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NJC
New Journal of Chemistry
Accepted Manuscript
A journal for new directions in chemistry

This article can be cited before page numbers have been issued, to do this please use: S. K. N, J.
Ramachandran, N. Shivalingegowda, L. Neratur Krishnappagowda and D. R. Trivedi, New J. Chem., 2018,
DOI: 10.1039/C7NJ04400C.

Volume 40 Number 1 January 2016 Pages 1–846 This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
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 Page 1 of 32 New Journal of Chemistry
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DOI: 10.1039/C7NJ04400C

Cocrystal/Salt Synthesis of Flucytosine Drug: Structural and Stability Aspects

Sunil Kumar Nechipadappua$, Jeeshma Ramachandrana$, Naveen Shivalingegowdab, Neratur

Krishnappagowda Lokanathc and Darshak R. Trivedia*

New Journal of Chemistry Accepted Manuscript

a
Supramolecular Chemistry Laboratory, Department of Chemistry, National Institute of
Technology Karnataka (NITK)-Surathkal, Srinivasnagar-575 025, Karnataka, INDIA
Published on 28 February 2018. Downloaded by Fudan University on 01/03/2018 11:01:46.

b
Department of Physics, School of Engineering and Technology, Jain University, Bangalore-
562112, Karnataka, INDIA
c
Department of Studies in Physics, University of Mysore, Manasagangotri, Mysuru-570 006,
Karnataka, INDIA
$: Authors contributed equally
*Corresponding author: Dr. Darshak R. Trivedi, Email: [email protected]
Phone No: +91-824-2473205, Fax: +91-8242474033
Abstract: 5-fluorocytsine or Flucytosine (FLC) is a well-known drug for anti-fungal medication
and it’s one of the essential medicines needed in a health system. The main disadvantage of FLC
drug is the instability due to hydration under storage conditions. In the present work,
cocrystal/salt screening experiment resulted three molecular salts of FLC with dihydroxybenzoic
acid derivatives (2,3-dihydroxybenzoic acid (2,3HBA), 3,5-dihydroxybenzoic acid (3,5HBA),
and 2,6-dihydroxybenzoic acid (2,6HBA) and two cocrystals with gallic acid (GAA) and glutaric
acid (GLA). Since, FLC drug is highly susceptible for hydration, the present work concentrated
on the stability of the synthesized molecular salt/cocrystal at different relative humidity (RH)
conditions. All the newly formed crystalline adducts were characterized structurally, and the
crystal structures were determined by Single-Crystal X-ray diffraction techniques (SC-XRD).
FLC-2,6HBA salt was found to be monohydrate, whereas, FLC-3,5HBA salt was crystallized as
hemipentahydrate. FLC-2,3HBA and FLC-GLA were crystallized in 2:1 equimolar ratio of FLC
and the coformer. FLC-GAA cocrystal crystallized in 1:1 equimolar ratio. Two point
heterosynthon between FLC and the coformer were observed in all the crystalline structure
except FLC-GLA, where it was formed through single point heterosynthon. Stability study at
different relative humidity conditions shown the non-hygroscopicity of synthesized molecular
salt/cocrystal. It was found that FLC-2,3HBA salt, FLC-GAA, and FLC-GLA cocrystal did not
experience any hydration under accelerated humidity conditions (both 70-75% RH and 90-95%
1
 New Journal of Chemistry Page 2 of 32
View Article Online
DOI: 10.1039/C7NJ04400C

RH) at ambient temperature (~30 °C). However, FLC-2,6HBA and FLC-3,5HBA were found to
be hygroscopic at 70-75% RH conditions. Furthermore, all the synthesized salt/cocrystal except
FLC-3,5HBA were found to be stable for 2 months at ambient conditions (~30 °C, 60-65% RH).

New Journal of Chemistry Accepted Manuscript

Therefore, FLC-2,3HBA salt, FLC-GAA, and FLC-GLA cocrystals are a better candidate for the
preparation of new drug products of FLC.
______________________________________________________________________________
Published on 28 February 2018. Downloaded by Fudan University on 01/03/2018 11:01:46.

Keywords: Supramolecular Chemistry; Crystal Engineering; Pharmaceutical salts;

Pharmaceutical cocrystal; Stability; Hygroscopicity

1. INTRODUCTION

Supramolecular chemistry along with crystal engineering facilitate design and synthesis of new
solid form of Active Pharmaceutical Ingredient (API) with desired physicochemical properties
by exploring the advantage of supramolecular interactions and become a most important area of
chemical research.1-9 Over the past few years, the field of pharmaceutical cocrystal attains
special attraction from scientists because of its technological importance and patentability of new
solid forms.10 A pharmaceutical cocrystal11-17 of an API with a GRAS (Generally Recognized as
Safe) coformer or another active molecule enables to improve the physicochemical properties of
API such as stability, solubility, bioavailability, compatibility, tabletability, and compressibility
without altering the pharmacological activity of API.18-21 Both the salt and the cocrystal have
superior solid state properties than that of pure/neutral drug molecule.21-24 The salt formation can
be adopted for APIs which possesses ionizable sites in the molecular structure.

5-Fluorocytosine/Flucytosine (4-amino-5-fluoro-1,2-dihydropyrimidin-2-one) (FLC), a

fluorinated analog of cytosine, is an antimetabolite which acts as an antifungal agent.25
Flucytosine intrafungally converts into fluorouracil by deamination by the enzyme cytosine
deaminase (CD) present in fungal cells and that will inhibit fungal DNA synthesis.26 The
molecule was first synthesized in 1957 and released as an antifungal agent in the year 1968. It is
also introduced as a potential drug for cancer treatment in combination with CD and the
activation of FLC in tumor tissue is achieved by GDEPT (gene-directed enzyme prodrug
therapy).27-29 FLC is a biopharmaceutical classification system (BSC) class III drug due to high
solubility and low permeability in water.30 The solid stability is an important factor for the
2