Science and Technology Indonesia
e-ISSN:2580-4391 p-ISSN:2580-4405
Vol. 10, No. 4, October 2025
Review Paper

Microwave-Assisted Synthesis: A Green Chemistry Approach for Drug Cocrystals
Synthesis
Oktavia Eka Puspita1,2 , Melanny Ika Sulistyowaty1,3 , Rudy Salam2,4 , Dwi Setyawan1,5,6,7*
1

Department of Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Airlangga, Surabaya, 60115, Indonesia
Department of Pharmacy, Faculty of Medicine, Universitas Brawijaya, Malang, 65415, Indonesia
3
Drug Development Research Center, Universitas Airlangga, Surabaya, 60115, Indonesia
4
Department of Biophysics and Physical Chemistry, Faculty of Pharmacy, Charles University, Akademika Heyrovského, Hradec Kralove, 1203, 500 05, Czech Republic
5
Pharmaceutical Material Engineering and Processing Research Group, Universitas Airlangga, Surabaya, 60115, Indonesia
6
Skin and Cosmetic Technology (SCT) Centre of Excellent, Universitas Airlangga, Surabaya, 60115, Indonesia
7
Faculty of Advanced Technology and Multidiscipline, Universitas Airlangga, Surabaya, 60115, Indonesia
*Corresponding author: dwisetyawan-90@ff.unair.ac.id
2

Abstract
Microwave-assisted synthesis (MAS) presents a promising approach to the formation of pharmaceutical cocrystals, offering notable
improvements in solubility, dissolution rate, stability, and bioavailability of active pharmaceutical ingredients (APIs). This review aims to
evaluate the potential of MAS as a green and efficient strategy for drug cocrystal synthesis, particularly in comparison to conventional
methods such as solvent evaporation, slurry crystallisation, and grinding techniques. A systematic literature review was conducted
following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, to ensure a comprehensive
selection of relevant studies. The analysis focused on reported synthesis methods, cocrystal formation under microwave exposure,
reaction conditions, yields, purity, and scalability outcomes of MAS compared to conventional techniques. This review also highlight
current applications, critical synthesis parameters, and challenges such as penetration depth, reaction uniformity, and thermal
control. Findings indicate that MAS significantly reduces reaction time, minimizes solvent use, and enhances product purity and
yield. Its compatibility with solvent-free or minimal-solvent processes aligns closely with green chemistry principles, making it
a sustainable alternative. Furthermore, MAS effectively addresses solubility mismatches and process inefficiencies commonly
encountered in traditional methods. The future prospect of MAS lies in its integration with continuous manufacturing, automation,
and drug repurposing efforts, which could revolutionize pharmaceutical formulation by accelerating innovation while adhering to
environmental and regulatory standards.
Keywords
Microwave-Assisted Synthesis, Green Chemistry, Drug Cocrystal Synthesis
Received: 3 May 2025, Accepted: 21 July 2025

https://doi.org/10.26554/sti.2025.10.4.1130-1147

1. INTRODUCTION
The discovery of new chemical entities (NCEs) often encounters significant physicochemical challenges, such as poor solubility, low permeability, and limited bioavailability (Hodgson, 2001) . In fact, nearly 90% of drug candidates in development exhibit poor solubility (Loftsson and Brewster, 2010) .
As a result, reformulating existing medicines has become a
more viable and profitable strategy than developing new ones.
The pharmaceutical industry, facing a shortage of innovative
molecules that can successfully reach the market (Drews and
Ryser, 1996) , has increasingly turned to enhancing existing
drugs through better formulations. These reformulations offer
opportunities to improve efficacy and marketability, especially

for drugs already known to suffer from poor solubility (Kalepu
and Nekkanti, 2015) .
Various techniques have been developed to address these
solubility issues. Salt formation is among the most established
methods (Serajuddin, 2007; Joshi and Roy Choudhury, 2018) ,
while others include the use of nanoparticles (Zeng et al., 2021) ,
cosolvency (Miyako et al., 2010) , and solid dispersions (Wegiel
et al., 2014) . However, salt formation is only applicable to ionisable compounds, and other methods may suffer from thermodynamic instability. An emerging alternative is the formation
of cocrystal, which offer the advantage of increased solubility
without requiring ionisable functional groups (Liu et al., 2022) .
Additionally, cocrystals tend to exhibit greater thermodynamic

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stability and better mechanical properties, making them wellsuited for tablet formulation (Yadav et al., 2009; Taylor and
Day, 2018) .
Pharmaceutical cocrystals are defined as multicomponent
crystalline materials composed of an active pharmaceutical ingredient (API) and one or more coformers, held together by
noncovalent interactions within the same crystal lattice (Desiraju, 1995) . According to the FDA, cocrystals are “crystalline
materials composed of two or more different molecules, typically active pharmaceutical ingredients and cocrystal formers,
in the same crystal lattice” (Food and Drug Administration, U.S.
Department of Health and Human Services, 2018) . These
components are present in defined stoichiometric ratios and
interact through hydrogen bonding, 𝜋-𝜋 stacking, or van der
Waals forces (Aitipamula et al., 2012; Alvani and Shayanfar,
2022) . Cocrystals are widely studied in both academia and
industry for their potential to enhance solubility (Zhou et al.,
2016; Kang et al., 2017) , bioavailability (McNamara et al.,
2006; Smith et al., 2011) , stability (Trask et al., 2006; Huang
and Rodríguez-Hornedo, 2011) , hygroscopicity (Wang et al.,
2011) , and compressibility (Ouyang et al., 2024) .
Among various methods for producing cocrystals, solution
crystallisation is frequently used (Liu et al., 2022) . However,
this method is unsuitable when the solubilities of the API and
coformer differ significantly and typically requires large volumes of solvent, which may result in environmental contamination (Friščić and Jones, 2010; Friščić, 2012; Pagire et al.,
2013) . Other strategies, such as neat and liquid-assisted grinding, are more environmentally friendly (Karki et al., 2007)
but may yield cocrystals with low purity and poor crystallinity.
Liquid-assisted grinding is also hindered by its dependence on
solvent type, stoichiometric variability, and limited scalability
(Trask and Jones, 2005) . Solvent-free methods like twin-screw
extrusion and melt crystallisation show promise, yet carry risks
of thermal degradation and high mechanical stress (Medina
et al., 2010; Kelly et al., 2012; Pagire et al., 2013; Yan et al.,
2015) .
Given these limitations, there is a growing need for greener,
more efficient synthesis techniques. Green chemistry offers a
sustainable path forward by minimising hazardous substances,
energy use, and waste throughout the drug development cycle
(Martinengo et al., 2024; Ahmad et al., 2024) . Conventional
cocrystal synthesis methods often fall short of these principles
due to high solvent use, long reaction times, and scalability
issues (Kappe, 2004; Pagire et al., 2013) . Adopting green
chemistry approaches can enhance both environmental safety
and manufacturing efficiency.
A promising solution is microwave-assisted synthesis (MAS),
a technique aligned with green chemistry principles that has
been successfully applied in organic synthesis (de la Hoz et al.,
2016; Kumar et al., 2020; Xochicale-Santana et al., 2021; Li
et al., 2024) . Although MAS is well-known in organic chemistry, its application to cocrystal synthesis is still emerging.
Microwave irradiation offers rapid, uniform heating, which
drastically reduces reaction time and often eliminates the need
© 2025 The Authors.

Science and Technology Indonesia, 10 (2025) 1130-1147

for organic solvents (Gawande et al., 2014; Kou et al., 2023;
Ahmad et al., 2024) . This method enhances process efficiency
and minimises environmental impact (de la Hoz et al., 2016;
Xochicale-Santana et al., 2021; Anastas and Warner, 2023;
Ahmad et al., 2024) .
While green approaches have been explored in cocrystal
synthesis, there remains a significant gap in the application of
microwave-assisted synthesis (MAS) for this purpose. Most
published studies focus on conventional synthesis methods
or explore MAS only in general chemical contexts, without
specific emphasis on its use in drug cocrystal formation. This
underexplored area represents an opportunity to advance both
the scientific understanding and practical application of MAS
in pharmaceutical formulation.
This review aims to address the research gap by systematically exploring the potential of microwave-assisted synthesis
in pharmaceutical cocrystal formation. It focuses on understanding the underlying heating mechanisms, evaluating key
process parameters, and assessing the method’s suitability for
industrial-scale application. In addition, this review presents
current research findings on MAS in pharmaceutical applications and provides practical guidance for laboratory setup and
troubleshooting during synthesis.
To answer the main research questions-how cocrystals form
under microwave irradiation and what critical parameters must
be controlled during synthesis-a systematic literature review
was conducted following PRISMA guidelines (Page et al., 2021) .
Articles were retrieved from Scopus and Google Scholar using the keywords “microwave” and “cocrystals.” The review
included studies published between 2010 and 2025 that reported the synthesis and characterisation of drug cocrystals
using MAS, either alone or in combination with other methods.
Review articles and studies not directly related to drug cocrystal synthesis were excluded. Due to the limited number of
publications specifically focused on MAS in cocrystal synthesis,
references from broader chemical synthesis literature were also
included to provide foundational understanding and contextual
relevance.
2. PRINCIPLES OF MICROWAVE HEATING
Microwave irradiation is electromagnetic irradiation, in which
the region lies between infrared and radio frequencies (Figure
1). Microwave reactors for synthesis operate at a frequency of
2.45 GHz. In the microwave irradiation area, an electric field
will arise. Therefore the microwave-assisted synthesis (MAS)
principle is based on the dielectric heating principle. This
heating only occurs when materials are polar, i.e. molecules
with a permanent or induced dipole moment that respon to
the electric field (Kappe and Stadler, 2005) .
Dielectric heating in an electric field resulting from microwave irradiation occurs via dipolar polarisation and ionic
conduction (Lidström et al., 2001; Kappe and Stadler, 2005) .
Dielectric heating transforms electric energy into kinetic energy, leading to heat generation. In the dipolar polarisation
mechanism (Figure 2a), the material must be polar, i.e., the
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Figure 1. Electromagnetic Spectrum: Microwave Irradiation is Electromagnetic Irradiation in the Frequency Range 0.3 Ghz To

300 Ghz

molecule structure is partly negatively and positively chargedonly these materials can absorb microwave energy. Microwave
irradiation generates an electric field that oscillates. The polar
molecule absorbs energy when its electric field dipoles align
with the oscillating field. This molecular dipole alignment creates friction at the molecular level, which is converted into
heat as long as microwave exposure, i.e. electric field exposure.
The ability of the molecule to align itself with the frequency
of the applied field will determine the amount of heat generated (Lidström et al., 2001; Kappe and Stadler, 2005) . While
in the ionic conduction (Figure 2b) heating mechanism, the
requirement for this induction is that the molecule must be
completely dissolved and ionised. The ionic molecule oscillates back and forth under microwave irradiation, i.e. electric
field. This oscillation causes frequent collisions of the charged
particles with neighbouring molecules, creating heat energy
(Kappe and Stadler, 2005) .
Whether dipolar polarisation or ionic conduction, microwa
ve irradiation simultaneously raises the temperature of the
whole reaction mixture volume. This heating process is called
bulk heating (Adepu and Ramakrishna, 2021) . Microwave
irradiation interacts selectively and directly with the "core" of
the material. While in conventional heating, heat is transferred
from the surface of the vessel or material mixture to the core
through conduction (Sabelström et al., 2014; Dandia et al.,
2021) . This is why microwave irradiation produces uniform
and efficient heating throughout the sample (Wäppling Raaholt
and Isaksson, 2017; Jeon et al., 2022; Tangjaideborisut et al.,
2025) compared to conventional heating. This mechanism
significantly reduces reaction times and enhances reaction rates
(Bogdal, 2005; Gawande et al., 2014) .
The heating efficiency in microwave-assisted synthesis (MA
S) is determined by the dielectric properties of the material,
including the dielectric constant (𝜀 ′ ), dielectric loss (𝜀 ′′ ), and
polarity. 𝜀 ′′ (dielectric loss) represents the efficiency of the
material in absorbing and converting electromagnetic radiation
into heat. 𝜀 ′ is the dielectric constant describing the polarizability of the molecules in the electric field. At a particular

© 2025 The Authors.

frequency and temperature under microwave irradiation, the
capability of a substance in generating heat is expressed as the
loss factor tan 𝛿=𝜀/𝜀 (Kappe, 2004; Kappe and Stadler, 2005;
Kappe et al., 2013) .
Based on the above explanation, microwave irradiation
generates heat differently with different solvents, reagents, and
catalysts in the reaction mixture, depending on each dielectric
property. Thus, it is rational that the process can be modified by
combining other materials to the reaction mixture to enhance
the heating efficiency, i.e. heat rate and intensity. Commonly
used materials to alter the process besides the catalysts in the
reaction mixture include organic solvents. They are typically
classified based on the dielectric loss (tan 𝛿) into high (tan 𝛿
>0.5), medium (tan 𝛿 = 0.1-0.5), and low microwave absorbing
(tan 𝛿 <0.1). The higher the tan 𝛿 value of a substance, the more
rapid its heating under microwave irradiation (Bao et al., 2023) .
It explains that it is still possible for non-polar materials to be
synthesised using MAS as long as polar solvents are included
to absorb microwave energy, leading to heat generation.
The selectivity of microwave interaction with materials that
can only absorb its energy results in heating efficiency during
synthesis. The interaction makes the heating process fast and
efficient because it does not go through the process of initiating
surface induction on the vessel but directly on the core of the
material (molecule level heating) (Figure 3a). Initial surface
heating on the material or vessel surface is a process in which
conventional heating is applied (Figure 3b). This process is
usually lengthy because the heat does not generate directly but
has to travel deeper into the reaction mixture. In contrast, microwave irradiation heats the mixture on a molecular level by
direct interaction with molecules and avoids the initial heating
of the vessel surface. By microwave irradiation, the temperature inside the reaction mixture rises throughout the volume
simultaneously (bulk heating) (Meloni et al., 2023; Horikoshi
et al., 2024) . The rapid heat distribution prevents the formation of hot spots, ensuring a homogeneous temperature
distribution and uniform heating throughout the material.

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Figure 2. Illustration of Dielectric Heating Dipole Alignment in Oscillating Electric Field (E), a) Dipolar Polarisation, b) Ionic

Conduction

Figure 3. Heat Introduction and Temperature Distribution Into and Inside A Reaction Mixture for (a) Conventional Heating and
(b) Microwave Heating

3. FEASIBILITY OF USING MICROWAVE-ASSISTED
COCRYSTAL SYNTHESIS FOR COCRYSTALS
The feasibility of using microwave-assisted synthesis (MAS)
for cocrystal formation is strongly influenced by the material
properties of the active pharmaceutical ingredient (API), coformer, and any solvents used—particularly their dielectric and
thermal characteristics. One of the key advantages of MAS
lies in its ability to selectively and rapidly heat materials based
on their dielectric properties. Polar compounds exhibit high
dielectric constants (𝜀 ′ ) and loss tangent values (tan 𝛿), making them highly responsive to microwave irradiation and thus
feasible to be synthesized using MAS. This inherent responsiveness significantly improves reaction rates and energy efficiency
© 2025 The Authors.

(Kappe and Stadler, 2005; Kumar et al., 2020) .
For non-polar compounds, MAS remains feasible through
the use of polar solvents or additives, which can enhance the
overall dielectric properties of the reaction mixture. Because
solvent dielectric constants and tan 𝛿 values are well-document
ed, they are often used as practical indicators to estimate the
heating efficiency of the entire reaction system. In most cocrystal systems, either the API or the coformer is polar, making
it highly likely that the reaction mixture will be suitable for
microwave heating. A list of solvents with commonly reported
tan 𝛿 values is presented in Table 1 (Bao et al., 2023) , serving
as a useful reference for selecting suitable conditions.
Since microwave heating is driven by the dielectric constant,
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Puspita et. al.

Table 1. Common Organic Solvents and Their Tan 𝛿

Solvent

𝜀′

𝜀”

tan 𝛿

Ethanol
Dimethyl
sulfoxide
Formic acid
Methanol
Ethanoic acid
Dichloroethane
Water
Ethyl acetate
Acetone
Hexane

24.3

22.86

0.941

Microwave
Adsorption
Capacity
high

48.9

40.34

0.825

high

58.5
32.6
6.19
10.4
80.4
6.03
20.7
1.9

42.24
21.48
1.08
1.32
9.89
0.356
1.11
0.038

0.722
0.659
0.174
0.127
0.123
0.059
0.054
0.020

high
high
medium
medium
medium
low
low
low

Note: 𝜀 ′ Is the dielectric constant, 𝜀 ′′ is the dielectric loss, and tan 𝛿 is
the tangent of loss or loss factor. The microwave absorption capacity is
categorised into "high" for tan 𝛿 > 0.5, "medium" for 0.1 < tan 𝛿 < 0.5,
and "low" for tan 𝛿 < 0.1. Source: (Bao et al., 2023)

dielectric loss, and polarity of the material, its effectiveness correlates directly with polarity during the reaction process (Mishra
et al., 2015) . All those variables are influenced by the solvent’s
functional groups, and together they determine its microwave
absorption capacity. Polarity arises from the presence of polar
functional groups, such as hydroxyl ( OH), carboxylic acid
( COOH), or sulfoxide (S O), which create molecular dipoles.
These polar groups generally increase the dielectric constant
(𝜀 ′ ), measure of the material’s ability to store electrical energy
in an electric field. However, efficient microwave heating also
depends on the solvent’s ability to dissipate that energy as heat,
represented by the dielectric loss (𝜀 ′′ ). The ratio of 𝜀 ′′ to 𝜀 ′ ,
known as the loss tangent (tan 𝛿), ultimately defines how well
a solvent absorbs microwave energy. For example, solvents
with highly polar functional groups and high 𝜀 ′′ values, such as
ethanol, formic acid, and dimethyl sulfoxide, exhibit high microwave absorption capacity (high tan 𝛿) (see Table 1). From
Table 1, it can be concluded that we cannot say that the more
polar a material is, the higher its absorption capacity will be.
We must consider the dielectric loss of a material, given that
microwave absorption capacity is calculated based on the ratio
of dielectric loss to dielectric constant.
In addition to dielectric behavior, thermal stability of the
materials is crucial. All reactants and the resulting cocrystal
must withstand the temperatures reached during microwave
exposure. If thermal degradation occurs, MAS may not be
appropriate for that system. Nevertheless, for a wide range of
pharmaceutical compounds with adequate thermal tolerance
and dielectric responsiveness, MAS offers a highly feasible, efficient, and environmentally friendly synthesis route for cocrystal
formation.

© 2025 The Authors.

4. MECHANISMS OF COCRYSTAL FORMATION VIA
MAS
The fundamental principle of forming a cocrystal depends on
the molecules recognising one another to make intermolecular
interactions, forming a supramolecular synthon (Friščić, 2012) ,
leading to nucleation and finally crystallisation (Desiraju, 2013) .
In cocrystal, the interaction is particularly through hydrogen
bonding, 𝜋-𝜋 stacking, and van der Waals interactions that
drive the formation of cocrystals (Desiraju, 2010; Pindelska
et al., 2017; Saha et al., 2023) . The molecules must move,
meet, and align to build a crystal nucleus and grow. In this
context, molecules need energy to move from the crystal lattice of each reactant, i.e. API and coformer, and ensure that
intermolecular interactions occur to form a new crystal lattice.
It should be emphasised that there is no bond breaking in the
molecular structure in this process, and the intermolecular interactions are noncovalent. This limitation is in line with the
definition of cocrystal (Desiraju, 1995; Aitipamula et al., 2012;
Bolla et al., 2022) .
Thus, the primary goal of obtaining energy from microwave
irradiation is not to induce covalent bond formation or breaking
but to facilitate molecules’ mobility and noncovalent interaction. When molecules in the reaction mixture can interact with
an electric field, i.e. dielectric heating mechanism, the heat will
accumulate and increase the kinetic energy of the material and
enables chemical reactions (Bogdal, 2005) . The kinetic energy
leads to molecular mobility enhancement and intermolecular collisions’ frequency. This mechanism is advantageous in
cocrystal synthesis, where molecules must move and interact
with other molecules (Huang et al., 2021) . Consequently, the
probability of hydrogen bond formation between functional
groups is improved. Intermolecular interactions form immediately once molecules find energetically favourable orientations
(Musumeci et al., 2011) . This indicates that for the purpose
of cocrystal formation, the control lies in the setting of the
energy level, i.e. the level of heating produced by microwave
irradiation. If the microwave power is too high or the exposure
is too long, the energy can lead to the degradation of hydrogenbonded assemblies or even decomposition. This isothermal
holds at strategic temperatures is employed, especially near
the melting point of the components. This provides sufficient
molecular mobility for alignment into the desired supramolecular synthon formation without crossing into decomposition
or chemical reaction regimes.
The primary difference between MAS and conventional
methods in cocrystal formation lies in the speed and efficiency
of the process. In contrast, the fundamental principle in cocrystal nucleation remains the same (molecule mobility, alignment,
and supramolecular synthon formation) (Desiraju, 2013; Bavishi and Borkhataria, 2016) . Direct molecules heating through
dielectric heating, causing rapid heating at the molecular level.
This leads to quicker molecular motion, higher collision frequency, leading to more efficient hydrogen bonding or noncovalent interactions. Meanwhile, conventional methods such as
solvent evaporation, slurry mixing, or grinding rely on slower
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heat transfer via conduction or convection. This means reactions typically require longer times to reach the necessary
temperatures, and heat may not be uniformly distributed, leading to less efficient formation of cocrystals and possibly uneven
crystallisation.
How exactly do the cocrystals start to form a nucleus and
grow after microwave heating. Cocrystals form when two
(or more) different molecules, an API and a conformer, selfassemble driven by noncovalent interactions like hydrogen
bonding, 𝜋–𝜋 stacking, or van der Waals forces (Friščić, 2012) .
For this to happen, the molecules must move and meet, and
that is where diffusion comes in. Microwaves at 2.45 GHz
can enhance diffusion. Transport of an active species is a ratelimiting step in a reaction, and microwaves enhance the diffusion of that species. The diffusion enhancement leads to
an enhanced reaction rate compared to conventional heating
(Antonio and Deam, 2007) . The alternating electromagnetic
field appears to promote the solid phase transformation beyond
the effect of just the temperature increase (Ahuja et al., 2020) .
Increased molecular mobility and complementarity will initiate the cocrystal formation (Jayasankar et al., 2006; Chadwick
et al., 2007; Guo et al., 2010) . Below are the ordered steps of
cocrystal formation (Figure 4):
1. Microwave irradiation. Delivers dielectric heating, activating polar molecules.
2. Molecular mobility. It means molecular diffusion. Molecul
es must move to come into contact and establish intermolecular interactions. This can occur in solution (bulk
diffusion), solid–liquid interface (surface diffusion), or
solid–solid contact surfaces (limited but possible at elevated energy levels, e.g., microwave, grinding). With
the presence of microwave irradiation, the electric field
will interact with polar molecules, i.e., API, coformer,
solvent, causing dielectric heating. This molecular interaction leads to rapid and uniform heating throughout
the reaction mixture. This heating increases molecular
motion, promoting the diffusion of API and coformer
molecules. This enhanced mobility allows the molecules
to come into proximity, promoting interactions necessary for cocrystal formation. Diffusion must always involve building molecular aggregation because molecules
must meet, align, and interact. No matter the method,
molecules must move from one place to another to find
each other, form noncovalent interactions, and build a
crystal lattice. This is why the diffusion rate directly affects nucleation speed, which depends on heat generation.
It can be stated that microwave irradiation helps push the
"pedal" of the molecules to move. At the same time, the
diffusion is the engine that drives molecules to find each
other and align properly based on the supramolecular
synthon principle to build a cocrystal.
3. Molecular orientation. When molecules are mobile, it
means they begin to diffuse. The orientation of API
molecules and conformer is directional since the molecul
es meet the requirement of supramolecular synthon the© 2025 The Authors.

Science and Technology Indonesia, 10 (2025) 1130-1147

ory (Desiraju, 1995, 2010, 2013) .
4. Nucleation. Once API and conformer molecules align
properly and build noncovalent interactions repeatedly,
they form a nucleus — the seed of a cocrystal (Desiraju, 2010; Bavishi and Borkhataria, 2016) . Through
noncovalent interactions such as hydrogen bonding, 𝜋–𝜋
stacking, or van der Waals forces, the API and coformer
organise into a new crystalline lattice, forming the desired
cocrystal. Continued diffusion brings more molecules to
the nucleus, allowing it to grow into a visible crystal.
5. Crystal growth. Diffusion continues to supply new molecul
es to the crystal front. The crystal will grow as long as the
system remains supersaturated (in solution) or activated
by energy input (in the solid state).
Crystallisation of cocrystal is about getting molecules to
meet, align properly, and interact noncovalently. For that to
be possible, molecular diffusion - the movement of molecules
through a solvent or between solid particles - is key. It indicates
that even if there is no solvent as a medium, it is still possible to
form a cocrystal by surface contact between the materials in the
reaction mixture. In MAS, diffusion is enhanced by localised
heating in which microwaves heat selectively, i.e. polar materials absorb energy quickly. Even a small amount of polar solvent
can help enhance the heat efficiency, leading to the mobilisation of molecules at the particle surfaces immediately. This
creates localised "hot spots" and increases molecular motion,
accelerating interface diffusion.
In addition to assisting in heating, using solvent in MAS
will serve as a medium and enhance diffusion. Even a small
amount of solvent can help mobilise molecules at the particle
surfaces. This is the basis of solvent-drop grinding or liquidassisted grinding. The reactants do not need to dissolve entirely
in the solvent during crystallisation. A study by Ahuja et al.
(2020) demonstrates that microwave-assisted slurry conversion crystallisation significantly accelerates cocrystal formation
compared to conventional heating methods (Guo et al., 2018;
Ahuja et al., 2020) . Even in solid-state systems like neat grinding, the conventional method of cocrystal synthesis, there is
still surface diffusion (limited molecular contact zones). Hence,
increased kinetic energy of molecules by microwave irradiation
will accelerate diffusion on both molecular and interfacial scales
and increase the speed of forming cocrystals even in the solid
state of the reaction mixture. Without diffusion, molecules
would stay locked in their original positions, and no cocrystal
would form. So, regardless of method, diffusion is the fundamental molecular engine. What changes are speed, energy
source (microwave, mechanical, thermal), and medium (liquid,
surface, vapour, solid). In combination with rapid and efficient
heating, a high-pressure environment in closed microwave systems, pressure builds up. This can increase solvent penetration
and accelerate diffusion into the particle.

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Figure 4. Steps Oof Cocrystal Formation Under MAS

5. COMPARISON OF MAS WITH CONVENTIONAL
METHODS
The most commonly used conventional methods for synthesising cocrystals include solvent evaporation, slurry crystallisation,
neat grinding, and liquid-assisted grinding (Guo et al., 2021) .
In conventional methods of cocrystal formation, general principles of cocrystal formation remain applicable, i.e. diffusion
is the primary initial driving force for intermolecular interactions and the formation of noncovalent cocrystal components
(Kuroda et al., 2004; Friščić and Jones, 2009; Karimi-Jafari
et al., 2018) .
In the solvent evaporation method, the active pharmaceutical ingredient (API) and the coformer are dissolved in a suitable
solvent. When the solvent evaporates, supersaturation of the
solution components is achieved. This supersaturation leads
to closer contact between the molecules, making it more likely
for intermolecular interactions to be established. The solvent
evaporation rate and concentration gradient are critical in controlling cocrystal nucleation and growth (Weyna et al., 2009;
Modani et al., 2020) .
In the slurry crystallisation method, a solid API is suspended in a solvent containing the coformer. Over time, diffusion allows the coformer molecules to move toward the API
particles, forming cocrystals at the solid-liquid interface. In
this method, each component gradually dissolves and forms a
complex to promote the nucleation and growth of cocrystals.
The efficiency of this process depends on factors such as temperature, solvent choice, and the stirring rate, which influence
the diffusion rates of the coformer molecules (Huang et al.,
2019; Pantwalawalkar et al., 2025) .
Meanwhile, neat grinding methods involve the API and
coformer being physically mixed in grinding techniques. This

© 2025 The Authors.

method sometimes needs a small amount of solvent (liquidassisted grinding). The mechanical energy applied during
grinding increases the surface area and promotes molecular
diffusion between the components, leading to cocrystal formation. In grinding methods, molecular diffusion happens in
the solid state, where components are brought into close contact mechanically. This method facilitates molecular diffusion
at a microscopic level as the components grind against each
other. While this does not rely on diffusion through a solvent,
the mechanical force enables the molecules to interact and
form cocrystals. Though diffusion is still a factor, conventional
grinding may not reach the localised heating or pressure that
microwaves can provide, leading to slower formation of the
cocrystals than MAS (Hossain Mithu et al., 2021; Rong et al.,
2023; Pantwalawalkar et al., 2025) .
In essence, diffusion occurs both in conventional and MAS,
but in conventional methods, it tends to be slower due to less
uniform heating and longer reaction times. The advantages of
MAS compared to the conventional method of cocrystal synthesis is that the heating mechanism provides a rapid and efficient
process. MAS accelerates molecular diffusion by delivering
rapid and uniform heating, making molecular interactions and
cocrystal formation faster and more efficient. This increases
molecular mobility, allowing molecules to diffuse more effectively and interact quickly to form hydrogen bonds. When
solvent is involved, the localised heating in MAS often creates higher supersaturation and more rapid nucleation, which
speeds up the entire process, including diffusion.
Energy efficiency was reported to be multiple times better
for microwave-heated processes than conventionally heated
processes (Priecel and Lopez-Sanchez, 2019) . This is one of
the main advantage of MAS. Microwaves enable direct and
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selective heating of reactants, minimising wasted energy and
lowering overall consumption. This allows significantly faster
synthesis, leading to much shorter reaction times than conventional grinding or solvent-based methods (Pagire et al.,
2013) . A good yield and purity of cocrystal obtained using
microwave-assisted synthesis are another benefit of using this
method (Sahoo and Banik, 2020; Martina et al., 2021; Ioniţă
et al., 2024) .
Compared to the conventional method, however, solvent
dependency, stoichiometric diversity and lack of scalability
are important issues in the liquid-assisted grinding technique,
which limit its applicability. Another well-explored technique
for cocrystal synthesis is neat or liquid-assisted grinding (Trask
et al., 2006) . It is an environmentally friendly approach limited
by the lack of purity of the resulting cocrystal and the formation of disordered crystals with reduced particle size (Trask and
Jones, 2005) . Conventionally, cocrystals are produced by solution crystallisation. However, this is unsuitable when there is a
significant difference in the solubility of the two components
(Guo et al., 2010; Friščić, 2012) .
Despite its advantages, MAS also faces several limitations.
The effect of penetration depth must also be considered in
microwave reactions. Penetration depth refers to the depth
at which the microwave intensity decreases from its original
intensity (Zhang and Hayward, 2006) . It should be noted that
if the penetration depth is much smaller than the size of the
material, only the surface of the incident wave will absorb the
energy, leading to non-uniform heating (Li et al., 2025) . MAS
also presents optimisation challenges, as the precise control
of reaction uniformity and reproducibility can be difficult to
achieve, especially in heterogeneous mixtures where microwave
absorption varies between components (Priecel and LopezSanchez, 2019) . An additional drawback is the risk of thermal
degradation, where the localised and rapid heating intrinsic to
microwave irradiation can lead to overheating and decomposition of thermally sensitive active pharmaceutical ingredients
(APIs) and coformers (Kappe, 2004; Kappe and Stadler, 2005) .
Table 2 below summarises the comparison between the MAS
cocrystal synthesis method and the conventional method.
6.
CRITICAL PARAMETER PROCESS ON
MICROWAVE-ASSISTED COCRYSTAL SYNTHESIS
6.1 Microwave Power (Wattage)
Microwave power refers to the amount of energy the microwave
delivers to the reaction system, typically measured in watts (W),
i.e. the temperature setting. Understanding and controlling
this parameter is essential because it directly influences how
fast and how much the sample heats up (Kappe and Stadler,
2005) . Maintaining an optimal energy level during chemical
processes ensures efficient reaction progress without surpassing
the reactants’ or products’ thermal stability limits. Overheating
may occur if the energy input is too high, causing the breaking
of chemical bonds and resulting in undesirable side reactions or
complete decomposition of the target compound. In a standard
commercially available microwave for chemical synthesis, the
© 2025 The Authors.

Science and Technology Indonesia, 10 (2025) 1130-1147

temperature is set at a desired target temperature, and the
system automatically adjusts the power to maintain it. In the
next section, this paper will discuss a technical approach and
troubleshooting in setting up the microwave power (Kappe,
2004) .
6.2 Temperature Target
The desired temperature target must be achieved and maintained during synthesis, where the reaction is expected to be
completed. The temperature target should balance reaction
speed while preventing thermal decomposition. Control of
target temperature is critical for optimal nucleation and crystal
growth without damaging the reactant. For a cocrystal formation, setting the temperature below the melting points of
the individual components will be sufficient while preventing
material decomposition (Pagire et al., 2013; Lin et al., 2014;
Ketkar et al., 2016; Ioniţă et al., 2024) . If the heat is above
or above the melting points, it is more likely to cause thermal
degradation.
6.3 Reaction Time
Reaction time refers to the period during which the reactants
are exposed to microwave irradiation at the desired set conditions (usually a controlled temperature and pressure). This
reaction time is also termed the hold time. Since irradiation
time will determine the heat generated on the reaction mixture (Wang et al., 2011) , insufficient hold time may lead to an
incomplete reaction. In contrast, excessive time could lead to
decomposition or undesired phases.
6.4 Pressure
The MAS system is usually in a closed vessel. When microwaves heat the reaction mixture, the temperature can rise
rapidly, causing the solvent and reactants to vaporise and generate pressure. This elevated pressure allows the reaction mixture
to remain in the liquid phase at temperatures above its normal
boiling point, often accelerating reaction rates.
Commercially available microwave reactors became controllable by temperature monitoring and pressure sensing, and
therefore safe and reproducible. The combination of sealed
vessels and rapid microwave heating opens up new possibilities
in chemistry, allowing reactions to be performed quickly and
efficiently under elevated temperature and pressure conditions
(Kappe, 2004) .
6.5 Stirring
Stirring promotes uniform heat and mass transfer throughout
the reaction mixture. Microwaves tend to heat materials unevenly, especially in heterogeneous systems where differences
in dielectric properties can cause localised hotspots (Horikoshi
et al., 2013; Mohd Fuad et al., 2019; Li et al., 2025) . Stirring helps to distribute heat evenly, preventing temperature
gradients that might lead to side reactions or incomplete conversion of reactants. Stirring can also increase inter-molecular
or inter-particle collisions, thus improving reaction kinetics. In

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Table 2. Comparison Between MAS and Conventional Cocrystal Synthesis Methods

Method

Heating Type

Solvent Use

Reaction Time

Purity/Yield

Energy
Efficiency

Microwave-Assisted
Synthesis

Rapid, volumetric
(dielectric)

Optional

Minutes

High

High

Solvent Evaporation

External heating

High

Hours to days

Moderate to high

Low to
moderate

External heating

Moderate

Hours to days

Moderate

Low

Mechanical energy

None

Minutes to hours

Variable

Moderate

Mechanical

Minimal

Minutes to hours

Moderate

Moderate

Slurry
Crystallisation
Neat Grinding
Liquid-Assisted
Grinding

solid-liquid or multiphase systems, stirring prevents sedimentation and maintains consistent contact between the reactants
(Kappe, 2004; Kappe and Stadler, 2005) .
6.6 Microwave Exposure Mode (Continuous vs. Pulsed)
Microwave exposure mode refers to how microwave energy is
delivered to a reaction system during Microwave-Assisted Synthesis (MAS). The two main modes are continuous and pulsed.
In continuous mode, microwave energy is supplied steadily
at a constant power level throughout the reaction time. This
provides consistent heating, which is ideal for reactions requiring stable and uniform temperatures. Continuous mode helps
maintain a steady reaction rate and often leads to faster completion, especially for processes that benefit from sustained high
temperatures. In pulsed mode, microwave energy is delivered
in intervals; the power switches on and off in cycles. This mode
helps control excessive heat and pressure buildup, especially
in sensitive reactions or when working with volatile solvents.
Pulsed exposure allows the reaction mixture to cool slightly
between microwave bursts, preventing overheating, reducing
decomposition risks, and allowing for better control over reaction kinetics (Kappe, 2004; Herrero et al., 2008; Kappe et al.,
2013) .
7. ECO-FRIENDLY ASPECTS OF MICROWAVEASSISTED COCRYSTAL SYNTHESIS
Microwave-assisted cocrystal synthesis is an environmentally
friendly approach that aligns with the 12 Principles of Green
Chemistry (Anastas and Warner, 2023) . Microwave irradiation promotes rapid and energy-efficient heating, significantly
reducing reaction times and minimising energy consumption.
This aligns with Principle number 6 of 12 Principles of Green
Chemistry, i.e. Design for Energy Efficiency. Microwaveassisted processes also enable solvent-free or minimal-solvent
conditions (Principle 5: Safer Solvents and Auxiliaries), decreasing the reliance on hazardous organic solvents and reducing waste generation (Principle 1: Prevention). The enhanced
reaction control achievable through microwave irradiation also
supports safer operational conditions (Principle 12: Inherently
Safer Chemistry for Accident Prevention) by minimising the
risk of thermal runaway and pressure build-up (Kappe, 2004) .
© 2025 The Authors.

Furthermore, the precision of microwave heating can improve
product selectivity and yield, which contributes to minimising
by-products and resource waste (Principle 2: Atom Economy
and Principle 9: Catalysis when applicable). These aspects
demonstrate that microwave-assisted cocrystal synthesis is an
effective strategy for pharmaceutical and material science applications and a sustainable methodology that embodies the core
values of green chemistry (Loupy, 2004; Martinengo et al.,
2024) .
8. CURRENT APPLICATIONS OF MAS IN COCRYSTAL SYNTHESIS
In the range of 2010-2025, the author has searched for research publications related to the use of MAS for drug cocrystal synthesis (Table 3). The scope of the search is limited to
research results that apply MAS singly or combined with other
conventional methods for drug cocrystal synthesis.
9. FUTURE PERSPECTIVES
9.1 Perspective on Development and Scale-Up
The future perspective on the industrial adoption of MAS is
promising, particularly as advancements in reactor design and
process control continue to address existing limitations (Ku
et al., 2002; Priecel and Lopez-Sanchez, 2019; Martina et al.,
2021; Li et al., 2025) . A key focus for future development
is the creation of large-scale, automated microwave reactors
capable of delivering uniform energy distribution across substantial reaction volumes, which would resolve one of the main
challenges associated with scaling up laboratory-scale protocols. Overcoming equipment limitations, such as microwave
penetration depth and temperature measurement accuracy,
will make MAS a viable alternative for large-batch chemical
production (Kappe and Stadler, 2005; Wäppling Raaholt and
Isaksson, 2017; Kalinke et al., 2022) . Optimising critical process parameters, including temperature control, power, operating pressure, stirring efficiency, and microwave exposure
mode, will ensure reproducibility, product consistency, and
drug safety at an industrial scale (Anandam and Selvamuthukumar, 2014; Makgabutlane et al., 2020; Albuquerque et al.,
2021; An et al., 2025) . The technique shows strong scalability
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Table 3. Key Features of Cocrystallisation Involving MAS

API-coformer

Caffeine–Maleic
acid

Theophylline
(THE) –
Acetylsalicylic
acid (ASA)

Procedure
Solvent-free and
solvent (water,
methanol, acetone,
toluene, ethyl
acetate) mediated
cocrystallisation
experiments

Heating Profile
Using a microwave
reactor Monowave 300,
Anton Paar Gmbh,
Austria, with a target
temperature set at
80◦ C, a hold time of
60s was used.

Slurry mixture in
ethanol, then subject
to microwave
irradiation

Microwave irradiation
at 600W for 6 min

Indometacin
Nicotinamide

Cocrystal was
prepared using
solvent evaporation
and neat grinding,
then subjected to
microwave
irradiation for
evaporation.

A domestic microwave
oven (TMO-202;
Tatung Company,
Taipei, Republic of
China) with a power of
800W is used to heat
and evaporate the
sample to
approximately 78◦ C
after 3 min of
irradiation.

Carbamazepine
Succinic acid

Cogrinding slurry
method (absolute
ethanol) following
the subjection of the
physical mixture to
microwave
irradiation

Slurry mixture using
ethanol, then
subjected to
microwave
irradiation

Caffeic acid
phenethyl ester
(CAPE) –
caffeine (CAF),
isonicotinamide
(INIC), and
nicotinamide
(NIC)

© 2025 The Authors.

Observation

Ref.

The overall process depends on the solubility
of solvent components and the solutions’
dielectric properties <the researchers do not
report thermal analysis>

(Pagire
et al.,
2013)

The microwave-assisted irradiation of the
grinded mixture accelerates the cocrystal
formation between the two precursors.
Cocrystal was not obtained by simply mixing
ASA and THE in the absence of microwave
irradiation, both in the presence and absence
of absolute ethanol as solvent. Based on
DSC measurement, the endothermic peak is
272.9◦ C for theophylline and 140.2◦ C for
acetylsalicylic acid. The new cocrystal has an
endothermic peak at 129.3◦ C.
Microwave heating quickly results in
cocrystal formation compared to slow
evaporation with or without stirring at
ambient temperature, fast evaporation at
50◦ C, and solvent-assisted grinding (20 min
in a ceramic mortar) after adding three drops
of ethyl acetate. It is strongly suggested that
cocrystal formation would be accelerated and
assisted by the thermal effect of microwave
irradiation via the rapid evaporation of ethyl
acetate. Based on DSC measurement, the
indometacin has an endothermic peak at
163◦ C and 131◦ C for nicotinamide, while
the resulting cocrystal is 126◦ C.

(Fuliaş
et al.,
2014)

(Lin
et al.,
2014)

Using the Elta domestic
oven at 500W for 7 min

The cocrystal formation was easy and
reproducible. Based on the DSC
measurement, the carbamazepine has an
endothermic peak at 187◦ C and succinic
acid at 189◦ C, while the resulting cocrystal is
209◦ C.

(Fuliaş
et al.,
2015)

Using microwave
reactor Monowave 300,
Anton Paar, Gmbh,
Austria. The operating
conditions were set at a
target temperature of
80◦ C and a hold time
of 60 s, followed by
cooling to 40◦ C

The study confirms successful formation of
novel cocrystals using microwave-assisted
cocrystallisation of the para-methoxy
cinnamic acid technique. CAPE has a
melting point of 129◦ C, 129.4◦ C for NIC,
158.23◦ C for INIC, 236.73◦ C for CAF,
while the resulting crystalline CAPE-NIC
has a melting point of 107.01◦ C,
CAPE-INIC has 106.35◦ C, and CAPE-CAF
has 113.64◦ C.

(Ketkar
et al.,
2016)

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Cocrystal sample synthesised
using the microwave radiation
method provides the highest
solubility and dissolution
because the microwave
radiation during the synthesis
process could induce better
formation of cocrystals. The
pMCA and caffeine have
endothermic peaks at
173.56◦ C and 235.87◦ C,
respectively. At the same time,
the resulting cocrystal has
enothermic peak around
150-125◦ C.
Synthesis using microwave
irradiation was faster (20 min)
than solvent evaporation 48
hrs. The pMCA has an
endothermic peak at 173.56◦ C
and succinic acid at 189.31◦ C.
The resulting cocrystal has an
endothermic peak at 159.50◦ C

Paramethoxy
cinnamic
acid
(pMCA)

Manual mixing in
water, then subjected
to microwave
irradiation

Using a domestic microwave
oven at 450 Watts of radiation
power (Sharp R-728 (W)
-IN) set for 15 min.

para
methoxycinnami acid
(pMCA)Succinic
Acid

Manual mixing in
methanol, then
subjected to
microwave irradiation

Domestic microwave at 540W
for 20 min

The reactant mixture
was prepared in two
ways prior to being
subjected to
microwave irradiation:
Solubilisation in
ethanolic solution;
Slurry mixture

Using Miniflow 200SS
microwave laboratory
equipment: Sample in
solution: the experiments
were conducted at 30◦ C,
40◦ C, 50◦ C and 60◦ C under
magnetic stirring of 50 rpm,
50W microwave irradiation
power and a frequency of
2450 MHz, for 6 min. Also
assessed at 40◦ C within 12
min of microwave irradiation;
Sample in slurry: the
experiments were performed
using a temperature of 30◦ C,
a power of 100W and 200
rpm magnetic stirring, for 5,
10 and 15 min.

Shorter synthesis time
compared to conventional
methods (2–15 min).
Reproducible synthesis of the
resveratrol-piperazine
cocrystal. All the resulting
cocrystal has endothermic
peaks around 205.7–206.8◦ C,
piperazine has an endothermic
peak at around 100-125◦ C,
and resveratrol at around
250-275◦ C

(Ioniţă et al.,
2024)

Using microwave automatic
reactor, ATPIO XO-SM100,
0–1000W. Temperature set at
70◦ C for 4 minutes under
continuous stirring at 120
rpm

Microwaves, as the heating
source, are found to increase
the rate at which co-crystals
are formed, compared to
standard heating

(Ahuja et al.,
2020)

Domestic microwave (MW)
with low energy (399W) and
observed in 1 minute

A stable and uniform
diclofenac-proline co-crystal
was efficiently generated

(Nugrahani
et al., 2019)

Resveratrol
Piperazine

Sulfamethazine
Nicotinamide,
SulfamerThe slurry mixture
azine
was then subjected to
Anthranilic
microwave irradiation
acid, Sulfamerazine
Salicylamide
Liquid-assisted and
Diclofenac
neat grinding then
acid subjected to
Proline
microwave irradiation

© 2025 The Authors.

(Sulistyowaty
et al., 2024a)

(Sulistyowaty
et al., 2024b)

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Puspita et. al.

Diclofenac
acid Proline

Top-down and bottom-up methods
were used to produce nano-sized
cocrystals. The top-down process
was carried out by wet milling
procedure and neat grinding
procedures, while the bottom-up
process used globule inversion
phase and fast evaporation assisted
microwaving-ach of the resulting
mixtures was subjected to
microwave irradiation.

Using a domestic
microwave SHARP,
R-230R(S), Tokyo, Japan ,
776 W for about 10 min.

potential, particularly its compatibility with continuous-flow
microwave reactors, making it an attractive option for laboratory research and industrial-scale production (Priecel and
Lopez-Sanchez, 2019) .
Continuous flow microwave reactors offer a scalable and
efficient pathway for mass production, including in pharmaceutical manufacturing. Continuous flow is the performance
of chemical reactions using a continuous stirred tank reactor
rather than in a traditional batch stirred vessel. A large-scale
continuous flow chemistry processing has been widely used
in industrial chemical production (Harmsen, 2010; Baumann
et al., 2020) . This approach addresses the common limitations of batch microwave processing, such as poor scalability
and uneven heating, while significantly reducing reaction times
and energy consumption. Several companies have integrated
continuous flow microwave reactors into their pharmaceutical development pipelines. For example, CEM Corporation
has commercialised a microwave reactor which has been used
for both small-scale and scale-up microwave-assisted organic
synthesis (Ferguson, 2003; Goyal et al., 2020) .
9.2 Research Opportunities
Future research on microwave-assisted synthesis (MAS) of
drug cocrystals should aim to deepen understanding of the fundamental mechanisms that govern energy transfer and molecular interaction under microwave irradiation. This includes investigating how different microwave parameters-such as power
input, frequency, and irradiation time-influence nucleation,
crystal growth, and polymorphic outcomes across various drug
coformer systems. Moreover, integrating MAS with real-time
analytical techniques such as in situ spectroscopy or thermal
imaging could enable better monitoring and control of cocrystal
formation processes.
Additionally, integrating MAS with milling techniques such
as ball milling (Fischer et al., 2016; Ioniţă et al., 2024) , is an
exciting research prospect, particularly for drug cocrystal synthesis. Both techniques have procedures that minimise the use
of solvents, coupled with the advantages of efficient MAS in
terms of synthesis time efficiency. Hence, combining the two
is an interesting strategy for green chemistry. The potential
synergism between these two approaches is that milling results
in small particle sizes that allow for increased surface contact

© 2025 The Authors.

Nano-sized cocrystal of
diclofenac acid-proline was
successfully produced using
the fast evaporation assisted
by the microwave method.

(Nugrahani
and Auli,
2020)

between particles. At the same time, microwave heating accelerates molecular interactions and energy transfer at the reaction
site.
MAS offers significant research opportunities when integrated with Quality by Design (QbD) (Ross et al., 2024) principles and Process Analytical Technology (PAT) (Moradiya
et al., 2016; Chavan et al., 2018) , both of which aim to enhance process understanding, control, and product quality in
pharmaceutical manufacturing. QbD emphasises designing
processes that consistently yield products meeting predefined
quality attributes, with MAS providing a robust platform for
process optimisation. In conjunction with PAT, which involves
real-time monitoring and control of critical process parameters, MAS can facilitate continuous feedback loops to optimise
reaction conditions. For example, sensors integrated into microwave reactors can measure real-time temperature, pressure
and concentration. Such a design allows data to be obtained
that can be used for product quality control to obtain consistent
results. Thus, applying MAS in pharmaceutical manufacturing
aligns with good drug manufacturing practices’ QbD and PAT
requirements.
10.
RESEARCH TECHNIQUES AND TROUBLESHOOT IN MAS
10.1 Getting Started with MAS for Cocrystal Synthesis
Since microwave-assisted synthesis was introduced, experiments were typically carried out in sealed vessels utilising domestic household microwave ovens without any chance for
temperature or pressure measurement. The results were often
uncontrolled heating, which led to degradation. The situation
changed when microwave reactors were introduced in 2000 for
scientific use. Microwave synthesis reactions have now become
controllable by temperature monitoring and pressure sensing,
and therefore safe and reproducible (Kappe, 2004; Kappe and
Stadler, 2005) .
Considering the importance of controlling critical process
parameters in MAS, it is necessary to define the appropriate
instrument settings, including target temperature, ramp temperature, holding time, and stirring speed. Many specialised
microwave reactors are commercially available, which allows researchers to establish those parameters. Below are the ordered
steps to getting started:

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1. Target temperature. Target temperature is the specific reaction temperature the microwave system aims to reach
and maintain during the synthesis. The instrument adjusts the microwave power automatically to reach and
maintain that temperature. In this case, the delivery input energy is set based on the temperature needed to
initiate the desired reaction. Determining the microwave
temperature target for cocrystal synthesis depends on
factors like solvent choice, the thermal stability of API,
and the coformer. A high microwave absorption solvent,
a polar solvent like ethanol and methanol, uses lower
temperatures, i.e. lower power (300–400 W), to prevent
excessive heating. Low microwave absorption, especially
for solid-state reactants or non-polar solvents, uses higher
temperatures, i.e. higher power (500–600 W), to ensure
efficient heating (Bao et al., 2023) . Estimating the right
temperature for cocrystal formation in MAS is important; if it is too low and nothing happens, it is too high,
and we risk decomposition or eutectic melting instead of
cocrystallisation. To determine the optimal target temperature for MAS of cocrystals, the melting points of the
active pharmaceutical ingredient and the coformer serve
as essential reference points. Since cocrystallisation often occurs below the melting temperature of either pure
component, setting the MAS temperature approximately
10-30◦ C lower than the lowest melting point helps avoid
decomposition or unwanted eutectic formation. If differential scanning calorimetry (DSC) data are available,
a new endothermic peak corresponding to the cocrystal
can further refine this estimate. In general, the MAS
temperature should fall within 60–80% of the expected
cocrystal melting point, ensuring sufficient molecular mobility for cocrystal formation without crossing into the
melting or degradation zone of the components. The
estimated target temperature will determine the holding
time at which the cocrystal is fully formed.
2. Ramp time. It will determine how quickly the microwave
reaches the target temperature. It usually takes 2–5 minutes. Shorter ramp means faster heating, leading to more
uniform activation. Longer ramp means gentler heating
that avoids overheating or “hot spots” in sensitive samples. An example in determining the ramp time is heating
the samples once the temperature target has been determined. For example, Pagire et al. (2013) determined
their setting by heating the equal moles (0.25 mol) of
each solvent alone and 0.4 mmol of caffeine, malic acid or
caffeine–malic acid mixture in 0.25 mol of each solvent
were subjected to microwave irradiation in 30 ml capacity glass tubes in a microwave reactor (Monowave 300,
Anton Paar Gmbh, Austria). Each sample was heated to
80◦ C under continuous stirring at 600 rpm. Time and
microwave power required to reach 80◦ C were noted.
3. Hold time. The holding time refers to the duration for
which the reaction mixture is held at the target temperature after it has been reached under continuous mi© 2025 The Authors.

Science and Technology Indonesia, 10 (2025) 1130-1147

crowave irradiation. Once the target temperature is
determined, we must observe whether it can promote
cocrystal formation and how long it takes. Thus, we need
to optimise the holding time. A good starting point to
optimise the hold time range would be 1–10 minutes
at the temperature target. For example, start with a 1minute holding time. Then, cocrystal formation will be
observed using PXRD, DSC, FTIR, and/or direct visual
observation. Further, we can adjust based on the results
(e.g., incomplete conversion or degradation signs). At
this stage, we can adjust the temperature to raise or lower
it.
4. Microwave exposure mode. Exposure mode can be continuous or pulsed. Both continuous and pulsed microwave
irradiation modes can be used for cocrystal synthesis.
The limitations for their selection depend on the thermal
sensitivity of the cocrystal components to temperature
exposure. Continuous irradiation provides rapid and
continuous heating, making it suitable for systems that
can stabilise at high temperatures on a sustained basis.
Previous experience with the kinetics of cocrystal synthesis using a particular material can also be decisive, as
it will help determine the intensity of radiation exposure and the desired heating profile. However, pulsed
irradiation offers greater thermal control by delivering
energy in short bursts, which helps minimise the risk of
degradation for thermally sensitive compounds.
5. Stirring speed. It will control homogeneity and contact
between components. The proper stirring in MAS will
also prevent a hot spot in the reaction vessel. 400–800
rpm is preferred for most slurries and suspensions, and
0 rpm is preferred if neat-MAS is used (no solvent). As
a rule, use higher stirring for high-viscosity samples or
slurries.
10.2 Potential Troubleshooting Issues
Using microwave-assisted synthesis might encounter some issues. Below are possible issues and the troubleshooting:
1. Incomplete cocrystal formation. The possible cause might
be insufficient heating time or temperature. Material
properties, such as poor molecular diffusion in the solidstate method or incorrect molar ratio, can be the cause.
These issues can be addressed by increasing heating time
in small increments (e.g., an additional 2–5 min), using
solvent-assisted MAS to improve diffusion, and confirming a stoichiometric ratio (1:1 or 1:2).
2. Decomposition. The possible cause might be excessive
microwave power and prolonged holding time. These
issues can be addressed by reducing microwave power
and shortening microwave pulses (e.g., 30 sec ON, 30
sec OFF).
3. Poor cocrystal yield or low purity. The possible cause might
be the presence of unreacted starting materials. These
issues can be addressed by optimising temperature, holding time, and solvent choice (e.g., ethanol helps control
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nucleation) or by trying alternative synthesis techniques
(e.g., solution evaporation if solid-state fails).
11. CONCLUSIONS
Microwave-assisted synthesis offers a fast, energy-efficient, and
environmentally sustainable alternative for pharmaceutical cocr
ystal production. It enhances molecular diffusion and interaction through dielectric heating, leading to efficient noncovalent
bonding. Compared to conventional methods, MAS reduces
solvent consumption, shortens synthesis time, and yields highpurity products. Yet, its industrial application is still emerging.
Future research should focus on process optimization, integration with quality-by-design (QbD) strategies, and development
of continuous flow microwave reactors. MAS holds promise
for drug repurposing and extending drug lifecycles, presenting
a strategic advantage in pharmaceutical innovation. With increasing emphasis on green manufacturing, MAS represents
a forward-thinking platform for modern drug formulation as
well as drug safety.
12. ACKNOWLEDGMENT
The authors would like to acknowledge the The Indonesia Endowment Fund for Education Agency (Indonesian: Lembaga
Pengelola Dana Pendidikan) (Grant numbers SKPB-6942/LP
DP/LPDP.3/2024) for educational scholarship and the writing
of this article is part of that academic pursuit.
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