shown that palladium-based catalysts could be
used for the hydroamination of cyclohexadiene with a broad
spectrum of amines [77,78]. Unfortunately, in a fast screening
experiment, it was found that tetrakis-triphenylphosphine-
palladium(0) (Pd(PPh3)4) (promising according to Löber et al.[78]) did not provide any significant improvements of the rate of
Table 2
Information collected and design decisions taken throughout the application of the design framework to the alkylation reaction (step 4.2 of the framework).
Alkylation (Grignard reaction) – THF solvent
Step 4.2 – reactor design Information collected Output/decision taken
Step 4.2.1 Phases – reactant solubility CTX sparingly soluble in THF
Qualitative analysis Phases – reactant solubility Grignard reagent soluble in THF
Phases – product solubility Alkoxide soluble in THF
Reaction generic type Grignard reaction, alkylation on ketone
Reactivity issues Grignard reagent reactive toward air/humidity
Heterogeneity Heterogeneous/homogeneous (solvent use?)
Step 4.2.2 Kinetics Very fast reaction
Calorimetric studies and short kinetic analysis Reaction enthalpy Exothermic (167 kJ/mole)
Step 4.2.3 Stoichiometry Excess of Grignard reagent leads to side-products
Exploratory design of experiments Concentration High Grignard reagent concentration leads to impurity formation
Temperature Temperature below 35–40 C does not have significant effect
on impurity formation
Kinetics/mixing Very fast kinetics, mixing controlled
Solubility CTX solubility curve vs. temperature obtained
Dissolution rate CTX dissolution rate found
Step 4.2.4 Reaction class Reaction class A (very fast, exothermic)
Reaction classification and identification of limitations Limitations Mass and heat transfer limited
Step 4.2.5 Cost driver 1 Yield (low side-product formation)
Determination of cost drivers and sustainability indicators Cost driver 2 Solvent consumption
Cost driver 3 Man-power and safetySustainability driver Solvent consumption
Batch or continuous? Decision Small-scale continuous reactor with improved mixing and heat
transfer, improved safety, more automation
Step 4.2.6 Cost driver 1 – yield Multiple injection microreactor (side-entries)
Reactor design Cost driver 2 – solvent use Filter reactor
Cost driver 3 – operational Automation, in-line monitoring
Step 4.2.7 Problem formulation Minimize solvent use and impurity formation
Solve optimization problem Solution method Heuristics and experimentation
Constraints Operational constraints dominate (precipitation)
Economic evaluation of the project Capital and operational costs Economic advantage of removing large reactor and
substitute by small-scale reactor
Improved yield expected
Lower solvent consumption
Work-up greatly facilitated
Increased automation and safety
Less manual operations (e.g., solid feeding)
A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456 447
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 12/20
hydroamination of ‘‘butadiene’’ with HEP, with or without addition
of a co-catalyst (trifluoroacetic acid). Future work should thus
investigate whether it is possible to increase the reaction rate
and/or yield of the hydroamination reaction, where the latter is
the priority both from an economical and environmental point of
view. With the current limited knowledge about this reaction, it
is most advisable to perform this reaction in batch mode.
3.3.3. Separation and purification design – step 4.3
Once the four reaction steps were characterized, it was investi-
gated whether it was indeed possible to simplify the process flow-
sheet as in Fig. 7. If the simplified process was infeasible, other
process options could be considered as discussed in Section 3.3.1.
3.3.3.1. Analysis of intermediate products and by-/side-product
formation – step 4.3.1. The following information was obtained
from the study of the four reaction steps:
The continuous alkylation produced very low amount of side-
products under the conditions described by Müller Christensen
et al. [31] and Cervera-Padrell et al. [70].
The continuous hydrolysis did not produce any side-products.
However, if an excess of Grignard reagent is present after the
alkylation, propene gas will be produced. CTX is unaffected by
the hydrolysis.
The continuous dehydration in THF mainly produces ‘‘butadi-
ene’’, but it may also produce an unknown impurity in very
low concentration. The product, however, was considered to
be of very high quality [75].
The hydroamination has not been studied with enough detail in
this work. However, preliminary studies show that the reaction
yield is typically between 50% and 70% with almost total con-
version of ‘‘butadiene’’. It is speculated that a fraction of the
‘‘butadiene’’ would polymerize.
3.3.3.2. Evaluation of base-case design and solvent exchange opera-
tions – step 4.3.2. The original batch-wise process used to produce
clopenthixol (base-case design) includes many solvent exchange
operations, washing steps, and separation steps. Table 6 lists all
the tasks and subtasks involved in the traditional process. For
every subtask, the table indicates the amount of feed and waste
materials, that is, materials entering and leaving the process. The
materials that are kept in the process (going from one subtask to
the next one) are either transformed in a reaction or they remain
in solution. These are not indicated in the table, since the purpose
here is to evaluate the process footprint in the following steps of
the design framework. The function of each washing/separation/
solvent-exchange task in the original process has been analyzed
and its relevance with respect to a simplified process flowsheet
(e.g., Fig. 7) questioned. This information has been summarized
in Table 7.
3.3.3.3. Assessment of intermediate product degradation profiles and
cross-interactions – step 4.3.3. Potential degradation and cross-
interaction issues have been summarized in Table 8 taking as a ref-erence the base-case design (batch-wise process). Some of these
Table 3
Information collected and design decisions taken throughout the application of the design framework to the hydrolysis of the alkoxide intermediate (step 4.2 of the framework).
Hydrolysis of alkoxide product – THF solvent
Step 4.2 – reactor design Information collected Output/decision taken
Step 4.2.1 Phases – reactant solubility Alkoxide soluble in THF
Qualitative analysis Phases – product solubility ‘ ‘Allylcarbinol’’ soluble in THF (organic phase)
Phases – product solubility Mg salts soluble in acidic water (aqueous phase)
Reaction generic type Hydrolysis of alkoxide from Grignard reaction
Safety issues Excess Grignard reagent produces propene gas
Heterogeneity Two liquid phases. Partial solid heterogeneity can be expected: potential
CTX excess and insoluble Mg(OH)Cl. Potential propene formation
Step 4.2.2 Kinetics Very fast reaction
Calorimetric studies and short kinetic analysis Reaction enthalpy Exothermic
Step 4.2.3 Stoichiometry Use enough water to solubilize MgCl2 salts
Exploratory design of experiments Use enough acid to convert Mg(OH)Cl to MgCl2
Concentration No concentration issues
Temperature Temperature only affects solubility
Kinetics/mixing Very fast kinetics, mixing controlled
Solubility High solubility of ‘ ‘allylcarbinol’’ and MgCl2 salts
Dissolution rate Not measured – could be important to measure time
for Mg(OH)Cl solubilization in form of MgCl2; however, expected fast
Step 4.2.4 Reaction class Reaction class A (very fast, exothermic)
Reaction classification and identification of limitations Limitations Mass and heat transferred limited
Step 4.2.5 Cost driver 1 Capital cost (small-scale reactor)Determination of cost drivers and sustainability
indicators
Cost driver 2 Man-power
Batch or continuous? Decision Small-scale continuous reactor with improved mixing and heat
transfer, improved safety, more automation. Should handle solids
Step 4.2.6 Cost driver 1 – capital cost Simple tubular reactor
Reactor design Cost driver 2 – operational Automation, in-line monitoring
Heterogeneity handling Segmented-flow tubular reactor or hydrocyclone
(4 phases, i.e., S–L–L–G) Integrate gas venting device
Step 4.2.7 Problem formulation Minimize capital cost, water use
Solve optimization problem Solution method Heuristics and experimentation
Constraints Operational constraints dominate (precipitation)
Economic evaluation of the project Capital and operational
costs
Economic advantage of removing large reactor and substitute by small-scale
reactor
Hydrocyclone integrates reaction + separation
Increased automation and safety
448 A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 13/20
issues may not be relevant in a simplified process flowsheet (e.g.,
Fig. 7).
3.3.3.4. Setting constraints for composition of intermediate streams –
step 4.3.4. Based on the information collected in the previous step,
the general recommendation is to keep solutions under nitrogen
cover and avoid extreme temperatures. No important issues were
identified, except the potential degradation of ‘‘butadiene’’. If pos-
sible, the ‘‘butadiene’’ solution in THF should be stored for a short
period (the degradation profile still needs to be quantified) before
the hydroamination, at low temperature, and with nitrogen cover.
There could be a potential interaction between the acid used in the
dehydration step and the hydroamination reaction. However, it isnot known whether this interaction would be positive or negative,
since acid co-catalysts are typically used in combination with cat-
alysts of the hydroamination reaction [76–78].
3.3.3.5. Elimination of unnecessary separation/purification steps – step
4.3.5. Since the quality of the ‘‘allylcarbinol’’ product obtained in
the continuous alkylation reactor is higher than in batch mode, it
is expected that the isolation of ‘‘allylcarbinol’’ by crystallization
is not needed. This means that subtask 2.3 and tasks 4, 5, 6, and
7 in Table 6 are not needed. Furthermore, since the dehydration
of ‘‘allylcarbinol’’ with HCl/water in THF proved successful, the
use of toluene, acetic acid anhydride, and acetyl chloride in the
dehydration step can be avoided (Fig. 7). Finally, if it is experimen-
tally demonstrated that the acid catalyst used in the dehydrationdoes not have a negative effect on the hydroamination reaction,
subtasks 8.1–8.17 (Table 6) would not be needed. These changes
greatly simplify the original process and result in a considerably
reduced list of tasks as shown in Table 9.
3.3.3.6. Design of separation and purification operations – step
4.3.6. According to Table 9, two types of separation operations
are present in this case-study: L–L separation of an organic and
an aqueous phase, and solvent exchange by distillation. Due to
the relatively simple structure of the process and the lack of rigor-
ous knowledge of the thermodynamics of these separation steps
(this process is only handled by H. Lundbeck A/S), a knowledge-
based design approach based on basic physical insights was fol-
lowed, while much of the development time was invested indesigning, constructing, and experimentally validating a surface-
tension based continuous L–L membrane separator [73].
L–L phase separation – task S3 (Table 9). The separation of THF
containing ‘‘allylcarbinol’’ and water containing magnesium
salts is challenging due to the partial miscibility of THF and
water even with dissolved API and salts (salting-out effect).
The densities of the two phases differ by only about 25 kg/m3,
meaning that separation by decantation is a very slow process,
where coalescence of droplets is a great challenge. Since the
alkylation and hydrolysis reactions can be performed in small
continuous reactors, it is more convenient to perform the L–L
phase separation continuously as well. A surface-tension based
separation method using a hydrophobic membrane has beenproposed [73].
Table 4
Information collected and design decisions taken throughout the application of the design framework to the dehydration of ‘‘allylcarbinol’’ (step 4.2 of the framework).
Dehydration of ‘‘allylcarbinol’’ – THF solvent
Step 4.2 – reactor design Information collected Output/decision taken
Step 4.2.1 Phases – reactant solubility ‘‘Allylcarbinol’’ soluble in THF
Qualitative analysis Phases – product solubility ‘‘Butadiene’’ soluble in THF
Phases – product solubility Water partially soluble in THF with API interm.
Reaction generic type Dehydration of a tertiary alcohol
Safety issues Potential ‘‘butadiene’’ polymerization or oxidation (many double bonds)?
Heterogeneity Two liquid phases when water is formed
Step 4.2.2 Kinetics Slow reaction at normal pressure (>45 min)
Calorimetric studies and short kinetic analysis Reaction enthalpy Slightly endothermic
Step 4.2.3 Stoichiometry Not relevant (only one reactant)
Exploratory design of experiments Concentration ‘‘Allylcarbinol’’ and acid concentration affect reaction rate (kinetic model found)
Temperature Temperature increases reaction rate (kinetic model found)
Kinetics/mixing Slow kinetics
Solubility No issues found
Dissolution rate Not relevant
Step 4.2.4 Reaction class Reaction class B (slow reaction, potentially faster by increasing pressure and
temperature)Reaction classification and
identification of limitations Limitations Kinetic-limited
Step 4.2.5 Cost driver 1 Capital cost (small-scale reactor)
Determination of cost drivers and sustainabilityindicators
Cost driver 2 Man-powerCost driver 3 and
environmental impact
No need to use acetyl chloride and acetic acid
anhydride
Batch or continuous? Decision Small-scale pressurized high-temperature
continuous reactor, improved safety, more automation
Step 4.2.6 Cost driver 1 – capital cost Small-scale pressurized tubular reactor
Reactor design Cost driver 2 – operational Automation, in-line monitoring
Cost driver 3 – catalyst Use of HCl catalyst from hydrolysis and phase separation
Step 4.2.7 Problem formulation Minimize reaction time (and reactor volume)
Solve optimization problem Solution method Kinetic modeling, experimentation, heuristics
Constraints Potential impurity formation at high temperature
Economic evaluation of the project Capital and operational costs Economic advantage of removing large reactor and substitute by small-scale
reactor
Avoid use of acetyl chloride and acetic acid anhydride, use inexpensive HCl
Increased automation and safety
A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456 449
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 14/20
Distillation-based solvent exchange to HEP – task S5 (Table 9).
This operation is coupled with the hydroamination reaction.
So far, limited knowledge has been accumulated about the
hydroamination reaction and the solvent exchange to HEP.
Experimental results show that the reaction is very slow and
is probably best combined to the solvent exchange step by
batch distillation. It has also been considered to evaporate a
fraction of the solvent in the ‘‘butadiene’’ solution after releas-ing the pressure of the dehydration reaction.
L–L phase separation – tasks S6.3, S6.5 and S6.7 (Table 9). This
part of the process has not been experimentally tested yet. Sol-
vent selection has not been considered either. Therefore, the
process has been assumed as in the base-case design. If needed,
the operations could be performed in continuous mode as with
the previously described THF-water separation.
3.3.4. Process simulation and/or experimental validation – step 4.4
The simplified process flowsheet (Fig. 7) has been experimen-
tally validated. Alkoxide products of different concentrations were
obtained using a continuous filter reactor in series with a side-en-
try reactor, demonstrating that it was possible to maintain impu-
rity formation at a similar level to the product isolated bycrystallization using the traditional production method [31,70],
thereby confirming that this purification step was not required.
The alkoxide solutions were subsequently hydrolyzed in continu-
ous mode and the organic and aqueous phases were continuously
separated using a hydrophobic membrane device [73].
The dehydration of ‘‘allylcarbinol’’ in THF using HCl as catalyst
was successfully performed in continuous mode with low impurity
formation [75]. The ‘‘butadiene’’ obtained in THF was hydroami-
nated with HEP in batch mode. First, THF and water were removedby batch distillation. Then, ‘‘butadiene’’ was consumed to produce
clopenthixol, a slowprocess that produces some impurities. In con-
clusion, all the operations have been validated, but the hydroamin-
ation reaction requires further development.
3.3.5. Scale-up/scale-out – step 4.5
Due to the limited annual production of the API studied (ca. 4
tonnes/year), the scale-up factor of the industrial alkylation reactor
(filter reactor + side-entry reactor) with respect to the laboratory
equipment was only about one order of magnitude (industrial-
scale flow rate is in the order of 300 mL/min). No units in parallel
were required to scale-up the process, and operations involving
solids (e.g., continuous solid charging) were actually simpler inindustrial scale than in laboratory scale, due to the lack of small-
Table 5
Information collected and design decisions taken throughout the application of the design framework to the hydroamination reaction (step 4.2 of the framework).
Hydroaminaton of ‘‘butadiene’’ with HEP – solvent-free (HEP excess)
Step 4.2 – reactor design Information
collected
Output/decision taken
Step 4.2.1 Phases – reactant
solubility
‘‘Butadiene’’ soluble in HEP
Qualitative analysis Phases – product
solubility
Clopenthixol soluble in HEP
Reaction generic
type
Anti-Markovnikov hydroamination of diene
Safety issues Potential ‘‘butadiene’’ polymerization or oxidation (many double bonds)?
Heterogeneity Not to be expected unless polymerization occurs
Step 4.2.2 Kinetics Very slow reaction (24 h at 90 C)
Calorimetric studies and short kinetic
analysis
Reaction enthalpy Slightly exothermic [76]
Step 4.2.3 Stoichiometry HEP excess favorable
Exploratory design of experiments Concentration No issues found
Temperature Temperature increases reaction rate, but may decrease product yield (selectivity). Reaction
equilibrium may be limited at high temperature.
Kinetics/mixing Slow kinetics
Solubility No issues found
Dissolution rate No issues found
Catalyst Pd(PPh3)4 – no effect on reaction rate
Step 4.2.4 Reaction class Reaction class C (slow reaction, potentially faster by increasing pressure and temperature)
Reaction classification and identification
of limitations
Limitations Kinetic-limited
Step 4.2.5 Cost driver 1 Yield (product selectivity)
Determination of cost drivers and
sustainability indicators
Cost driver 2 Capital cost (large reactor)
Cost driver 3 Low throughput
Batch or continuous? Decision Batch most obvious and simple solution.
If reactionrate couldbe increased, a continuous tubular reactor or series CSTR shouldbe considered.
Continuous reactor could lead improved temperature control and yield.
Step 4.2.6 Cost driver 1 – yield T emperature control, avoid hot-spots
Reactor design Cost driver 2 –
capital cost
Batch reactor probably easiest solution
Cost driver 3 –
throughput
No solutions found unless reaction rate can be increased
Step 4.2.7 Problem
formulation
Maximize product yield
Solve optimization problem Solution method Kinetic modeling, experimentation, heuristics
Constraints Potential impurity formation at high temperature
Economic evaluation of the project Capital and
operational costs
Yield is to be maximized
450 A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 15/20
Table 6
List of tasks and subtasks needed to obtain clopenthixol using the traditional batch-wise process, indicating material inputs (positive values) and waste streams (negative values)
in L/kg reference. The PMI is calculated summing the material inputs, assuming that the densities are approximately 1 kg/L. Values with symbol ‘‘–?’’ indicate that a certain
amount is released but the exact value is not known. Data obtained from H. Lundbeck A/S internal documents. Panel a corresponds to the production and isolation of
‘‘allylcarbinol’’. Values are referred to 1 kg of CTX as reference, while the PMI is calculated for 1 kg of ‘‘allylcarbinol’’. Panel b corresponds to the production of clopenthixol from
‘‘allylcarbinol’’. Values are referred to 1 kg of ‘‘allylcarbinol’’, while the PMI is calculated for 1 kg of clopenthixol. Comments: (1) Mg salts are solubilized using acetic acid; (2) the
pH is increased to avoid formation of impurities downstream; (3) the miscibility of THF and water is unknown; (4) remaining water is unknown; (5) dry conditions are avoided to
prevent ‘‘butadiene’’ formation; (6) distillation stopped at 85 C to avoid drying; (7) cristallization is initiated with ‘‘allylcarbinol’’ crystals; (8) yield expected 80–115%; (9) PMI
referred to kg of ‘‘allylcarbinol’’ product; (10) used to evaporate traces of water; (11) dehydration agent; (12) catalyst; (13) removes polar impurities (e.g., acetic acid); (14)
removes polar impurities; (15) increase to pH 9–11; (16) 6.5 M excess of HEP to ‘‘butadiene’’; solvent exchange lasts ca. 4 h; hydroamination is prolonged for 20 h; (17) aqueousstream sent for regeneration of HEP; (18) remove polar impurities; (19) assuming 70% yield; (20) value will be ca. 26 kg/kg if recycled HEP is subtracted.
Panel a
Task/subtask THF CTX (s) AllylMgCl
(1.4M in THF)
Water Acetic acid
(80% aq)
Ammonia
(25% aq)
Ethanol Allylcarbinol Comments Unit
1. Alkylation 3.5 Ref (1 kg) 3.25 R.
B1
2. Hydrolysis R.
B2
2.1 Water addition 5.1 R.
B2
2.2 Mg salts solub. 0.45 1 R.
B2
2.3 pH correction 0.06 2 R.
B2
3. L–L separation –? 5 –? –? 3 R.
B24. Solvent exchange R.
B2
4.1 Batch distillation 2.1 –? 4 R.
B2
4.2 Water addition 0.4 5 R.
B2
4.3 Batch distillation –? –? 6 R.
B2
4.4 Ethanol addition 5.8 R.
B2
4.5 Water addition 2 R.
B2
5. Crystallization Seed 7 R.
B2
5.1 Water addition 3.8 R.
B2
6. Filtration N. 1
6.1 Filter crystals –? 6 5.8 Approx. N. 1
6.2 First wash 1.2 N. 1
6.3 Filter crystals 1.2 N. 1
6.4 Second wash 0.6 0.6 N. 1
6.5 Filter crystals 0.6 0.6 N. 1
7. Drying –? –? N. 1
Total inputs (L) 3.5 1 kg 3.25 13.1 0.45 0.06 6.4
Product 0.9–1.35 kg 8
PMI (kg/kg) 20–
30
9
Panel b
Task/subtask Water Ammonia
(25% aq)
Allylcarbinol Toluene Acetic acid
anhydride
Acetyl
chloride
HEP E/Z
clopenthixol
Comments Unit
8. Dehydration R.
B3
8.1 Charging/loading Ref (1 kg) 3 R.
B38.2 Evaporate toluene 2 10 R.
B3
8.3 Add acetic acid anhydride 0.36 11 R.
B3
8.4 Add acetyl chloride 0.005 12 R.
B3
8.5 Add toluene 2.4 R.
B3
8.6 First wash 1.15 R.
B3
8.7 L–L separation 1.15 13 R.
B3
8.8 Second wash 1.15 R.
B3
8.9 L–L separation 1.15 14 R.
B3
(continued on next page)
A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456 451
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 16/20
scale instruments able to perform certain operations in a robust
manner at laboratory scale.
The continuous alkoxide hydrolysis and phase separation is also
relatively simple to scale up, since high flow rates may be achieved
with relatively small membrane areas [73]. Alternatively, a hydro-
cyclone (or centrifugal contactor separator) integrating mixing,
reaction, and phase separation could be used [72]. The main chal-
lenge of the hydrolysis reaction is the possible co-existence of 4
phases (propene gas in case of AllylMgCl excess, two liquid phases
and possible Mg salts precipitation), which mayentail safety issues.
The rate of the dehydration reaction was increased to a point
where almost total conversion could be obtained in less than 2 or
3 min (120 C, 5 bar), which is manageable using a tubular reactorof reasonable length, even at high throughputs. However, it is ex-
pected that the reaction rate could be increased even further with
low impurity formation if the residence time is optimized. The
hydroamination reaction has not beenstudiedwith sufficient detail
to predict how scale-up should be approached. It is speculated that
very long batch reaction times would entail substrate or product
loss, and thus, future research will focus on the optimization of the
reaction rate. Solvent exchange from THF/water to HEP should be
considered in combination with thehydroaminationreactordesign.
3.4. Monitoring and control – step 5 of the design framework
The selection of monitoring techniques has been done by in-house expertise, and in-line and at-line applications have been
integrated with the process development activities whenever pos-
sible. The large potential of NIR spectroscopy for in-line and at-line
analysis has been demonstrated for a variety of processes
[70,73,75], which can lead to a reduction of process development
time.
Thus far, the simplest approach toward adopting continuous
pharmaceutical production is to convert individual synthetic or
separation steps from batch to continuous mode, and use buffer
tanks to store intermediate compounds. This is due to potential
drastic changes in process conditions, differences in characteristic
times, and limited experience on continuous production. There-
fore, one of the main challenges for the control of a continuous
pharmaceutical manufacturing plant resides in obtaining a contin-uous stream from raw materials to product while being able to re-
spond to process disturbances, which is left for further research.
3.5. Intensification, integration, optimization – step 6 of the design
framework
No further intensification or optimization efforts were done
other than the ones discussed in the previous sections. Mass and
heat integration have not been considered yet. However, an impor-
tant step has been the quantification of the amount of THF solvent
released in the aqueous stream after phase separation, which was
surprisingly high (150–300 g/L [73]). Therefore, it should be con-sidered to recover this solvent from the aqueous stream rather
Table 6 (continued)
Panel b
Task/subtask Water Ammonia
(25% aq)
Allylcarbinol Toluene Acetic acid
anhydride
Acetyl
chloride
HEP E/Z
clopenthixol
Comments Unit
8.10 Extraction with aq ammonia 1.15 0.125 15 R.
B3
8.11 L–L separation 1.15 0.125 14 R.
B3
8.12 Third wash 1.15 R.B3
8.13 L–L separation 1.15 14 R.
B3
8.14 Fourth wash 1.15 R.
B3
8.15 L–L separation 1.15 14 R.
B3
8.16 Fifth wash 1.15 R.
B3
8.17 L–L separation 1.15 14 R.
B3
9. Solvent exchange and
hydroamination
3.4 2.95 16 R.
B4
10. Solvent exchange to toluene &
aqueous extraction of HEP
R.
B4
10.1 Add toluene 5 R.
B410.2 Add water 2.6 R.
B4
10.3 L-L separation 2.6 -2.5 17 R.
B4
10.4 First wash 2 R.
B4
10.5 L-L separation 2 18 R.
B4
10.6 Second wash 2 R.
B4
10.7 L-L separation 2 18 R.
B4
TOTALS in (kg) 13.5 0.125 1 10.4 0.36 0.005 2.95
PRODUCT 1 19
PMI (kg/kg) 28 20
R. Reactor; N. Nutsche.
452 A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 17/20
than treating it as waste. Alternatively, the use of a different ethe-
real solvent should be considered, as discussed in Section 3.3.1.
3.6. Process assessment – step 7 of the design framework
The PMI (material footprint) has been evaluated for the tradi-
tional batch process (see PMI result in Table 6) and the simplified
process (see PMI result in Table 9), assuming that the final work-
up step (extraction of clopenthixol with toluene and extraction of HEP with water) is the same for both (which could potentially be
simplified). Although the analysis does not consider the recovery
of excess HEP for simplicity, it is noteworthy that the material
footprint for the simplified process is roughly half as much as
the footprint of the traditional process. This figure could be de-
creased by further optimization of the simplified process (note
that a worst-case scenario has been assumed for the simplified
process, for example, regarding the water consumption in the
phase separation step), as well as by implementing solvent recov-
ery strategies. The PMI is assumed to be correlated to processoperating costs. Nevertheless, previous economic analyses show
Table 7
Analysis of the function of every task in the base-case design and comparison with the proposal of a simplified process.
Task
#
Operation Tasks/subtasks performed Effect on impurity separation Relevant in simplified process flowsheet?
1 Alkylation Reaction No work-up included Yes
2 Hydrolysis Reaction+ work-up: This is a reaction step but some
of the subtasks are used as preparation of following
tasks. Acetic acid is used to improve the solubility of
the Mg salts formed. The acid is added until the pH is
5–6. However, if the acid was left in the solution, it
would catalyze the formation of an impurity in task 4
that would impair the crystallization (task 5). For this
reason, aqueous ammonia is added to remove the
acetic acid from the organic phase. Besides, acetic
acid is used instead of a stronger acid (e.g., HCl) to
avoid formation of ‘‘butadiene’’, which also impairs
the crystallization
Mg salts solubilized in the
aqueous phase
Alkoxide quench and magnesium salt
solubilization are needed. All other subtasks
are only needed when ‘‘allylcarbinol’’ is
crystallized (see task 5)
3 L–L separation The aqueous phase is discarded Mg salts and the aqueous phase
are separated. Polar impurities are
removed.
Yes
4 Solvent exchange
to ethanol/water
THF and water are removed by batch distillation.
Ethanol and water are added. This solvent
combination is optimal to perform the controlled
crystallization of ‘‘allylcarbinol’’ in the subsequent
step
None No (see task 5)
5 Crystallization of
‘‘allylcarbinol’’
‘‘Allylcarbinol’ ’ is crystallized Impurities are separated if the
crystallization is well controlled
If the alkoxide is obtained in a continuous
Grignard reactor with higher quality, this
step could be avoided
6 Filtration The mother liquor is separated from the
‘‘allylcarbinol’’ crystals. Next, the crystals are washed
with water to remove remaining impurities. A final
wash with water and ethanol is done to facilitate
drying
Remaining impurities are
separated
No (see task 5)
7 Drying Ethanol and water are evaporated until dry
‘‘allylcarbinol’’ powder is obtained
Ethanol and water are evaporated No (see task 5)
8 Dehydration of
‘‘allylcarbinol’’
Toluene is distilled off to ensure that water (with a
lower boiling point) is not present before the catalyst
(acetyl chloride) is added to start the dehydration. A
molar excess (ca. 110%) of acetic acid anhydride is
used to eliminate water by forming acetic acid. When
the reaction is complete, up to 2 washing steps are
done to remove most of the acetic acid and polar
impurities formed during the dehydration. Then, an
extraction with aqueous ammonia is carried out to
remove any remains of acetic acid from the organic
phase. Up to 3 washing steps, finalize the reaction
work-up by removing remains of acetic acid or
aqueous ammonia
Catalyst and dehydration agent
(both converted to acetic acid) are
removed. Polar impurities are also
washed out
The dehydration is needed. The work-up
washing steps are only required if the acid
catalyst impairs the hydroamination (task
9)
9 Solvent exchange
and
hydroamination
The toluene-‘‘butadiene’’ solution is added to a warm
solution of HEP, from which toluene is slowly
removed by batch distillation. The hydroamination
reaction starts with the ‘‘butadiene’’ addition to HEP
Solvent used in the dehydration
(in this case toluene) is removed
Yes
10 Solvent exchange
to toluene and
aqueous
extraction of HEP
Toluene is added to the product from the
hydroamination reaction to dissolve the clopenthixol
product. At high pH, the amine groups in the
clopenthixol molecule are not protonized and the
product is more soluble in toluene than in HEP. Then,water is added to extract the HEP. The aqueous phase
is sent for regeneration of HEP (by distillation).
Finally, the organic phase is washed twice in order to
remove polar impurities
HEP and polar impurities are
removed
Yes
A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456 453
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 18/20
that raw material costs are typically 30–80% of the operating
costs, meaning that yield and quality are typically the main cost
drivers [29,37,66].
Considering the last column of Tables 6 and 9, it is interesting
that while there is an obvious reduction in the number of tasks
performed when switching to a simplified process containing con-
tinuous units, the number of physical units needed to perform
these tasks is kept constant or even increases. This occurs because
batch reactor B2 in the original process can perform the hydrolysis,
L–L phase separation, solvent exchange, and crystallization opera-
tions. In contrast, a continuous process requires two continuous
alkylation reactors and one continuous hydrolysis reactor, option-
ally integrated with a continuous L–L phase separator. Despite the
fact that there may be a large decrease in unit sizes (smaller phys-
ical footprint), the capital cost may be similar for a batch reactor
and a continuous unit [29,37]. Furthermore, the potential savings
Table 8
List of inputs and outputs to relevant tasks in the base-case design, analysis of possible cross-interactions, and potential degradation issues.
Task # Reactants, reagents,
catalysts, and solvents
Products, catalysts, and
solvents
Degradation issues Cross-interactions
1 – Alkylation CTX, AllylMgCl, THF Alkoxide, CTX?,
AllylMgCl?, THF
Keep N2 atmosphere to avoid
hydrolysis. Avoid high temperature
None
2 – Hydrolysis Alkoxide, CTX?, AllylMgCl?,
THF, Water, Acid
‘‘Allylcarbinol’’, CTX?,
Propene?, THF, Water,
Acid?, MgCl2
None Acid may dehydrate
‘‘allylcarbinol’’
to ‘‘butadiene’’
4 – Solvent exch. ‘‘Allylcarbinol’’, CTX?, THF,
Water, Ethanol, Acid?
‘‘Allylcarbinol’’, CTX?,
Ethanol, Water, Acid?
Avoid high temperature using
vacuum
distillation
Acid may catalyze the formation
of
an impurity from ethanol and
‘‘allylcarbinol’’
5 – Crystallization As product #4 As product #4 None ‘‘Butadiene’’ or impurities may
impair the crystallization
6 – Filtration As product #4 ‘‘Allylcarbinol’’, Ethanol
traces, Water traces
None None
7 – Drying As product #6 ‘‘Allylcarbinol’’ None None
8 – Dehydration ‘‘Allylcarbinol’’, Toluene,
Acetic acid anhydride,
Acetyl chloride
‘‘Butadiene’’, Toluene,
Acetic acid?
‘‘Butadiene’’ may degrade by
polymerization. Avoid high
temperature. Use N2 atmosphere
None
9 – Hydroaminaton ‘‘Butadiene’’, HEP, Toluene, Acetic
acid?
Clopenthixol, HEP,
Aceticacid?
As #8 Acid may have a (positive
/negative?) influence on thehydroamination reaction
10 – Solvent exch. Clopenthixol, HEP, Toluene, Water Clopenthixol, Toluene Use N2 atmosphere None
Table 9
List of tasks and subtasks needed to obtain clopenthixol using the simplified process, indicating material inputs (positive values) and waste streams (negative values) in L/kg of
CTX. The PMI is calculated summing the material inputs, assuming that the densities are approximately 1 kg/L. Values marked with are assumed as for the base-case design but
could potentially be reduced or eliminated. Comments: (1) if the concentration of AllylMgCl was increased to 1.5 M, this value would be reduced to 2.7 L/kg, reducing THF
consumption in the Grignard reagent formation; (2) a volume increase of 35% is expected due to API intermediate in solution; a worst-case scenario has been considered where
the volumetric flow ratio between acidic water and alkoxide solution is 2:1; otherwise, this value could be decreased; (3) THF in the aqueous waste stream has been calculated
assuming a concentration of 200 g/L; (4) more HCl is added in case the pH after L–L separation is not low enough for catalysis; (5) assuming 6.5 M excess of HEP with respect to
‘‘butadiene’’ as in the base-case design, but the values are corrected to refer to 1 kg of CTX; (6) the aqueous stream is sent for regeneration of HEP; (7) removes polar impurities;
(8) removes polar impurities; (9) overall yield from CTX assumed as 70%; (10) value will be ca. 26–27 kg/kg if recycled HEP is subtracted.Task THF CTX
(s)
AllylMgCl (1 M
in THF)
Water HCl (37% aq) Toluene HEP E/Z
clopenthixol
Comments Reactor
S1. Alkylation Ref
(1 kg)
4.1 1 Reactors C1
and C2
S2. Hydrolysis 10.9 0.34 2 Reactor C3
S3. L–L separation 2.4 11.23 Consumed to
MgCl2
3 Separator C1
S4. Dehydration 0.03 4 Reactor C4
S5. Solvent exchange and hydroamination 1.4 0.08 3.5⁄ 5 Reactor B5
S6. Solvent exchange to toluene and
aqueous extraction of HEP
Reactor B5
S6.1 Add toluene 5.9⁄ Reactor B5
S6.2 Add water 3⁄ Reactor B5
S6.3 L–L separation 3⁄
2.9⁄ 6 Reactor B5
S6.4 First wash 2.3⁄ Reactor B5
S6.5 L–L separation 2.3⁄ 7 Reactor B5
S6.6 Second wash 2.3⁄ Reactor B5
S6.7 L–L separation 2.3⁄ 8 Reactor B5
Totals in (kg) 4.1 18.7⁄ 0.37 5.9⁄ 3.5⁄
Product 1.1 9
PMI (kg/kg) 29⁄ 10
454 A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 19/20
obtained from less manual operations may be compensated by
higher costs needed to implement in-line sensors and actuators.
Hence, while a new pharmaceutical process of these characteristics
would most likely be designed and implemented according to the
simplified process shown in Fig. 7 (or a further optimized process),
moving the traditional batch process toward the simplified process
including continuous operations can only be justified based on a
rigorous economical and environmental analysis.
The mode of operation of each unit will most likely be consid-
ered on a case by case basis and depending on the short-term
and long-term strategies of the manufacturing company. In this
particular case study, it is clear that changing the alkylation reac-
tion to continuous mode brings an obvious product quality
improvement that enables the elimination of a solvent exchange
step, crystallization, filtering, drying, collecting the product, and fi-
nally the storage. Therefore, it is an obvious advantage in terms of
operating cost as well as capital cost. It is less clear whether mov-
ing the dehydration reaction to continuous mode will result in
immediate savings. However, avoiding the use of toluene, acetyl
chloride, and acetic acid anhydride in this reaction, as well as elim-
inating the numerous subsequent washing steps (subtasks 8.5–
8.17 in Table 6) may in the long term compensate the investment
needed to establish a small-scale continuous tubular reactor run-
ning at high temperature under pressure. Yet, the eventual connec-
tion of a continuous dehydration reactor with a discontinuous
hydroamination reaction may be a challenge.
3.7. Process implementation – step 8 of the design framework
The continuous alkylation reactor has been implemented at H.
Lundbeck A/S, demonstrating a production of high quality alkoxide
with low solvent consumption using smaller scale equipment. The
product is continuously monitored using in-line NIR spectroscopy
measurements, which assist the operators in troubleshooting situ-
ations. The simplified process in Fig. 7 will be gradually imple-
mented at H. Lundbeck A/S on a step-by-step basis as the processexperience increases. This is probably the safest method for retro-
fitting an existing production plant with respect to guaranteeing
that product supply can be maintained.
4. Conclusions
A systematic framework has been proposed to design continu-
ous pharmaceutical manufacturing processes, that is, processes
that exploit the advantages of continuous flow. The framework fol-
lows the drug product and process development cycle and pro-
motes the synergic interaction of PSE and microfluidic techniques
throughout it, emphasizing the importance of solvent selection,
reactor design, and separation process design. The application of
the framework starts already at the drug discovery level, whereefficient interaction with medicinal chemists can result in reduced
development time, selection of environmentally friendly synthetic
routes, and smoother scale-up. Guidelines are suggested to ascer-
tain when to perform a certain operation in batch or in continuous
mode, while a final process evaluation in terms of cost, environ-
mental footprint, quality, and safety must be performed to evalu-
ate the viability of a design project.
The design framework has been applied to retrofit an existing
batch-wise manufacturing plant used by H. Lundbeck A/S to pro-
duce clopenthixol. The process includes a set of reaction steps with
different characteristic times, L–L phase separations, and solvent
exchange steps by distillation. The use of continuous reactors re-
sulted in improved product quality, thus avoiding the isolation of
an intermediate product by crystallization and eliminating prepa-ration (solvent exchange to anti-solvent) and subsequent steps (fil-
tration, drying, and storage). It was shown that the simplification
of the process used to manufacture clopenthixol yields a reduction
of the material footprint of the process (evaluated by the process
mass intensity index) with at least 50%. This reduction is correlated
with the environmental footprint and to operating costs. The cap-
ital costs of the plant could also be reduced by the elimination of
some of its large units, isolation, and storage facilities. The design
framework assisted in structuring the different and challenging
design problems faced and could especially be useful for the devel-
opment of novel continuous pharmaceutical manufacturing pro-
cesses through increased process understanding.
Acknowledgements
We thank the Technical University of Denmark and H. Lundbeck
A/S for technical and financial support.
References
[1] N.A.M. Tamimi, P. Ellis, Drug development: from concept to marketing!,
Nephron Clin Pract. 113 (2009) 125–131.
[2] K. Plumb, Continuous processing in the pharmaceutical industry - changing
the mindset, Chem. Eng. Res. Des. 83 (2005) 730–738.[3] A. Behr, V.A. Brehme, C.L.J. Ewers, H. Grön, T. Kimmel, S. Küppers, I. Symietz,
New developments in chemical engineering for the production of drug
substances, Eng. Life Sci. 4 (2004) 15–24.
[4] U.S. Department of Health and Human Services, Food and DrugAdministration,
PAT – A Framework for Innovative Pharmaceutical Development,
Manufacturing, and Quality Assurance, 2004.
[5] R.L. Hartman, K.F. Jensen, Microchemical systems for continuous-flow
synthesis, Lab Chip 9 (2009) 2495–2507.
[6] J.P. McMullen, K.F. Jensen, Integrated microreactors for reaction automation:
newapproaches to reaction development, Annu. Rev. Anal.Chem. 3 (2010) 19–
42.
[7] K.V. Gernaey, R. Gani, A model-based systems approach to pharmaceutical
product-process design and analysis, Chem. Eng. Sci. 65 (2010) 5757–5769.
[8] J.P. McMullen, K.F. Jensen, Rapid determination of reaction kinetics with an
automated microfluidic system, Org. Process Res. Dev. 15 (2011) 398–407.
[9] R.K. Henderson, C. Jiménez-González, D.J.C. Constable, S.R. Alston, G.G.A. Inglis,
G. Fisher, J. Sherwood, S.P. Binks, A.D. Curzons, Expanding GSK’s solvent
selection guide – embedding sustainability into solvent selection starting at
medicinal chemistry, Green Chem. 13 (2011) 854–862.
[10] C. Jiménez-González, P. Poechlauer, Q.B. Broxterman, B. Yang, D. am Ende, J .
Baird, C. Bertsch, R.E. Hannah, P. Dell’Orco, H. Noorman, S. Yee, R. Reintjens, A.
Wells, V. Massonneau, J. Manley, Key green engineering research areas for
sustainable manufacturing: a perspective from pharmaceutical and fine
chemicals manufacturers, Org. Process Res. Dev. 15 (2011) 900–911.
[11] K.V. Gernaey, A.E. Cervera-Padrell, J.M. Woodley, A perspective on PSE in
pharmaceutical process development and innovation, Comput. Chem. Eng. 42
(2012) 15–29.
[12] V. Hessel, Novel process windows – gate to maximizing process intensification
via flow chemistry, Chem. Eng. Technol. 32 (2009) 1655–1681.
[13] L. Kang, B.G. Chung, R. Langer, A. Khademhosseini, Microfluidics for drug
discovery and development: from target selection to product lifecycle
management, Drug Discov. Today 13 (2008) 1–13.
[14] D. Webb, T.F. Jamison, Continuous flow multi-step organic synthesis, Chem.
Sci. 1 (2010) 675–680.
[15] R. Singh, R. Rozada-Sanchez, T. Wrate, F. Muller, K.V. Gernaey, R. Gani, J.M.
Woodley, A retrofit strategy to achieve ‘‘fast, flexible, future (F3)’’
pharmaceutical production processes, Comput. Aided Chem. Eng. 29 (2011)291–295.
[16] R. Singh, K.V. Gernaey, R. Gani, An ontological knowledge-based system for the
selection of process monitoring and analysis tools, Comput. Chem. Eng. 34
(2010) 1137–1154.
[17] V. Venkatasubramanian, C. Zhao, G. Joglekar, A. Jain, L. Hailemariam, P. Suresh,
P. Akkisetty, K. Morris, G.V. Reklaitis, Ontological informatics infrastructure for
pharmaceutical product development and manufacturing, Comput. Chem. Eng.
30 (2006) 1482–1496.
[18] R. Gani, P. Arenas Gómez, M. Folic, C. Jiménez-González, D.J.C. Constable,
Solvents in organic synthesis: replacement and multi-step reaction systems,
Comput. Chem. Eng. 32 (2008) 2420–2444.
[19] D.J.C. Constable, C. Jiménez-González, R.K. Henderson, Perspective on solvent
use in the pharmaceutical industry, Org. Process Res. Dev. 11 (2007) 133–137.
[20] R. Gani, C. Jiménez-González, D.J.C. Constable, Method for selection of solvents
for promotion of organic reactions, Comput. Chem. Eng. 29 (2005) 1661–1676.
[21] M. Folic, C.S. Adjiman, E.N. Pistikopoulos, Design of solvents for optimal
reaction rate constants, AIChE J. 53 (2007) 1240–1256.
[22] J. Chen, B.L. Trout, Computer-aided solvent selection for improving the
morphology of needle-like crystals: a case study of 2,6-dihydroxybenzoicacid, Cryst. Growth Des. 10 (2010) 4379–4388.
A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456 455
7/23/2019 Active Pharmaceutical Ingredient API Production Involving Continuous Processes a Process System Engineering PSE…
http://slidepdf.com/reader/full/active-pharmaceutical-ingredient-api-production-involving-continuous-processes 20/20
[23] R. Gani, C. Jiménez-González, A.T. Kate, P.A. Crafts, M. Jones, L. Powell, J.H.
Atherton, J.L. Cordiner, A modern approach to solvent selection, Chem. Eng. –
New York (March) (2006) 30–43.
[24] D.C. Weis, D.P. Visco, Computer-aided molecular design using the signature
molecular descriptor: application to solvent selection, Comput. Chem. Eng. 34
(2010) 1018–1029.
[25] D. Hsieh, A.J. Marchut, C. Wei, B. Zheng, S.S.Y. Wang, S. Kiang, Model-based
solvent selection during conceptual process design of a new drug
manufacturing process, Org. Process Res. Dev. 13 (2009) 690–697.
[26] Y. Li, Y. Yang, V. Kalthod, S.M. Tyler, Optimization of solvent chasing in API
manufacturing process: constant volume distillation, Org. Process Res. Dev. 13(2009) 73–77.
[27] J.C. Lin, A.G. Livingston, Nanofiltration membrane cascade for continuous
solvent exchange, Chem. Eng. Sci. 62 (2007) 2728–2736.
[28] P.A. Santacoloma, G. Sin, K.V. Gernaey, J.M. Woodley, Multienzyme-catalyzed
processes: next-generation biocatalysis, Org. Process Res. Dev. 15 (2011) 203–
212.
[29] D.M. Roberge, L. Ducry, N. Bieler, P. Cretton, B. Zimmermann, Microreactor
technology: a revolution for the fine chemical and pharmaceutical industries?,
Chem Eng. Technol. 28 (2005) 318–323.
[30] R.L. Hartman, J.R. Naber, N. Zaborenko, S.L. Buchwald, K.F. Jensen, Overcoming
the challenges of solid bridging and constriction during Pd-catalyzed C–N
bond formation in microreactors, Org. Process Res. Dev. 14 (2010) 1347–1357.
[31] K. Müller Christensen, M. Jønch Pedersen, K. Dam-Johansen, T. Lønberg Holm,
T. Skovby, S. Kiil, Design and operation of a filter reactor for continuous
production of a selected pharmaceutical intermediate, Chem. Eng. Sci. 71
(2012) 111–117.
[32] D.M. Roberge, An Integrated approach combining reaction engineering and
design of experiments for optimizing reactions, Org. Process Res. Dev. 8 (2004)
1049–1053.
[33] J.P. McMullen, K.F. Jensen, An automated microfluidic system for online
optimization in chemical synthesis, Org. Process Res. Dev. 14 (2010) 1169–
1176.
[34] G. Franceschini, S. Macchietto, Model-based design of experiments for
parameter precision: state of the art, Chem. Eng. Sci. 63 (2008) 4846–4872.
[35] N. Kockmann, D.M. Roberge, Harsh reaction conditions in continuous-flow
microreactors for pharmaceutical production, Chem. Eng. Technol. 32 (2009)
1682–1694.
[36] R.L. Hartman,J.P. McMullen, K.F. Jensen, Deciding whether to go with the flow:
evaluating the merits of flow reactors for synthesis, Angew. Chem. Int. Edit. 50
(2011) 7502–7519.
[37] D.M. Roberge, B. Zimmermann, F. Rainone, M. Gottsponer, M. Eyholzer, N.
Kockmann, Microreactor technology and continuous processes in the fine
chemical and pharmaceutical industry: is the revolution underway?, Org
Process Res. Dev. 12 (2008) 905–910.
[38] C. Jimenez-Gonzalez, C.S. Ponder, Q.B. Broxterman, J.B. Manley, Using the right
green yardstick: why process mass intensity is used in the pharmaceutical
industry to drive more sustainable processes, Org. Process Res. Dev. 15 (2011)912–917.
[39] A. Carvalho, R. Gani, H. Matos, Design of sustainable chemical processes:
systematic retrofit analysis generation and evaluation of alternatives, Process
Saf. Environ. Prot. 86 (2008) 328–346.
[40] N. Kockmann, M. Gottsponer, D.M. Roberge, Scale-up concept of single-
channel microreactors from process development to industrial production,
Chem. Eng. J. 167 (2011) 718–726.
[41] D. Hildebrandt, D. Glasser, The attainable region and optimal reactor
structures, Chem. Eng. Sci. 45 (1990) 2161–2168.
[42] A.C. Kokossis, A.F. Christodoulos, Optimizationof complex reactor networks—I.
Isothermal operation, Chem. Eng. Sci. 45 (1990) 595–614.
[43] V.L. Mehta, A.C. Kokossis, Nonisothermal synthesis of homogeneous and
multiphase reactor networks, AICHE J. 46 (2000) 2256–2273.
[44] P. Lutze, R. Gani, J.M. Woodley, Process intensification: a perspective on
process synthesis, Chem. Eng. Process. 49 (2010) 547–558.
[45] P. Lutze, R. Gani, J.M. Woodley, Phenomena-based process synthesis and
design to achieve process intensification, Comput. Aided Chem. Eng. 29 (2011)
221–225.
[46] D.I. Gerogiorgis, P.I. Barton, Steady-state optimization of a continuouspharmaceutical process, Comput. Aided Chem. Eng. 27 (2009) 927–932.
[47] S.D. Barnicki, J.J. Siirola, Process synthesis prospective, Comput. Chem. Eng. 28
(2004) 441–446.
[48] J.C. Brunet, Y.A. Liu, Studies in chemical process design and synthesis: 10. An
expert system for solvent-based separation process synthesis, Ind. Eng. Chem.
Res. 32 (1993) 315–334.
[49] C.A. Jaksland, R. Gani, K.M. Lien, Separation process design and synthesis based
on thermodynamic insights, Chem. Eng. Sci. 50 (1995) 211–530.
[50] L. d’Anterroches, R. Gani, Group contribution based process flowsheet
synthesis, design and modelling, Fluid Phase Equilib. 228–229 (2005) 141–
146.
[51] E. Bek-Pedersen, R. Gani, Design and synthesis of distillation systems using a
driving-force-based approach, Chem. Eng. Process. 43 (2004) 251–262.
[52] R.L. Hartman, H.R. Sahoo, B.C. Yen, K.F. Jensen, Distillation in microchemical
systems using capillary forces and segmented flow, Lab Chip 9 (2009) 1843–
1849.
[53] J.G. Kralj, H.R. Sahoo, K.F. Jensen, Integrated continuous microfluidic liquid-
liquid extraction, Lab Chip 7 (2007) 256–263.
[54] A. Ziogas, V. Cominos, G. Kolb, H. Kost, B. Werner, V. Hessel, Development of a
microrectificationapparatus for analytical and preparative applications, Chem.
Eng. Technol. 35 (2012) 58–71.
[55] International Conference on Harmonisation (ICH), Quality Guidelines Q8
(Pharmaceutical Development, R2, 2009), Q9 (Quality Risk Management,
2006) and Q10 (Pharmaceutical Quality System, 2009), U.S. Department of
Health and Human Services, Food and Drug Administration, Center for Drug
Evaluation and Research (CDER), Rockville, MD.
[56] K.F. Jensen, Microreaction engineering – is small better?, Chem Eng. Sci. 56(2001) 293–303.
[57] M. Mendorf, H. Nachtrodt, A. Mescher, A. Ghaini, D.W.Agar, Designand control
techniques for the numbering-up of capillary microreactors with uniform
multiphase flow distribution, Ind. Eng. Chem. Res. 49 (2010) 10908–10916.
[58] P. Barthe, C. Guermeur, O. Lobet, M. Moreno, P. Woehl, D.M. Roberge, N. Bieler,
B. Zimmermann, Continuous multi-injection reactor for multipurpose
production – Part I, Chem. Eng. Technol. 31 (2008) 1146–1154.
[59] H.S. Pordal, C.J. Matice, T.J. Fry, The role of computational fluid dynamics in the
pharmaceutical industry, Pharm. Technol. (February) (2002).
[60] G. Wernet, S. Conradt, H. Isenring, C. Jiménez-González, K. Hungerbühler, Life
cycle assessment of fine chemical production: a case study of pharmaceutical
synthesis, Int. J. Life Cycle Ass. 15 (2010) 294–303.
[61] S. García Muñoz, S. Dolph, H.W. Ward II, Handling uncertainty in the
establishment of a design space for the manufacture of a pharmaceutical
product, Comput. Chem. Eng. 34 (2010) 1098–1107.
[62] R. Singh, K.V. Gernaey, R. Gani, ICAS-PAT: a software for design, analysis and
validation of PAT systems, Comput. Chem. Eng. 34 (2010) 1108–1136.
[63] A. Malcolm, J. Polan, L. Zhang, B.A. Ogunnaike, A.A. Linninger, Integrating
systems design and control using dynamic flexibility analysis, AICHE J. 53
(2007) 2048–2061.
[64] M.K.A. Hamid, G. Sin, R. Gani, Integration of process design and controller
design for chemical processes using model-based methodology, Comput.
Chem. Eng. 34 (2010) 683–699.
[65] A.A. Linninger, A. Malcolm, Pollution prevention for batch pharmaceutical and
specialty chemical processes, in: E. Korovessi, A.A. Linninger (Eds.), Batch
Processes, CRC Press, Taylor & Francis Group, Boca Raton, Florida, US, 2006.
[66] S.D. Schaber, D.I. Gerogiorgis, R. Ramachandran, J.M.B. Evans, P.I. Barton, B.L.
Trout, Economic analysis of integrated continuous and batch pharmaceutical
manufacturing: a case study, Ind. Eng. Chem. Res. 50 (2011) 10083–10092.
[67] G.S. Silverman, P.E. Rakita, Handbook of Grignard Reagents, CRC Press, New
York, 1996.
[68] D.F. Aycock, Solvent applications of 2-methyltetrahydrofuran in
organometallic and biphasic reactions, Org. Process Res. Dev. 11 (2007) 156–
159.
[69] K. Watanabe, N. Yamagiwa, Y. Torisawa, Cyclopentyl methyl ether as a new
and alternative process solvent, Org. Process Res. Dev. 11 (2007) 251–258.
[70] A.E. Cervera-Padrell, J.P. Nielsen, M. Jønch Pedersen, K. Müller Christensen, A.R.Mortensen, T. Skovby, K. Dam-Johansen, S. Kiil, K.V. Gernaey, Monitoring and
control of a continuous Grignard reaction for the synthesis of an active
pharmaceutical ingredient intermediate using in-line NIR spectroscopy, Org.
Process Res. Dev. 16 (2012) 901–914.
[71] D.M. Roberge, N. Bieler, M. Mathier, M. Eyholzer, B. Zimmermann, P. Barthe, C.
Guermeur, O. Lobet, M. Moreno, P. Woehl, Development of an industrial multi-
injection microreactor for fast and exothermic reactions – Part II, Chem. Eng.
Technol. 31 (2008) 1155–1161.
[72] G.N. Kraai, F. van Zwol, B. Schuur, H.J. Heeres, J.G. de Vries, Two-phase
(bio)catalytic reactions in a table-top centrifugal contact separator, Angew.
Chem. Int. Edit. 47 (2008) 3905–3908.
[73] A.E. Cervera-Padrell, S.T. Morthensen, D.J. Lewandowski, T. Skovby, S. Kiil, K.V.
Gernaey, Continuous hydrolysis and L-L phase separation of an active
pharmaceutical ingredient intermediate using a mini-scale hydrophobic
membrane separator, Org. Process Res. Dev. 16 (2012) 888–900.
[74] B.K.H. Yen, A. Günther, M.A. Schmidt, K.F. Jensen, M.G. Bawendi, A
microfabricated gas–liquid segmented flow reactor for high-temperature
synthesis: the case of CDSE quantum dots, Angew. Chem. 117 (2005) 5583–
5587.[75] A.E. Cervera-Padrell, Moving from Batch Towards Continuous Organic-
Chemical Pharmaceutical Production, PhD Thesis, Technical University of
Denmark, Kgs. Lyngby, 2012.
[76] T.E. Müller, K.C. Hultzsch, M. Yus, F. Foubelo, M. Tada, Hydroamination: direct
addition of amines to alkenes and alkynes, Chem. Rev. 108 (2008) 3795–3892.
[77] J.F. Hartwig, Development of catalysts for the hydroamination of olefins, Pure
Appl. Chem. 76 (2004) 507–516.
[78] O. Löber, M. Kawatsura, J.F. Hartwig, Palladium-catalyzed hydroamination of
1,3-dienes: a colorimetric assay and enantioselective additions, J. Am. Chem.
Soc. 123 (2001) 4366–4367.
[79] K.G. Tomazi, A.A. Linninger, J.R. Daniel, Batch processing industries, in: E.
Korovessi, A.A. Linninger (Eds.), Batch Processes, CRC Press, Taylor & Francis
Group, Boca Raton, Florida, US, 2006.
456 A.E. Cervera-Padrell et al. / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 437–456