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146 Cocrystals in Pharmaceutical Sciences
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153
Inderbir Singh, Subrata Mallick and Ritu Rathi (eds.) Cocrystals in Pharmaceutical Sciences:
Design to Applications, (153–188) © 2025 Scrivener Publishing LLC
6
Advancements and Applications
of Herbal Cocrystals
Rajat Goyal
1
, Pankaj Popli
2
, Kashish Wilson
1
, Hitesh Chopra
3
*,
Sonia Dhiman
2
and Sumeet Gupta
1
1
MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University),
Mullana-Ambala, Haryana, India
2
Chitkara College of Pharmacy, Chitkara University, Punjab, India
3
Department of Biosciences, Saveetha School of Engineering, Saveetha Institute of
Medical and Technical Sciences, Chennai, Tamil Nadu, India
Abstract
Cocrystals have drawn the attention of the pharmaceutical sector through the
introduction of regulatory guidelines by the US Food and Drug Administration
(FDA) because of their growing patent portfolios. e drug’s physicochemical
properties depend on the qualities of the active pharmaceutical ingredient (API)
that it possesses, as well as its formulation type. e existing and newly discov-
ered APIs present signicant challenges in drug development. ese challenges
are mostly caused by APIs’ poor water solubility which inevitably leads to poor
bioavailability of the corresponding drugs in the patient. As a result, the prefor-
mulation of APIs mainly requires a brief knowledge of their solid-state features
and physicochemical properties. Cocrystallization dees a promising approach
for transforming API physical and pharmacological properties, viz, solubility, rate
of dissolution, stability, hygroscopicity, tablet ability, mechanical characteristics,
bioavailability, and ecient therapeutic potential. Herbal bioactives are promising
prospective for cocrystallization to improve solubility, taste masking, and bioavail-
ability. is chapter provides an extensive overview of the literature on the devel-
opment of cocrystals from various herbal bioactives, like curcumin, quercetin,
berberine, resveratrol, naringenin, and various other herbal chemical substances.
Various techniques are currently explored for producing medicinal cocrystals.
Instrumental and physicochemical characterization methods have been also
included. In conclusion, cocrystallization of herbal bioactives is a possible way to
*Corresponding author: chopraontheride@gmail.com
154 Cocrystals in Pharmaceutical Sciences
improve the physical characteristics of the aforementioned substances. However,
toxicological, stability, regulatory, and scale-up diculties need to be suciently
addressed before commercial viability can be anticipated.
Keywords: Herbal bioactives, cocrystals, physicochemical characterization,
bioavailability, solubility
6.1 Introduction
6.1.1 Denition and Overview
Crystal engineering nds diverse applications, including the utilization of
complementary molecules to create binary compounds [1]. In the pharma-
ceutical realm, molecules possess inherent recognition sites that selectively
bind to biomolecules, oering opportunities to construct supramolecular
self-assembling complexes with tailored physiochemical attributes [2].
A notable example is pharmaceutical cocrystals, which are crystalline
molecular complexes comprising two or more neutral molecules. ese
cocrystals represent a cutting-edge approach in supramolecular chemistry,
oering enhancements in various active pharmaceutical ingredient (APIs)
characteristics such as dissolution rate, mechanical characteristics, and
stability, as shown in Figure 6.1 [3]. Compared to traditional solid-state
modication techniques like salt formation, cocrystal formation presents
several potential advantages. For instance, virtually all types of drug mole-
cules have the potential to form cocrystals, obviating the need for covalent
modication of APIs [4]. Moreover, herbal medicines have a rich history
of use dating back to ancient times, particularly prominent in regions like
India where traditional systems such as Siddha and Ayurveda rely heavily
on herbal preparations [5].
In modern pharmaceutical practice, herbal drugs hold a signicant posi-
tion due to their well-known eects and minimal side eects. Additionally,
herbal drugs oer a promising avenue for cocrystal formation compared
to synthetic counterparts [6]. Despite their broad pharmacological poten-
tial across various diseases, herbal drugs oen exhibit limited eectiveness
within the human biological system due to factors such as poor absorp-
tion, inability to penetrate lipid membranes, large molecular size, and
reduced bioavailability [7]. As a result of these restrictions, some extracts
are not employed in medicinal applications. Cocrystals have evolved as
a dierent approach for enhancing the kinetic and dynamic characteris-
tics of herbal medicine molecules within biological systems to solve these
problems [8, 9].
Advancements and Applications of Herbal Cocrystals 155
In designing dosage forms, cocrystals are becoming a more desirable
option than polymorphs, salts, solvates, and crystal habit manipulation
because they oer the advantage of altering the bulk material and physical
and chemical properties of the medicinal product without sacricing its
inherent action [10]. Utilizing cocrystals to convert herbal medicine into
a solid form oers multiple advantages, one of which is the potential to
achieve a high dissolution rate that is equivalent to the amorphous form
while keeping the long-term chemical and physical stability related to crys-
talline forms [11]. Furthermore, cocrystallization can enhance functional-
ity and processability downstream. Pharmaceutical businesses may prot
from prospects for intellectual property protection, including the oppor-
tunity to prolong the life cycles of current APIs through this method [12].
6.1.2 Fundamentals of Cocrystal Formation
APIs can currently be modied physicochemically using pharmaceuti-
cal cocrystallization, a relatively recent technique that provides several
benets over salt forms. Initially, cocrystal formation’s value potential
increases by its mere existence that it can be utilized for a variety of APIs,
such as basic, acidic, and nonionizable compounds. Secondly, when com-
pared to salt forms, the range of potential “counter molecules” for cocrys-
tal production is broader due to their abundance, particularly nontoxic
compounds [13].
Herbal API
Co-former
Herbal Cocrystals
Figure 6.1 Herbal API and coformer forming the cocrystal formation.