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11.2 Mechanochemistry for Sustainable Processes 259
meet this principle. Furthermore, exploring solvent-free protocols under mechanochemistry
allowed the synthesis of products that were difficult to access using conventional method-
ologies [14]. In the case of LAG, the use of catalytic volumes of solvents can operate in mul-
tiple ways, whereas it can help to mimic the potential of a bulk solvent to accelerate or steer
chemical transformations, or even to discover and tune chemical reactivity [29, 30]. It is
important to understand that in LAG, the solvent is placed in the reaction vessel not to oper-
ate strictly as a reaction medium, but to work as a catalytic additive. From the sustainability
point of view, the small quantities employed make their use acceptable, regardless of their
safety profile. In what concerns solid auxiliaries, ionic salts (such as sodium chloride), silica,
and alumina are among the most used in mechanochemistry. Larger amounts are required
when compared to LAG, because their role is to dilute the reaction mixture or to disperse
catalysts. They can also absorb reactants, making the mixtures physically more suitable for
the milling process. These additives will necessarily cause more waste, and therefore their
application should be critically evaluated for the desired transformation [31, 32].
As far as energy efficiency is concerned, mechanochemistry can also make a strong contribu-
tion to meeting this green chemistry principle. Most mechanochemical transformations occur
without external heating, minimising the energy required for a given chemical process, espe-
cially when compared to their solvothermal counterparts. Despite the high value of achieving
chemical transformations without external heating from the energy and process safety points of
view, temperature control in mechanochemical transformations can be a suitable option to
increase the efficiency, reproducibility, and robustness of this kind of process [14, 33–35].
The use of renewable feedstocks, the seventh principle of green chemistry, also caught the
attention of researchers working in the field of mechanochemistry. Easy-to-perform protocols
allow the polymerisation, modification, and/or depolymerisation of relevant biopolymers, such
as chitin [36, 37], cellulose [38, 39], lignin [40, 41], among others. The use of biomass as starting
point to achieve high-value products, including materials, has also been reported [42, 43].
Reducing the use of chemical derivatives, corresponding to the eighth principle of green
chemistry, can be achieved in mechanochemistry by reducing derivatisation steps, simpli-
fying the synthetic route, and preventing the use of additional reagents and generation of
extra waste. One good example of the suitability of mechanochemistry to avoid over-
processing of raw materials is the use of mineral ores as catalysts directly in mechano-
chemical transformations, without their use to refine the material to a pure inorganic
metal catalyst, or even as a replacement for classical bases [14, 44–46].
Concerning catalysis, the ninth green chemistry principle, mechanochemistry has
opened the door to new endeavours in the field of catalysis research. For example, the sur-
face itself of the milling medium/container/balls can operate as a catalyst for a given chem-
ical transformation [47, 48]. Mechanochemistry apparatus has also proven to be suitable
for a wide range of metal catalysts [49], organocatalysts [50, 51], and biocatalysts [52].
The design for degradation principle is highly oriented to material synthesis in the mech-
anochemistry context. Several efforts have been developed to generate mechanochemical
protocols to prepare functional polymers with tunable degradability [14].
Over the past few years, considerable efforts have been dedicated to real-time monitoring
of mechanochemical reactions, increasing the compliance with principle eleven of green
chemistry. To achieve this goal, several analytical techniques were successfully coupled
with mechanochemistry equipment, including synchrotron powder X-ray diffraction [53],
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11 Mechanochemistry for Sustainable Drug Design and Active Pharmaceutical Ingredient Synthesis260
Raman spectroscopy [54], real-time thermal sensors [55], real-time manometric monitor-
ing [56], gas chromatography [57], non-dispersive infrared spectroscopy [58], X-ray absorp-
tion spectroscopy [59], X-ray diffraction [59], solid state nuclear magnetic resonance
(NMR) [60], real-time UV-Vis spectroscopy [61], and so on. The implementation of in-pro-
cess control systems in the field of mechanochemistry allows the elucidation of reaction
mechanisms, as well as investigation of the correlation between mechanochemical param-
eters and the course of the chemical reaction.
The development of inherently safe chemistry for accident prevention, the twelfth prin-
ciple of green chemistry, is driven, in the case of mechanochemistry, by the level of opera-
tional simplicity required, which can help to reduce risks and accident potential.
Nevertheless, transformations requiring contact-unstable or explosive reactants need to
have their risk potential assessed for each case, especially when scaling-up procedures are
considered [62, 63]. The previously described real-time monitoring, as well as the develop-
ment of low-temperature mechanochemical protocols, can also be suitable options to per-
form chemical transformations under safe conditions, namely exothermic reactions [33].
Figure 11.1 illustrates the main features of mechanochemical transformations, supporting
their application under the 12 principles of green chemistry. It becomes clear that the use of
mechanochemistry can provide green synthetic protocols for well-established reactions, as
well as to discover new chemical reactivity and synthetic routes, and to prepare elusive prod-
ucts under mild conditions that could not be prepared under conventional conditions.
11.3 Mechanochemistry Apparatus
The birth of mechanochemistry applied to organic chemistry is credited to the preparation
of quinhydrone derivatives [64]. Following a slow start, mechanochemistry is one of the
most recent techniques in organic synthesis and has great potential for the development of
faster and cleaner solvent-free synthetic methodologies for pharmaceuticals [65]. This
development goes hand in hand with the development of equipment to perform mechano-
chemistry at the lab scale.
Manual grinding, performed using a mortar and a pestle, was the first approach used to
perform mechanochemical transformations in the lab [66] and was extended to all types of
laboratories, including industry, academia, and secondary schools. However, the high reli-
ance on the operator and consequent lack of reproducibility led to the search for the devel-
opment of alternatives. Nowadays there are several types of grinding and milling apparatus
of diverse brands commercially available, including automatic mortars. Among them can
be highlighted ball milling instruments that include planetary ball mills and vibrational
ball mills, and extruders. These ball milling systems are an automated apparatus that ena-
bles the control of energy input by adjusting the milling frequency, allowing an increase in
reproducibility and performing reactions with longer reaction times [67]. The main differ-
ence between them is the type of movement to promote mechanical energy input: plane-
tary ball mills involve rotation, and mixer milling systems are based on back-and-forth
swinging. These laboratory-scale systems were designed for batch production and could
suffer from some reactor cleaning issues, especially when the final reaction crude is not a
free-flowing powder and the goal is to keep the entire process solvent free [68].
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11.4 Selected Examples of Active Pharmaceutical Ingredient Production Using Mechanochemistry 261
In addition, mechanochemical reactions can also be performed via flow extrusion tech-
niques, where the mixing of solid materials is promoted by forcing them through con-
strained spaces. This is an alternative mechanochemical process with great interest for the
pharmaceutical industry, but with limitations for the laboratory-scale development phase
of drugs, which requires the synthesis of a large number of molecules [69]. Depending on
the device used, the mechanical energy could be afforded via impact, compression, shear,
or friction, as depicted in Figure 11.2.
Several processes occur during mechanical grinding of solids, such as generation of new
surfaces, formation of dislocations and point defects in the crystalline structure, as well as
decrease of the particle size and phase transformations. The occurrence of chemical reac-
tions, which has been associated with the heat generated in the milling process and favoured
by phase transformations and the large area of contact between the solids, has been
explained using different models, namely the hot-spot theory [70–72], the magma-plasma
model [73], the hierarchical model [74, 75], or the theory of short-lived active centres [76].
The limitations and capabilities of mechanochemistry to scale up depend on the type of
equipment and technology used [77]. Ball mills, mixer mills, or planetary mills are batch-
mode systems, and their scaling up and applicability in the chemical industry, and particu-
larly in the pharmaceutical industry, have some limitations mainly due to safety issues, as
well as to localised hot spots and temperature control. However, extrusion (twin and sin-
gle-screw extruders) works in flow mode and has been used in the transformation industry.
Extrusion, along with flow chemistry in solution, was identified by IUPAC as one of the top
ten most relevant chemical innovations that could change the world [78]. These techniques
can provide a scalable continuous solution and, when fully developed, lead to the full
implementation of mechanochemistry in industry.
11.4 Selected Examples of Active Pharmaceutical Ingredient
Production Using Mechanochemistry
A wide range of equipment can be used to carry out API synthesis under mechanochemical
conditions. From the examples reported in the literature, ball milling is by far the method
most commonly used by researchers.
Figure 11.2 Schematic representation of (A) vibrational ball milling; (B) planetary ball milling;
and (C) single-screw extruder.
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11 Mechanochemistry for Sustainable Drug Design and Active Pharmaceutical Ingredient Synthesis262
Portada et al. explored the catalytic transfer hydrogenation of aromatic nitro derivatives
under mechanochemical conditions, and applied it successfully to two well-established
APIs [79], the analgesic and antipyretic paracetamol (or acetaminophen) [80] and the anti-
arrhythmic procainamide [81]. Paracetamol was obtained by solvent-free sequential mech-
anochemical hydrogenation of p-nitrophenol and acetylation of the newly formed amino
group (Figure 11.3A). Silica was used as a solid grinding auxiliary in both steps. In the case
of procainamide, a two-step procedure was also designed and optimised, with the first step
consisting of the amide coupling of 4-nitrobenzoylchloride and N,N-diethylenediamine
promoted by potassium carbonate to afford a 4-nitrobenzoyldiethylenediamine precursor,
which after chromatography-free purification (88% yield) was subjected to catalytic trans-
fer hydrogenation under LAG conditions (methanol was used as auxiliary) to provide the
desired API quantitatively (Figure 11.3B) [79].
Sulfonylureas, widely used in clinical practice in treatment of type 2 diabetes [82], are a
class of drugs that has been widely studied in synthetic approaches using mechanochemistry.
Fri
ščić and co-workers [83] reported the synthesis of first-generation sulfonylureas tolbu-
tamide and chlorpropamide using ball milling under LAG reaction conditions. The syn-
thetic protocol consisted in promoting the copper(I)-catalysed coupling reaction between
sulfonamides and isocyanates. Among the different catalysts screened, copper(I) chloride
proved to be suitable to promote the synthesis of tolbutamide at high yield (91%) even in
the absence of LAG. However, thorough screening of different grinding liquids showed
that nitromethane enabled the reaction to occur with a similar yield (90%), but with a con-
siderable decrease in the catalyst load required (from 20 mol% to 5 mol%), improving the
overall sustainability of the synthetic protocol (Figure 11.4A). With the best conditions in
hand, the researchers proved the protocol to be suitable for the synthesis of chlorpropa-
mide (92% yield) (Figure 11.4B) and could also be adapted to a two-step mechanochemical
protocol for the synthesis of second-generation glibenclamide (92% yield) (Figure 11.4C)
[83]. Later on, the same group explored the synthesis of tolbutamide using the same
Figure 11.3 (A, B) Mechanochemical synthesis of paracetamol and procainamide. n = number of
balls placed in the ball mill.
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11.4 Selected Examples of Active Pharmaceutical Ingredient Production Using Mechanochemistry 263
protocol, but this time assessing the suitability of this process for being performed in a
mixer mill and in a planetary ball mill [84]. The synthetic process included a work-up step,
performed under milling conditions, consisting of the addition of disodium dihydrogen
ethylenediaminetetraacetate dihydrate (Na
2
H
2
EDTA.2H
2
O) and water directly to the jar,
for removal of the copper catalyst through a complexation reaction (Figure 11.4D). This
example was developed in order to introduce the concept of mechanochemistry to students
and showcase the sustainability inherent in the application of these technologies for the
synthesis of APIs [84].
The versatility of mechanochemistry can also be portrayed by the ability to couple this
methodology with other sustainable approaches. Jiang et al. highlighted this versatility by
using a mechanochemical system to perform an enzyme-catalysed multicomponent reac-
tion [85]. Antihypertensive calcium channel blockers felodipine and nifedipine,
Figure 11.4 (A–D) Mechanochemical synthesis of sulfonylureas. n = number of balls placed in the
ball mill; EDC, N-ethyl-N’-(3-dimethylaminopropyl)carbodiimide.
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11 Mechanochemistry for Sustainable Drug Design and Active Pharmaceutical Ingredient Synthesis264
Figure 11.5 Enzyme-catalysed multicomponent reaction for the synthesis of calcium channel
blockers.
Figure 11.6 Mechanoenzymatic resolution of chiral amines as a key step in the mechanochemical
synthesis of (R)-rasagiline.
1,4-dihydropyridine derivatives, were prepared using the three-component Hantzsch reac-
tion, promoted by Lipozyme® (triacylglycerol acylhydrolase, EC3.1.1.3), in moderate yields
(69% and 54%, respectively) (Figure 11.5). The only auxiliary required was sodium chlo-
ride, which is very innocuous for the environment [85].
Enzymes can also be applied for deracemisation procedures. Pérez-Venegas and Juaristi
reported a mechanoenzymatic procedure for the resolution of racemic chiral amines and
applied it for the synthesis of API (R)-rasagiline [86], a monoamine oxidase inhibitor used
as a therapeutic option for Parkinson’s disease [87]. Briefly, immobilised Candida antarctica
Lipase B (CALB) enzyme promotes the enantioselective acylation of (R)-1-aminoindan with
ethyl acetate as the acylating agent. Next, propargyl mesylate was added, affording the (S)-
enantiomer of rasagiline. The acylated (R)-1-aminoindan is then deprotected in the pres-
ence of an acid, and the resulting enantiomeric pure (R)-1-aminoindan was milled with
propargyl mesylate to achieve the final (R)-rasagiline in enantiopure form (Figure 11.6) [86].
Teriflunomide, a drug approved for the treatment of multiple sclerosis [88], was synthe-
sised using planetary ball milling through the use of N,N’-carbonyldiimidazole (CDI)-
promoted amide bond formation. After milling 5-methyl-4-isoxazolecarboxylic acid in the
presence of CDI for 20 minutes, 4-(trifluoromethyl)aniline hydrochloride was added, and
the reaction allowed to proceed under solvent-free conditions. After completion of the
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11.4 Selected Examples of Active Pharmaceutical Ingredient Production Using Mechanochemistry 265
reaction, water was added and milled with the crude reaction, in order to optimise the
transfer to a round-bottomed flask, to promote the isoxazole ring opening in acidic condi-
tions (Figure 11.7) [89].
Yu and co-workers recently reported the use of a planetary ball mill to attain the API
axitinib [90], a drug used in clinical practice for the treatment of renal cell carcinoma [91].
A total of five reaction steps were performed under mechanochemical conditions, includ-
ing palladium-catalysed Heck-Migita coupling (Figure 11.8). This is a clear example of the
application of mechanochemistry for multistep synthesis, where fine tuning of the reaction
conditions can lead to satisfactory yields and great environmental gains [90].
Another example of API synthesis using a planetary ball mill was reported by Colacino
and co-workers [92]. In this case, phenytoin, used as an antiseizure drug in the treatment of
epilepsy [93], was successfully prepared using a water-assisted mechanochemical protocol.
Briefly, using 5,5-diphenylglycine methyl ester hydrochloride as a starting material, in the
Figure 11.7 Mechanochemical synthesis of teriflunomide.
Figure 11.8 Multistep mechanochemical synthesis of axitinib.
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11 Mechanochemistry for Sustainable Drug Design and Active Pharmaceutical Ingredient Synthesis266
presence of an excess of trimethylsilyl isocyanate (TMS-NCO) and water, leads to in situ
formation of the base hexamethyldisilazane (HMDS), crucial for the formation of the amino
nucleophile, after hydrolysis of the N-protected trimethylsilyl group. In a second step, cae-
sium carbonate is added and ground with the mixture, to afford the final phenytoin at a very
good yield (84%), without the requirement of a chromatography work-up procedure, which
contributes to the overall sustainability of this synthetic process (Figure 11.9).
Another hydantoin derivative, the muscle relaxant dantrolene used in the treatment of
malignant hyperthermia [94], was also synthesised using a mechanochemical approach.
The main novelty featured in this synthetic protocol is the ability to monitor the reaction
by in situ Raman spectroscopy, enabled by the use of translucid poly(methyl methacrylate)
(PMMA) plastic ball mills (Figure 11.10A). This approach was also carried out using a LAG
procedure with acetonitrile [95].
In the same year, the same research group used this API as a model to explore another
mechanochemistry apparatus, the twin-screw extrusion. As previously referred to, apart
from the difference in the type of mechanical forces, the twin-screw extrusion system
allows continuous manufacturing and easy scale-up of the API, while ball mill systems
only enable batch production. The synthetic protocol, using the same reaction as the previ-
ous example, does not require the presence of any solvent, and also does not require any
work-up procedure, supporting the overall compliance of this process with green chemis-
try principles. This mechanochemical apparatus also enabled synthesis of the antibacterial
drug nitrofurantoin (Figure 11.10B) [96]. Twin-screw extrusion presents several advan-
tages, since it can be easily fine-tuned, subjected to high temperatures, and when properly
optimised can drastically reduce reaction time [35].
Figure 11.9 Synthesis of phenytoin using planetary ball milling.
Figure 11.10 Mechanochemical synthesis of active pharmaceutical ingredients (A) dantrolene
and (B) nitrofurantoin.
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References 267
11.5 Conclusion
Mechanochemical approaches display several advantages for API synthesis, from the access to
unexplored reactivity to the high compliance with sustainability parameters and green chemis-
try principles. The wide variety of apparatus, the number of variables to optimise, and safety
concerns regarding scale-up procedures remain some of the most relevant challenges in years
to come in the field of mechanochemistry. The still fairly unexplored field of continuous manu-
facturing under mechanochemical conditions might open the door to new, safer, and cleaner
API synthesis protocols, easily applied in the industrial setting.
Acknowledgement
Authors thanks CQC supported by the Portuguese Agency for Scientific Research,
“Fundação para a Ciência e a Tecnologia” (FCT) through projects UIDB/00313/2020 and
UIDP/00313/2020, cofounded by COMPETE2020-UC and project CENTRO-45-2021-30 -
Sistema de Apoio à Investigação Científica e Tecnológica (SAICT) - 01/SAICT/2021 -
Projetos de Prova de Conceito (PdC); Project nº 180078. This work is financed by national
funds through the FCT - Foundation for Science and Technology, I.P., under the project
UIDB/04585/2020 (PB).
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