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26 Cocrystals in Pharmaceutical Sciences
103. Emami, S., Siahi-Shadbad, M., Adibkia, K.A.-O., Barzegar-Jalali, M., Recent
advances in improving oral drug bioavailability by cocrystals. Bioimpacts, 8,
305–320, 2018.
104. Feng, L., Karpinski, P.H., Sutton, P., Liu, Y., Hook, D.F., Hu, B., Blacklock,
T.J., Fanwick, P.E., Prashad, M., Godtfredsen, S., LCZ696: a dual-acting
sodium supramolecular complex. Tetrahedron Lett., 53, 275–276, 2012.
105. Katlama, C., Ingrand, D., Loveday, C., Clumeck, N., Mallolas, J., Staszewski,
S., Johnson, M., Hill, A.M., Pearce, G., McDade, H., Safety and ecacy of
lamivudine-zidovudine combination therapy in antiretroviral-naive patients: a
randomized controlled comparison with zidovudine monotherapy. JAMA,
276, 118–125, 1996.
106. Duggirala, N.K., LaCasse, S.M., Zaworotko, M.J., Krzyzaniak, J.F., Arora,
K.K., Pharmaceutical cocrystals: formulation approaches to develop robust
drug products. Cryst. Growth Des., 20, 617–626, 2019.
107. Vasoya, J.M., Shah, A.V., Serajuddin, A., Investigation of possible solubility
and dissolution advantages of cocrystals, I: Aqueous solubility and dissolution
rates of ketoconazole and its cocrystals as functions of pH. ADMET DMPK,
7, 106–130, 2019.
108. Brittain, H.G., Pharmaceutical cocrystals: e coming wave of new drug
substances. J. Pharm. Sci., 102, 311–317, 2013.
109. Harrison, W.T., Yathirajan, H., Bindya, S., Anilkumar, H., Escitalopram
oxalate: co-existence of oxalate dianions and oxalic acid molecules in the
same crystal. Acta Crystallogr., Sect. C: Cryst. Struct. Commun., 63, o129–
o131, 2007.
110. O’Nolan, D., Perry, M.L., Zaworotko, M.J., Chloral hydrate polymorphs and
cocrystal revisited: solving two pharmaceutical cold cases. Cryst. Growth
Des., 16, 2211–2217, 2016.
111. Videla, S., Gascón, N., Plata-Salamán, C., Commentary on the “Co-Crystal
of Tramadol-Celecoxib in Patients with Moderate to Severe Acute Post-
Surgical Oral Pain: A Dose-Finding, Randomised, Double-Blind, Placeboand
Active-Controlled, Multicentre Phase II Trial”. Implications for Cardiovascular
Safety. J. Cardiol. Cardiovasc. Sci., 3, 1–3, 2019.
112. Banerjee, M., Nimkar, K., Naik, S., Patravale, V., Unlocking the potential of
drug-drug cocrystals – A comprehensive review. J. Control. Release, 348,
456–469, 2022.
113. San Martín, O., Llombart, B., Hernández, G.C., Menéndez, A.F., Botella-
Estrada, R., Ceballos, E.H., Puig, S., Sonidegib in the treatment of locally
advanced basal cell carcinoma. Actas Dermo-Siliogr., 112, 295–301, 2021.
114. Alvani, A. and Shayanfar, A., Solution Stability of Pharmaceutical Cocrystals.
Cryst. Growth Des., 22, 6323–6337, 2022.
115. Díaz-Villamarín, X., Piñar-Morales, R., Barrero-Hernández, F.J., Antúnez-
Rodríguez, A., Cabeza-Barrera, J., Morón-Romero, R., Pharmacogenetics of
siponimod: A systematic review. Biomed. Pharmacother., 153, 113536, 2022.
Pharmaceutical Cocrystals 27
116. O’Sullivan, A., Long, B., Verma, V., Ryan, K.M., Padrela, L., Solid-state and
particle size control of pharmaceutical cocrystals using atomization-based
techniques. Int. J. Pharm., 621, 121798, 2022.
117. USFDA, https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213426s
000lbl.pdf.
118. Putra, O.D., Yoshida, T., Umeda, D., Higashi, K., Uekusa, H., Yonemochi,
E., Crystal structure determination of dimenhydrinate aer more than 60
years: solving salt–cocrystal ambiguity via solid-state characterizations and
solubil
29
Inderbir Singh, Subrata Mallick and Ritu Rathi (eds.) Cocrystals in Pharmaceutical Sciences:
Design to Applications, (29–54) © 2025 Scrivener Publishing LLC
2
Design and Structural Characteristics
of Pharmaceutical Cocrystals
Harpreet Singh
1
*, Bhuvnesh Kumar Singh
2
, Anil Kumar
2
, Arvind Kumar
1
,
Arun Kumar Mishra
3
, Ritu Rathi
4
and Inderbir Singh
4
1
School of Pharmaceutical Sciences (Faculty of Pharmacy), IFTM University,
Moradabad, Uttar Pradesh, India
2
Moradabad Educational Trust Group of Institutions, Faculty of Pharmacy,
Moradabad, Uttar Pradesh, India
3
SOS School of Pharmacy (Faculty of Pharmacy), IFTM University, Moradabad,
Uttar Pradesh, India
4
Chitkara College of Pharmacy, Chitkara University, Punjab, India
Abstract
is chapter deals with an in-depth focus on pharmaceutical cocrystals, basically
describing their design, synthesis, and structural features. Cocrystals, which are
the products of combining an API (active pharmaceutical ingredient) with a solid
molecular/ionic compound, have widespread impacts on solubility and stability,
leading to bioavailability essential for ecacy improvement. e chapter starts
with an in-depth analysis of cocrystallization via heteromolecular interactions,
including hydrogen bonds, halogen bonds, and charge transfer (CT) interactions.
It highlights the essential role of noncovalent synthesis in designing functional
molecules. Polymorphism and Form Selection of Cocrystals is chapter discusses
complexities in polymorphs and the salt-cocrystal continuum that aect cocrys-
tallization outcomes. Iondosekie et al. discussed key considerations in choosing a
coformer and how it leads to intermolecular interactions from both points of view,
highlighting that the designing strategies must always amalgamate these aspects
for the ecient design of solid-state forms as well. Structural characterization of
cocrystals, including X-ray diraction and hydrogen bonding analysis, helps to
determine the stability and functionalities using various physical methods. is
chapter discusses the regulatory and patent aspects of cocrystals, which is indic-
ative of their increasing role in medicinal chemistry. e techniques included in
*Corresponding author: harpreetproctor@redimail.com
30 Cocrystals in Pharmaceutical Sciences
this chapter are of great advantage to researchers working in pharmaceutical sci-
ences, bringing explicit methodologies for designing and synthesizing cocrystals.
e process of cocrystallization allows APIs to become more soluble and stable,
which, in turn, leads to better therapeutic results. is results in better drugs for
people, which have a potentially lower side eect as cocrystals outperform drug
delivery and bioavailability. e insights presented in this chapter are anticipated
to be instrumental in the development of innovative pharmaceutical products that
meet the stringent standards of contemporary medical practice.
Keywords: Pharmaceutical cocrystals, active pharmaceutical ingredient,
polymorphism, x-ray diraction, hydrogen bonding analysis
2.1 Introduction
Pharmaceutical cocrystals are a specic kind of crystalline structure formed
through the precise combination of an API (active pharmaceutical ingre-
dient) with other solid molecular or ionic compounds. e compounds
are formulated to maintain their solid state even when exposed at room
temperature [1]. e creation of these cocrystals requires the use of a vari-
ety of intermolecular forces such as hydrogen bonding, halogen bonding,
π-π stacking, and charge transfer interactions [2]. e processes involved
in this process make it possible to synthesize functional molecules through
noncovalent synthetic operations. Some of the reasons why this formula
is advantageous include that it is easy to process, manageable structures,
and aordable to implement. Organic cocrystals have been of interest in
the eld of molecular optoelectronics [3]. It is also relevant to appreciate
the importance of these frameworks concerning the general aim of relating
structure at the molecular level to the properties of the material [4]. ey
are not solely held by ionic bonds but held together through dierent
types of molecular interactions [5, 6]. Cocrystals in pharmaceuticals are
an interesting class of medicinal materials found to enhance physical
properties and stability and even may oer new chances for the solid-
state form under patent protection [7]. Crystal issues may arise due to the
formation of solvates, hydrates, and salts within the structure. Strategies
such as hydrogen bonding control and adjustments of solubility parameters
are crucial in the formulation of cocrystals. In the eld of design and
construction of new cocrystals and cocrystals, the incorporation of CT
interactions is extensively used as a driving force for the construction of
supramolecular cocrystals. ese interactions discussed in the study help in
enhancing the stability and quality of the crystals, leading to closely packed
morphology and size [8]. In organic cocrystals, CT interactions between a
Design and Characteristics of Pharmaceutical Cocrystals 31
donor and an acceptor have led to the development of new forms of organic
D-A system at a fast pace [9]. Pharmaceutical researchers are obsessed
with enhancing the physicochemical characteristics of APIs so that they
can deliver increased therapeutic potential. Some of the changes elicited by
altering the solid states of an API are changes in its melting point, solubility,
stability, permeability, bioavailability, and ability to form a tablet [10]. A
key challenge to the formulation of oral drugs is the capability of APIs,
which depend on their solubility and bioavailability. e enhancement of
the solubility of APIs has been the subject of several research studies, and
signicant advances have been achieved by scientists in the development of
techniques to improve solubility. Such strategies include prodrug formation,
solid dispersion, particle size reduction, cyclodextrin complexation, self-
emulsifying system, salt formation, surfactant application, polymorphism,
nanoparticle formation, and multicomponent molecular cocrystal formation
[11]. Both techniques show advantages and limitations, depending on the
nature of APIs and polymers being used; the eciency of each of these
methods can be greatly aected by the API’s characteristics [12]. In the US
and Europe, there are some rules concerning the regulatory classication
of API cocrystals. ese guidelines give basic information about product
registration [13]. In recent years, the focus has shied toward new crys-
talline forms like salts, polymorphs, hydrates, solvates, and, especially,
cocrystals. Pharmaceutical cocrystals are gaining recognition as an eec-
tive strategy for enhancing various physicochemical attributes, including
melting point, dissolution rate, stability, solubility, permeability, bioavail-
ability, and the ability to form tablets [14].
Cocrystals are formed when a drug and coformer or several other com-
ponents combine in an exact molar ratio and crystallize together. e for-
mation of cocrystals is facilitated by hydrogen bonding. ese components
are held together by dierent noncovalent interactions, such as hydrogen
bonds, van der Waals forces, and π-π interactions. e era of understanding
the structure, design, and bonding interactions will enable the enhance-
ment of the properties of pharmaceuticals in applications. Molecular
cocrystals, which are also referred to as molecular CC, are formed by asso-
ciating a neutral drug and a neutral coformer in a denite proportion be it
1:1 or 2:1. In the design strategy, one has to choose coformers that are capa-
ble of forming similar hydrogen bonds or any other forms of bond with the
drug, regarding their functional groups. e main types of bonding inter-
actions involve hydrogen bond, which relates to carboxylic acids, amides,
and alcohols. van der Waals forces present in the secondary model play
some role in stability and packing, while more stable packing is achieved
through aromatic interactions between π-rings [15–18].
32 Cocrystals in Pharmaceutical Sciences
Ionic cocrystals (also referred to as ionic CCs) are formed from denite
stoichiometric proportions of ionic species; in most cases, it has the drug
in its salt state and another species, which can be anionic or cationic in
nature. During the design strategy, it is mandatory to select ionic coform-
ers that are capable of forming an ionic or stable hydrogen bond with the
ionic drug. Strong ion/ion compensations, hydrogen bonds, and additional
secondary van der Waals forces are responsible for bond interaction that
contributes to structural integrity. Such relations are vital in the overall
stability of the system of such interactions. Cocrystals or solvates are drugs
solvated with solvent molecules, building a crystal lattice in which the ratio
of the solvent molecules to the drug molecules is xed, for instance, 1:1
or 1:2. e design strategy means the choice of the solvents that can form
certain interactions with the drug and stabilize the lattice [19–21].
Hydrated cocrystals, otherwise called hydrates, encompass a drug, a
coformer, and water molecules. ese cocrystals are resolved based on
the number of water molecules in relation to the involvement of the drug-
coformer pair. e design strategy leverages water to facilitate hydrogen
bonds with the material, in particular with the polar functional groups. e
bonding interactions in this system are multiple hydrogen bonds between
water molecules and the coformer as well as the drug. Also in view are van
der Waals forces contributing to stability, and sometimes there may be π-π
interactions in the case of the components present. Hydrated cocrystals
(or simply hydrates) consist of a drug, a coformer, and water molecules.
e stoichiometry of these cocrystals is determined by the ratio of water
molecules with respect to the drug-coformer combination. A design meth-
odology based on polar functional groups takes advantage of the presence
of water to assist in hydrogen bond formation using a supramolecular
motif based on a virtually innite network for hydrogen bonding involv-
ing water molecules, the drug, and the coformer. In turn, the system’s sta-
bility also depends on van der Waals forces that could lead to unexpected
π-π interactions. In addition, the molecular arrangements of the cocrystals
make solid forms of patent protection worthy of protection. Additionally,
cocrystals can increase the solubility of drugs, hence increasing the deliv-
ery of drugs and, therefore, leading to more therapeutic benets [23–25].
is chapter provides a comprehensive analysis of the design and struc-
tural characteristics of pharmaceutical cocrystals, along with their diverse
range of applications. Furthermore, it explores the diculties and potential
future developments of cocrystal research [22].
Design and Characteristics of Pharmaceutical Cocrystals 33
2.1.1 Polymorphism
Polymorphism refers to the ability of a substance, typically a solid, to exist
in various crystalline shapes or formations [26]. Figure 2.1 [27] illus-
trates that various polymorphic forms of a drug can exhibit unique phys-
ical properties, including solubility, melting temperature, and stability.
Dierent polymorphic forms can display varying levels of bioavailability
and rates of dissolution [28]. Below are a few illustrations: Sulfathiazole
exists in multiple polymorphic forms, each exhibiting a unique crystal
structure. Carbamazepine exists in many polymorphs, which can aect its
dissolution [29]. e molecular congurations inside the solid state are
responsible for the fundamental physical properties of crystalline materi-
als. Modifying these congurations or interconnections can signicantly
inuence the characteristics of the solid. Scientists in solid-state chemistry
employ many methodologies to alter the chemical and physical charac-
teristics of APIs. e approaches encompass the generation of salts, poly-
morphs, hydrates, solvates, and cocrystals, as seen in Figure 2.1.
Salt formation is a prevalent method for altering API properties, with
many medicines marketed as salts. is approach requires the API to have
an ionizable site. Cocrystals, however, are multicomponent structures sta-
bilized by noncovalent interactions and do not require ionizable groups,
thus broadening the scope for modifying APIs with nonionizable func-
tional groups. It is important to acknowledge that there is no universal
approach to enhancing the characteristics of every API. Each API’s molec-
ular structure and desired properties must be individually evaluated.
Guidelines for cocrystal design through supramolecular synthesis are cru-
cial in this assessment process.
Molecular or API Ions Solvent or Water Neutral
Drug Molecule Solvates or Hydrates Cocrystal Polymorph
Figure 2.1 Solid state polymorphism.
34 Cocrystals in Pharmaceutical Sciences
2.1.2 Salt Cocrystal Continuum
Crystalline structures known as salt forms are created when an API com-
bines with an ion, typically a counterion, resulting in the formation of a
salt (see Figure 2.1). Salts are crucial for improving the solubility, stability,
and bioavailability of APIs. Commonly used salt forms in pharmaceuticals
include hydrochloride salts (e.g., diphenhydramine hydrochloride), sulfate
salts, and citrate salts [30]. Cocrystals are crystalline substances consisting
of an API and one or more distinct cocrystal formers. ese cocrystals
can alter the properties of APIs while preserving their biological activity.
Examples include caeine-theophylline and carbamazepine-saccharin
cocrystals [31]. e salt-cocrystal continuum is a fascinating area of study,
where the distinction between salts and cocrystals becomes less clear [32].
e spectrum ranges from pure salts to pure cocrystals, encompassing a
range of hybrid structures in between [33]. Factors such as ionic charac-
ter, hydrogen bonding, and crystal packing determine the position on this
continuum. e diversity of solid forms signicantly aects drug proper-
ties and oers exciting opportunities for advancements in the eld of phar-
maceuticals [34].
2.2 Design of Pharmaceutical Cocrystals
e dierent parameters to be considered in designing cocrystals are
shown in Figure 2.2 [35].
e physicochemical properties of the API and coformer are the most
important factors to consider when selecting a coformer for cocrystal
development. e functional groups present in the API and coformer will
Physiochemical properties
Physiochemical properties
Other parameters
Other parameters
Cocrystal
Functional Groups
API
Coformer
Functional Groups
Solubility
Stability
Mechanical properties
Crystal packing
Solubility
Mechanical properties
Crystal packing
Slip planes
Layered Structure
Pharmacological activity
Pgp efflux/substrate
Strength of hydrogen bond
donors and acceptors
Permeability
Pgp efflux
Dose
Side effects
COOH
CONH
2
NH
2
OH
-COOH
-CONH
2
-NH
2
-OH
Figure 2.2 Parameters to be considered in coformer selection (adopted from Singh et al.,
2023; published under CC4 license) [35].
Design and Characteristics of Pharmaceutical Cocrystals 35
determine the type of interactions that can occur between them, which
will, in turn, aect the crystal structure and properties of the cocrystal.
Solubility, mechanical properties, crystal packing, and other parameters
are also important to consider, as they can aect the stability, bioavailabil-
ity, and ecacy of the cocrystal [35].
2.2.1 Molecular Recognition and Supramolecular Interactions
One of the key principles underlying the rational design of pharmaceutical
cocrystals is molecular recognition and the use of supramolecular inter-
actions [36]. Pharmaceutical cocrystals aim to manipulate properties like
solubility, dissolution rate, and bioavailability through supramolecular syn-
thon formation between the API and a cocrystal former at the molecular
level [37]. A fundamental understanding of the noncovalent interactions
driving molecular recognition events is thus crucial for the development
of improved cocrystal systems. e most commonly exploited supramo-
lecular synthons in pharmaceutical cocrystals include hydrogen bonding
and π-stacking interactions. APIs oen contain functional groups like
carboxylic acids and amides that are amenable to hydrogen bond dona-
tion/acceptance. Systematic screening of potential coformers containing
complementary hydrogen bonding functionalities allows the identication
of suitable molecular recognition events between the API and coformer.
For example, functionalities like amines/pyridines in coformers can act as
hydrogen bond acceptors to the acidic hydrogens in an API [38]. π-stack-
ing is another ubiquitous noncovalent interaction that can direct molec-
ular assembly in crystalline solids. Planar aromatic groups in APIs and
coformers contribute to stabilizing molecular packing through π-π stack-
ing. Such interactions inuence the preferred crystal packing and physi-
cal properties [39]. Understanding the preferred orientation, interplanar
distance, and relative displacement of aromatic systems through computa-
tional methods aids in selecting coformers.
By considering both the hydrogen bonding properties and the tendency
for π-stacking, computational tools in combination with high-throughput
screening allow for the identication of coformer:API pairs that form
robust and directional supramolecular synthons. Such synthons can tem-
plate the assembly of cocrystal structures possessing optimal properties
like improved aqueous solubility, leading to enhanced oral bioavailability
and therapeutic ecacy. e principles of molecular recognition serve as a
foundation for rational cocrystal design and the development of new solid
forms with improved performance [40]. Carbamazepine (CBZ) is a BCS
class II drug used as an anticonvulsant and antidepressant. However, its