ABSTRACT:
In this study we mainly focused on the synthesis of cocrystals and their subsequent
characterization to evaluate melting point, dissolution and anti oxidant properties.Co crystals are
being synthesized using various methods such as physical, solvent evaporation and microwave
assistance method, with the goal of enhancing the physicochemical properties and biological
efficacy of the target compounds.The characterization of co crystals has been carried out using
melting point apparatus to ascertain the melting point ,dissolution apparatus to find the rate of
dissolution[at 100rpm,370C temperature ,for 1hr] , Differential Scanning Calorimetry (DSC) is
to analyze thermal behavior, and anti oxidant property was estimated using 2,2-Diphenyl-1-
picrylhydrazyl [DPPH]
The cocrystals were formed using PABA as a co-former and Ferulic acid as the main drug in the
cocrystal which has low toxicity and possesses many physiological functions (anti-inflammatory,
anti oxidant,anti microbial activity anti cancer, and anti diabetic effect).
Keywords:
1. Co-crystals
2. Ferulicacid (FA)
3. Para-aminobenzoicacid(PABA)
4. Anti oxidant activity
5. Dissolution
6. Differential scanning calorimetry(DSC)
7. 2,2-Diphenyl-1-picrylhydrazyl [DPPH]
8. Solvent evaporation,
9. Microwave assistance method
CHAPTER-II
LITERATURE REVIEW
In this study they concluded
and investigated that APAP–
S.NO TITLE OF THE ARTICLE AUTHOR RESEARCH
OXA wasFINDING
more stable than
APAP–MLA in the
competitive reaction and
possessed relative stability.
This review offers standard
On the other hand, when
descriptions and examples of
grinding with moisture or
established and emerging
maintaining at high
cocrystal preparation routes.
temperatures and RHs,
Moreover, detailed insight is
APAP–MLA was more stable,
given on the
Comparison of the relative and OXA converted to OXA
proposed mechanisms of
stability of pharmaceutical dihydrate. Furthermore,they
1. A Review of Pharmaceutical NaotoKarimi-Jafari
Maryam Suzuki et al.et cocrystallization in different
cocrystals consisting of explained that the cocrystal
Cocrystal al. techniques. All demonstrated
paracetamol and dicarboxylic stability varied with the
application areas for
acids
Preparation Routes and polarity of the solvents used to
pharmaceutical cocrystals are
Applications dissolve the cocrystal. The
included in this review with
cocrystal with low-solubility
the aim of highlighting the
product in the solvent formed
wide ranging potential of these
preferentially. They studied ,
materials. It is anticipated that
APAP–OXA was more stable
cocrystals will become more
in aprotic solvents. These
and
observations of cocrystal
more routine in
stability under various
pharmaceutical development
conditions are useful coformer
as their benefits
criteria when cocrystals are
continue to be demonstrated
selected as the API form in
and routine routes of
drug development.
manufacturing are proven.
AnnaKaragianni,Maria co-crystals of ferulic acid and
Pharmaceutical Malamatari , Kyriakos PABA can enhance synergistic
Cocrystals:NewSolid Kachrimanis antioxidant and anti-
Phase Modification Approaches tubercular activities,
for the Formulation of APIs improvingtherapeutic efficacy
3.
In this study, three new co-
crystals: sulfamethazine–
nicotinamide, sulfamerazine–
anthranilicacid,sulfamerazine–
salicylamide have been found
and efficiently manufactured
by microwave irradiation
Microwave assisted slurry Åke C. Rasmuson et al. slurry conversion co-
4.
conversion crystallization. In slurry
crystallization for manufacturing conversion crystallization at
of new cocrystals the same elevated
temperature, microwaves as
of sulfamethazine and
the source of heating is found
sulfamerazine.
to increase the rate by which
co-crystals are formed,
compared to normal heating.
The spectroscopic studies
showed peak shifts in spectra
of co-crystals as compared to
those of pure components,
showing different bonding
patterns. The co-crystals show
improved dissolution
properties.
This work focuses on the
improvement of solubility and
dissolution of aceclofenac
by the cocrystal approach.
Aceclofenac was screened with
various coformers selected from
Generally
Recognized as Safe and Everything
Added to Foods in the United
States list using Molecular orbital
package
2016 software to find out novel
Synthesis, Characterization and cocrystals of aceclofenac with
5. Performance Evaluation Kumar et al improved biopharmaceutical
of Aceclofenac-Urea properties.Novel cocrystals of
Cocrystals aceclofenac with urea were
synthesized by mechanochemical
grinding method. The synthesized
cocrystals (Aceclofenac-Urea neat
grinding and Aceclofenac-Urea
liquid assisted grinding)
were characterized carefully by
Differential scanning calorimetry,
infrared spectroscopy and powder
X-ray diffraction to verify the
formation of the cocrystals.
Pharmaceutically significant
properties such as powder
dissolution rate, solubility, and
stability of the synthesized
cocrystals were evaluated. They
finally Compares to aceclofenac,
the synthesized cocrystals showed
improved solubility and dissolution
rate.
This study indicates that the co-
Co-crystals for Generic Maniyam Arun Pandian crystal screening has now become a
Pharmaceuticals: An Outlook Rajendran et al major component of the solid form
6.
on Solid Oral Dosage screening strategy during original
Formulations. product development. Co-crystal
can be a beneficial solid
form of generic filers’ strategy that
meets the requirements
of legal, stability, and
bioequivalence.
This study revealed that the
DSC method can be
successfully applied in order to
detect a co-crystallisation
process occurring in a
pharmaceutical mixture when
heated under non-isothermal
Patrycja Saganowska, conditions. Based on the
7. DSC as a screening tool for rapid Marek Wesolowski results obtained in this study,
co-crystal detection in binary 15 mixtures including
mixtures of benzodiazepines with diazepam, temazepam,
co-formers oxazepam, lorazepam and
clonazepam were selected as
capable of forming potential
co-crystals with co-formers
when heated.In this study ,the
preliminary results outlined
only indicate the direction of
study to enhance
benzodiazepine bioavailability.
In this study the FTIR data
suggest that the supramolecular
synthons formed in the QUE–
INA and QUE–PA cocrystals
are different, mainly regarding
the presence of the OH(phenol)
⋯N(aromatic ring) synthon
present in the QUE–INA
cocrystal, as already
determined by data of
8. Screening of coformers for Fayene Zeferino Ribeiro crystalline structure and absent
quercetin cocrystals through de Souza et al in the QUE-PA cocrystal. This
mechanochemical methods is also suggested by the
thermoanalytical data, since the
thermal stability of the QUE–
PA cocrystal is lower than that
of the QUE–INA cocrystal,
being associated with the loss
of free hydroxyl groups (not
participating in hydrogen
bonds) present in the QUE–PA
system.
co-crystalpreparation
methods—mortarand
9. pestle, magnetic
Advanced Techniques in stirring, microwave, and
Preparation of Cocrystals ZalteA.G.,SaudhagarR.B. solvent evaporation—are
valuable techniques
focusedonenhancing drug
properties and pharmaceutical
formulations.
In this study,they successfully
found the compound S-52372
from natural databases by
combing computer-aided
virtual screening and an
experimental protocol, which
possess similar bioactivities to
Anti-Oxidation and Anti- FA in terms of anti-
10. Inflammatory Potency Evaluation Jiazhong Li et al. inflammatory and antioxidant
of activities in Int. J. Mol. Sci.
2021, 22, 11305 14 of 15
Ferulic Acid Derivatives Obtained
RAW264.7 cells stimulated by
through Virtual Screening
LPS, through slightly hindering
the ROS production and
impacting the expressions of
inflammatory mediators,
including iNOS, COX-2, TNF
and IL-6. In the computer
prediction, they found that S-
52372 has better water
solubility and blood–brain
barrier permeability and lower
toxicity than FA. Thus, this
compound deserves further
research for potential usage for
skin anti-inflammation and
anti-oxidation.
CHAPTER III
DRUG PROFILE
Ferulic acid:
General Description:
A phenolic acid substance, is widely distributed in the plantkingdom, especially in
the umbrella family, Ranunculaceae and Gramineae, such as Angelica , Ligusticum chuanxiong ,
Cimicifuga, rhizoma spargani and reed root , etc. Ferulic acid is often cross-linked with lignin
and polysaccharide to form part of the cell wall of plants, but its free state is rare. the structure of
FA molecule is 4-hydroxy-3-methoxycinnamic acid (C10H10O4),which has CIS and trans
structures.
Ferulic processes,and brightening component.Nonetheless, its use is limited by its
tendency to be rapidly oxidized. acid has low toxicity and possesses many physiological
functions (anti-inflammatory,anti oxidant,anti microbial lactivity,anti cancer,and anti diabetic
effect).It has been widely used in the pharmaceutical, food, and cosmetics industry. Ferulic acid
is a free radical scavenger, but also an inhibitor of enzymes that catalyze free radical generation
and an enhancer of scavenger enzyme activity.Ferulic acid has a protective role for the main skin
structures: keratinocytes, fibroblasts, collagen, elastin. It inhibits melanogenesis,
Enhance sangiogenesis,and accelerates wound healing.It is widely applied in skin care
formulations as a photoprotective agent, delayer of skin photoaging.
Structure:
IUPAC Name: (2E)-3- (4-hydroxy-3-
methoxyphenyl)prop-2-enoic acid
Category: Hydroxycinnamic acid derivative
Chemical Formula : (CH3O)HOC6H3CH=CHCO2H
Molecular Weight : 194.186 g·mol−1
Physiochemical properties:
Melting Point : 168 - 171 °C
Partition Coefficeient: 1.51
pKa : 4.58
Solubility:
Water: Limited Solubility
Ethanol:Highly Soluble
DMSO: Highly Soluble
DMF: Highly Soluble
Storage:
Ferulic acid should be stored in a cool, dry place, away from direct sunlight and heat, ideally below 25°C
(77°F). It's also important to protect it from light and maintain solutions at neutral pH, often stored in
amber-colored containers.
Mechanism of action:
Overview:
(CO–FORMER)
PABA (Para-Aminobenzoic Acid) is a compound belonging to the vitamin B complex group and
is found in foods like whole grains, eggs, and liver. It is an essential precursor to folic acid and plays
a role in the synthesis of nucleic acids. PABA has antioxidant properties, helping to protect cells
from oxidative stress. It also supports the metabolism of proteins, fats, and carbohydrates. In
addition, PABA is known for its role inskinhealthand is often used insunscreens due to its ability to
absorb UV light. Some studies suggest PABA may help treat certaintypes of skin conditions, like
vitiligo. Though generally considered safe, highdoses of PABA can cause side effects such as skin
reactions or gastrointestinal discomfort. PABA is also used in the production of folate in the body,
which is important for cell division and DNA synthesis. However, its use in sunscreens has declined
due to concerns over potential skin irritation. Despite this, it remains a subject of interest in both
dermatology and nutrition.
Structure:
IUPAC Name:4-Aminobenzoic acid
Category: Benzoic acid derivatives
Chemical Formula: C7H7NO2
Molecular Weight: 137.14 g/mo
PhysiochemicalProperties:
MeltingPoint:187ºc
PartitionCoefficient:0.83to 1.2
pKa:4.83
Solubility:
The solubility of PABA(C₇H₇NO₂) varies depending on the solvent:
Water:1.4g/Lat25°C(sparinglysoluble)
Ethanol: Freely soluble
Methanol: Highly soluble
Acetone: Moderately soluble
Ether&Chloroform: Slightly soluble
DMSO&Alkaline solutions: Highly soluble( due to ionization of the- COOH group in basic
conditions)
Storage:
To maintain the stability and effectiveness of PABA(C₇H₇NO₂),follow these storage guidelines:
1. Temperature
Store at room temperature(15–25°C).
Avoid excessive heat or freezing.
2. Protection from Light&Air
Light-sensitive:Store in a light-resistant(amber-colored)container.
Oxidation-prone:Keep tightly sealed to prevent exposure to air and moisture.
3. Moisture Control
Store in a dry environment.
Use desiccants if necessary to prevent moisture absorption.
4. Stability Considerations
Can degrade over time due to oxidation, forming a brownish colour.
In alkaline conditions, it may ionize and dissolve more easily,so pH-
controlled storage is ideal.
Pharmacokinetic Properties:
Absorption:
Well-absorbed in the small intestine after oral administration.
Distribution:
Protein Binding:Moderate protein binding(~50-60%)to albumin, affecting its
free drug availability.
Excretion:
Excreted through Urine and Liver.
Mechanism of action:
Though PABA is not considered an essential vitamin for humans, it is often classified as a vitamin B-
complex-related compound due to its involvement in coenzyme formation and protein metabolism.
It has been studied for its potential antioxidant properties, which could help protect cells from
oxidative stress. Additionally, it has been explored for therapeutic applications in conditions like
vitiligo, where it may enhance melanin production, and certain connective tissue disorders, where it
may aid in collagen synthesis and elasticity maintenance.
CHAPTER IV
AIM AND OBJECTIVE
AIM:
This Research aims to develop ferulic acid cocrystals that possess improved bioavailability
properties.
OBJECTIVE:
To formulate Ferulic acid cocrystals using PABA as Co-former
To evaluate prepared cocrystals in terms of melting points, solubility, and
oxidative properties in in-vitro.
