co-crystallization technique its rationale and …
TRANSCRIPT
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CO-CRYSTALLIZATION TECHNIQUE ITS RATIONALE AND
RECENT PROGRESS
Ushma Kotak*, Vipul Prajapati, Himanshu Solanki, Girish Jani and Pritesh Jha
Department of Pharmaceutics, S.S.R College of Pharmacy, Saily-Silvassa Road, U.T. of
Dadra and Nagar Haveli-396230. India.
ABSTRACT
Majority of drugs marketed world wide is administered by oral route.
Nearly 40% of the new molecular entities coming from discovery were
never brought to the market because of biopharmaceutical issues like
low solubility, low dissolution rate, low permeability and first-pass
metabolism. There are various methods to improve the
dissolution/bioavailability of poorly soluble drugs including Pro-drug
approach, Salt synthesis, and Particle size reduction, Complexation,
Change in physical form, Solid dispersions & Spray drying. Salt
formation is one of the most frequently used approaches to improve
physiochemical properties of moieties which involve formation of
ionic bonds. Co-crystallization is a method of formation of mainly
hydrogen bond between the drug molecule and co-former so API
regardless of acidic, basic, or ionisable groups could potentially be co- crystallized. Co-
crystallization can improve physiochemical properties like solubility, dissolution rate,
chemical stability and melting point. Interactions which are responsible for the formation of
co-crystals include hydrogen bonding, π-stacking, and Van der Waals forces. The article
gives a brief review on the co-crystallization, their method of synthesis, its importance as an
alternative over salt formation, Characterization and applications.
KEYWORDS: Pharmaceutical co-crystal; method of preparation; Characterization of co
crystal; Polymorphism and high order cocrystals.
INTRODUCTION
Many a times an API cannot be formulated in its pure form due to various issues of
instability. Thus they are converted to solid forms such as polymorphs, salts, solvates,
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VVoolluummee 44,, IIssssuuee 0044,, 11448844--11550088.. RReevviieeww AArrttiiccllee IISSSSNN 2278 – 4357
*Correspondence for
Author
Ushma Kotak
Department of
Pharmaceutics, S.S.R
College of Pharmacy,
Saily-Silvassa Road, U.T.
of Dadra and Nagar
Haveli-396230. India.
Article Received on
10 Fab 2015,
Revised on 05 March 2015,
Accepted on 29 March 2015
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hydrates, amorphous, and co-crystals. Each of them imparts a different physiochemical
property and affects other performance. Now a day there is most challanging situation is to
enhance solubility of certain drugs. Common problems that challenge the successful drug
delivery and manufacture include deficiencies in their properties, such as solubility, stability,
bioavailability, organoleptic properties and mechanical properties. It‟s easy to solve solubility
problem of amorphous form, But difficult for crystalline drug. This review presents the
improvement in dissolution profile of drug, bioavailability & solubility by co crystallization
technique. Co-crystals basically consists of two components that are the API and the former.
Now, the former can be any other excipient or API which when given in combination reduces
the dose and also the side effects. Co crystallization is an effective crystal engineering
approach various properties of the drug as well as modifying crystal structure. A more refined
definition of a co-crystal can be “multicomponent crystal that is formed between two
compounds that are solids under ambient conditions, where at least one component is an
acceptable molecule or ion”. Some drugs marketed in the form of racemic co crystals include:
atenolol, atropine, certirazine, disopyramide, fluoxetine, ketoprofen, loratadine, modafinil,
omeprazole, warfare and zopiclone. Pharmaceutical co-crystals are non-ionic supramolecular
complexes and can be used to address physical property issues such as solubility, stability
and bioavailability in pharmaceutical development without changing the chemical
composition of the API. This complex can be formed by several types of interaction,
including pi-stacking, hydrogen bonding, and van der Waals forces. For nonionizable
compounds co-crystals enhance pharmaceutical properties by modification of chemical
stability, mechanical behaviour, moisture uptake, solubility, dissolution rate and
bioavailability.[1, 2]
Co-crystals differ from salts in such way as, In salts a proton is transferred
from the acidic to the basic functionality of the crystallization partner, as the pKa difference
between the partners is sufficiently large. In co-crystals, no such transfer takes place. The
relationships between various solid forms are shown in (Fig.1).
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Fig.1: The relationship between various solid dosage forms
Further, co-crystals are considered advantageous in the following situations: (i) drug
molecules lacking easily ionisable functional groups (such as those containing phenol,
carboxamide, weakly basic N-heterocyclic) can be intermolecular manipulated via co-crystals
to tune their physicochemical properties, (ii) compound having particular sensitive groups to
treatment of acid and base, (iii) overcoming problems in filterability through co-crystallizing
a compound.[3]
Co-crystallization covers major areas in pharmaceutical field which are shown
in (Fig. 2).
Fig.2: Areas covered by co-crystals in various pharmaceutical fields
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THEORY
A solid can exist in two forms i.e. crystalline or amorphous. In crystalline form a solid can
exist as polymorph, hydrate, solvate, or co-crystal. Mostly we prefer to deliver crystalline
forms of active compounds mainly due to the inherent stability of crystalline materials and
the impact of crystallization processes on purification and isolation of chemical substances.[4]
Pharmaceutical co-crystal is a multiple component crystal in which at least one component is
molecular and a solid at room temperature (the co-crystal former), and forms a
supramolecular synthon with a molecule or ionic API.[5]
A brief summary of the state of the
art of pharmaceutical co-crystals is shown in (Fig. 3).[6]
Fig.3: State of art of pharmaceutical cocrystals which described individual components
in some solid dosage forms.
The difference between a co-crystal and a crystalline salt lies merely in the transfer of a
proton. Proton transfer from one component to another in a crystal is dependent on the
environment. For this reason, cocrystals and crystalline salt may be thought of as two ends of
a proton transfer spectrum, where the salt has completed the proton transfer at one end and an
absence of proton transfer exists for cocrystals at the other end. [7]
Selection of appropriate coformer and preparation of cocrystals
Fig. 4: Selection of appropriate co-former by three theories
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2.1 Supramolecular Synthon Approach
The term synthon was given by Corey in the context of organic chemistry and defined as
“structural units within super molecules which can be formed and/or assembled by known or
conceivable intermolecular interactions”. It‟s a pattern that is composed of molecular and
supramolecular elements. In crystal structure when crystal patterns repeat regularly, the
pattern of interactions can be called a supramolecular synthon.
Supramolecular synthons are further divided into
(a) Supramolecular Homosynthon: Made up of identical self-complementary functionalities
(b) Supramolecular Heterosynthon: Made up of different but complementary functionalist.
Fig.5: Type of supramolecular synthons
2.2. Hansen Solubility Parameter (HSPs)
Hansen Solubility Parameter is used for prediction of Miscibility of a drug and coformer.
Predicting the miscibility of cocrystal components using solubility parameters can help the
selection of potential coformer prior to exhaustive cocrystal screening work. HSPs could
predict the compatibility of pharmaceutical materials, and their use is recommended as a tool
in the pre-formulation and formulation development of tablets. It is widely used to predict
liquid–liquid miscibility, miscibility of polymer blends, surface wettability, and the
adsorption of pigments to surfaces. The cohesive energy (solubility parameter) is the sum of
the forces i.e. covalent bonds, van der Waals interactions, ionic bonds and hydrogen bonds
which hold the material intact. Solubility parameter i.e. cohesive energy per unit volume is
termed the cohesive energy density (CED). It can be used to calculate the solubility
parameter (δ) based on regular solution theory restricted to non-polar systems, as follows.
δ = (CED) 0.5
= (ΔEv/Vm) 0.5
(1)
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Where EV is the energy of vaporization, Vm is the molar volume, δ is measured in units of
(J/cm3)0.5
or (cal/cm3)0.5
.
HSP proposed that the total force of the various interactions can be divided into partial
solubility parameters, i.e. dispersion (δd), polar (δp) and hydrogen bonding (δh). These partial
solubility parameters represent the possibility of intermolecular interactions between similar
or different molecules. The total solubility parameter (δt), also called the three-dimensional
solubility parameter, can be defined as follows.
δt = (δ2
d+ δ2
p + δ2
h)0.5
(2)
Various methods have been used to estimate the HSPs of a material such as various
theoretical and experimental methods based on solubility, calorimetry, sublimation,
vaporization, inverse gas chromatography and group contribution methods.
2.3. Cambridge Structural Database (CSD)
CSD is a depot for small molecule crystal structures. Pharmaceutical scientist use single-
crystal x-ray crystallography to determine the crystal structure of a compound. As the
structure is solved, information about the structure is saved but in CSD scientists can search
and retrieve structures from the database. They can use the CSD to compare existing data
with that obtained from crystals grown in their laboratories. This information can also be
used to visualize the structure in a variety of software such as atoms, powder cell etc.
Particularly this is important for analytical reasons because it facilitates the identification of
phases present in a crystalline powder mixture without the need for growing crystals.
2. SALT VERSUS CO-CRYSTAL FORMATION
Co-crystal and salts may sometimes be confused. The understanding of the fundamental
difference between a salt formation and a co-crystal is very important to both pre-formulation
activities and chemical/pharmaceutical development aspects. Indeed, salts and co-crystals can
be considered as opposite ends of multi-component structures.[8-10]
Salts are often chosen
instead of the free acid or base as these can improve crystallinity, solubility and stability of a
pharmaceutical compound. Co-crystals are used an alternative to salts when these do not have
the appropriate solid state properties or cannot be formed because of the absence of ionizable
sites in the API. Salt formation involves acid–base reaction between the API and an acidic or
basic substance. The widespread use of salt formation is evidenced by the large number of
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marketed crystalline salts of APIs.[11, 12]
Salt formation is a three component system having an
acid (A), a base (B) and one or more solvents. A salt is formed by transfer of a proton (H+)
from an acid (A) to base (B).
A-H + B → (A-) (B
+- H) (3)
Proton transfer is thought to mainly depend on the pKa values of the components. When there
is no such transfer and the components are instead present in the crystal as neutral entities,
the product is generally defined as a co-crystal. In other words, a co-crystal is an A-B
composite in which no proton transfer occurred.[13]
Salt formation includes acid–base reaction between the API and an acidic or basic substance.
Large numbers of crystalline salts of APIs are available in market. The formation of a salt or
co-crystal can be predicted from pKa value of acid (A) and a base (B). Salt formation
generally requires a difference of about 2.7 pKa units between the conjugate base and the
conjugate acid (A) i.e. [pKa (base) - pKa (acid) ≥ 2.7]. For example, succinic acid having pKa
4.2 form co-crystal with urea base (pKa 0.1) while succinic acid form salt with L-lysine base
having pKa9.5.Generally base pKa values are not sufficiently high to allow proton transfer
when co-crystal is formed. The output of co crystal and salt as co crystal Hydrate and Salt co-
crystal Hydrate is shown in (Fig. 6).
Fig. 6: The output of co crystal and salt as co crystal Hydrate and Salt co-crystal
Hydrate
Certain drug may give different output of solubility, dissolution & Bioavailability by
changing co-former of same drug. Table 1 shows certain problems of drug & overcome
techniques of these problems.[14- 27]
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Table 1: Drug, Biopharmaceutical problem & overcome techniques of those problems.
Ref
eren
ce
14,1
5,1
6
17
18
19
20
21
22
23
24
25
26
27
Met
hod
to O
ver
com
e p
rob
lem
Solu
tion C
o-c
ryst
alli
zati
on
Slu
rry C
on
ver
sion
Liq
uid
ass
iste
d g
rindin
g
Cry
stal
liza
tion f
rom
Mel
t
Solv
ent
Evap
oura
tion &
Slu
rry T
ech
niq
ue
Solv
ent
Evap
oura
tion,
Nea
t G
rindin
g,
Co
-
gri
ndin
g
Anti
solv
ent
Addit
ion
Slu
rry C
on
ver
sion
Solv
ent
evap
ora
tion m
ethod
Solv
ent
dro
p
gri
ndin
g
wit
h
met
han
ol
&
acet
onit
rile
Solv
ent
gri
ndin
g m
ethod
Flu
xet
ine
Hydro
chlo
ride
was
co
-cry
stal
lize
d
wit
h b
enzo
ic a
cid
(1:1
), S
ucc
inic
Aci
d (
2:1
)
via
tra
dit
ional
ev
apora
tio
n m
ethod.
In c
ase
of
fluoxet
ine
HC
L:
Succ
inic
ac
id
show
s tw
o
fold
incr
ease
in a
queo
us
solu
bil
ity
reac
tion c
ryst
alli
zati
on m
ethod
Wit
h L
-Tar
tric
aci
d (
1:1
) S
olu
tion a
nd
solv
ent
dro
p g
rindin
g m
ethod
wit
h c
itri
c ac
id (
3:2
) S
olv
ent
dro
p
gri
ndin
g a
nd s
olv
oth
erm
al m
ethod
wit
h M
andel
ic a
cid (
2:1
) S
olv
ent
dro
p g
rindin
g
& s
lurr
y m
ethod
W
ith p
ropio
nic
aci
d (
1:1
) so
luti
on m
ethod
Pro
ble
m
Low
Aqueo
us
Solu
bil
ity &
B.A
Low
E
ffic
acy &
B.A
Low
solu
bil
ity
Low
Abso
rpti
on i
n
Body
Low
wat
er
solu
bil
ity &
Dis
solu
tion l
imit
ed
B.A
Pra
ctic
ally
inso
luble
in w
ater
Low
Solu
bil
ity
Low
Solu
bil
ity
Sal
t fo
rm o
f dru
g
show
s dif
fere
nt
dis
solu
tion p
rofi
le
Low
Solu
bil
ity
Low
Solu
bil
ity
Cate
gory
Anti
-Infa
lmm
atory
,
Anal
ges
ic &
Anti
pyre
tic
Anti
-Mal
aria
l
Anti
fungal
Anti
epil
epti
c
NS
AID
Anti
-HIV
Anti
ret
ro v
iral
Anti
dep
ress
ant
CN
S s
tim
ula
nt
Psy
chost
imula
nt
CN
S s
tim
ula
nt
Dru
g
Ace
clofe
nac
&
Par
acet
amol
Art
esunat
e &
Nic
oti
nam
ide
Tad
anaf
il
Itra
con
azole
Car
bam
azep
ne
Indom
ethac
ine
Did
anosi
ne
&
Aro
mat
ic d
rug
(Ben
zoic
aci
d &
Sal
icyli
c ac
id)
Rit
onav
ir
Flu
xet
ine
Hydro
chlo
ride
Theo
phyll
ine
&
Nic
oti
nam
ide
Pir
acet
am
Caf
fein
e
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4. METHOD[28, 29]
4.1. Solvent evaporation
Solvent evaporation is the most conventional method in case of crystallization. In this
technique the all material is mixed with the common solvent serially and evaporated
completely. During evaporation stage the solution of molecules are expected to undergo
various hydrogen bonding reactions. But in case of co-crystallization which consists of
coformer and active ingredient, solubility of both in the selected solvent plays a great role. If
the solubility of both is not similar, then the one with low solubility than the other will
precipitate out. Molecule has ability to participate in the intermolecular interaction to form a
co-crystal. The major disadvantage of this method is that it requires large amount of solvent.
Example- Patent on Co-crystallization of Fluoxetine HCl and Benzoic Acid as reported in
Table 2.[30]
4.2. Grinding
Solid state grinding is where the materials are mixed, pressed and crushed in a mortar and
pestle. We can also crush in mill. This technique provides particle size reduction but in case
of co-crystallization these have proved to be a viable method for solid-state grinding along
with liquid state grinding. Many co-crystal materials can be prepared from both solid state
grinding and solution growth. Failure to form product of co-crystals by grinding may be due
to an inability to generate suitable co-crystal arrangements rather than due to the stability of
the initial phases. Although co-crystal formation by solid-state grinding has been established
for some time and in late 19th
century report solid state grinding is often cited as reference to
such a procedure. Now a day the recent technique of adding small amounts of solvent during
the grinding process has been shown to enhance the kinetics and facilitate co-crystal
formation and as lead to increased solid-state grinding as a method for co-crystal preparation.
Example- Paten on Co-crystallization of pterostilbene: Caffeine reported in Table 2.
4.2.1 Slurring
Slurry crystallization is simple process which includes the addition of crystallization solvent
in the API along with its acceptable former. The selection of this process is mainly depends
upon the physical stability of the crystallization solution to co crystals and its solid former or
a solid compound dissolved in solvent to form a solution. A solid coformer is added to the
solution, the suspension is stirred until the formation of cocrystal is complete. In some cases,
aliquots of Antisolvent may subsequently be added to the solution. Solid formed in the
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solution re filtered and dried. The solid is cocrystal of compound and coformer. While
preparation of co crystals for Trimethoprim and sulfamethoxazole through slurry technique
simple distilled water is used as solvent. The major disadvantage of this method is that the
yield obtained was not sufficient as compared with solvent drop grinding method.[32]
Example- Patent on Co crystals of celecoxib & venlafaxine (1:1) in Table 2.
4.2.2 Solvent drop grinding
Modification of solid grinding technique is this technique where two materials can be grinded
by adding a minor quantity of solvent. The criteria of this technique being the solvent added
is in very minute quantity which when added acts as a catalyst but does not form a part of the
end product. The usefulness of solvent-drop grinding was first demonstrated in the context of
co-crystallization rate enhancement in a system involving several co crystals of nitrogenous
bases with a cyclohexane tricarboxylic acid derivative, all of which were initially prepared by
solution growth. It was found that some co crystals could be readily prepared by solid-state
grinding, whereas others exhibited only minor co crystal content after grinding together
starting materials for a significant time. For those that did not proceed to completion upon
solid-state grinding, it was found that solvent-drop grinding could be used to prepare an
essentially phase-pure co crystal material after significantly reduced periods of time.
Example-Patent on Cocrystal of Pterostilbene and Carbamazepine by solvent drop or solvent
assisted grinding as in Table 2.
4.3 Antisolvent addition
This is one of the methods for precipitation or recrystalization of the co-crystal former and
active pharmaceutical ingredient. Solvents include buffers (pH) and organic solvents. Let we
take an example preparation of co-crystals of aceclofenac using chitosan, here coformer
solution i.e. chitosan solution was prepared by soaking chitosan in glacial acetic acid. A
weighed amount of the drug was dispersed in chitosan solution by using high dispersion
homogenizer. The prepared dispersion was added to distilled water or sodium citrate solution
to precipitate chitosan on drug.
Example- Patent on Preparation of VX-950 and 4-hydroxybenzoic acid co-crystal by
crystallization from dichloromethane, tetrahydrofuran and n-heptane solution using an anti-
solvent addition process.
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4.4. Supercritical fluid atomization process[36]
Supercritical fluids use offers additional advantages compared to the other co-crystal
production methods. Co-crystallization by supercritical solvent (CSS) is a method where an
API and a co-crystal former are mixed together by magnetic stirring after being pressurized
by supercritical CO2 in a high-pressure vessel. The Supercritical Anti-Solvent (SAS)
technique explores the anti-solvent effect of supercritical CO2 to precipitate particles (co-
crystals) from solutions; the supercritical fluid enhanced atomization SEA technique explores
essentially the CO2 atomization enhancement in a spray drying process. Theophylline-
saccharin co-crystal new form with a 1:2 stoichiometry was obtained by the supercritical
fluid enhanced atomization process method that has not been previously reported by
traditional screening methods. [37]
Pure co-crystals of itraconazole: malic acid was produced
using either supercritical CO2 or a traditional liquid solvent, such as n-heptane and were
confirmed by both XRD and DSC.[38]
Phase transformation during processing affect the
mechanism of conversion of crystalline drugs to co-crystal.[39]
Example- Patent on Co-crystallization of carbamazepine and acetyl salicylic acid (aspirin) by
supercritical Antisolvent as in Table 2.
4.5. Hot melt extrusion
Extrusion is useful method for synthesis of cocrystals, it involves highly efficient mixing and
improved surface contacts, Cocrystals are prepared without use of solvent. The selection of
this method primarily depends on thermodynamic stability of compound. This method was
studied with the use of four models for cocrystal formation. Solvent drop extrusion technique
used to optimize and make the process more flexible. Solvent drop extrusion technique gives
an advantage to carry out process at lower temperature. Hot melt extrusion method was used
in synthesis of Carbamazepine-nicotinamide cocrystals with polymer as former. Continuous
co-crystallization, API and coformer poured in the twin extruder. As a result of continuous
addition of mixture the barrel temperature also increases.[41]
Example- Patent on Cocrystals of sorbitol and mannitol by hot melt extrusion.
4.6. Sonocrystallization Method
The development of sonochemical method for preparation of organic cocrystals of very finite
size has been done. This method was primarily developed for preparation of nanocrystals.
Caffeine- maleic acid cocrystal preparation commenced with use of ultrasound method. The
comparative study of method of preparation of caffeine and theophylline as API and L-
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tartaric acid as coformer by Solvent drop grinding method and sonochemical method has
been commenced. The results of methods were consistent hence sonocrystallization proves to
be a significant approach.[43]
Example- Patent on Co-crustal of fluoxetine HCL & benzoic acid in acetonitrile by
sonication.
4.7. High throughput co-crystallization
High throughput crystallization includes three steps: designing of experiment, execution of
protocol and analysis of data. The design of experiments includes hardware and software.
These enable to analyze the data, drive conclusions, store them and retrieve them when
required. Thought this high throughput screening has already made a mark in pharmaceutical
industry, its existence in case of drug discovery especially in the solid screening area is
emerging. Hence it is important to distinguish both of them. The main goal of HT screening
is to get a small number of successful outcomes, which are then passed on to the next stage of
development. Little effort is typically made to learn why certain outcomes were positive and
why others were negative. While in HT experimentation, such as HT crystallization, is
carried out with the goal of having each point in the experiment produce multiple types of
data that can be interpreted, and the interpretation used to guide the experimental process to a
successful conclusion. Second, unlike traditional HT screening assays where experiments are
generally conducted under constant experimental conditions, HT crystallization experiments
for solid form discovery are best conducted using a variety of process methods, each having
varying experimental conditions (e.g., temperature variations as a function of time) over the
course of the experiment. HT crystallization experiments can yield hit rates ranging from tens
of percents to nearly 100%, depending on the type of experiment and the process mode(s)
used. A fully integrated HT crystallization system consists of a number of components,
including experimental design and handling hardware, robotic dispensing and execution
software, automated high speed micro-analytical tools, end-to-end sample tracking and
integrated cheminformatics analysis software for data visualization, modeling and mining.[45]
Example- Patent on High throughput screening of crystallization of materials.
4.8. By using intermediate phase
Using intermediate phases to synthesize these solid-state compounds are also employed. By
use of a hydrate or an amorphous phase as an intermediate during synthesis in a solid-state
route has proven to be successful in forming a cocrystal. We can also employ a metastable
polymorphic form of one cocrystal former. In this method, the metastable form acts as an
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unstable intermediate on the nucleation pathway to a cocrystal. As always, a clear connection
between pair wise components of the cocrystal is needed in addition to the thermodynamic
requirements in order to form these compounds. The most common formation methods are
based on solution and grinding method. Among two, first one is most important due to
formation of crystal by such method shows single X-ray diffraction testing (SXRD). Solution
method includes reaction crystallisation method, evaporation of a heterometric solution
method & cooling crystallisation. Grinding method includes neat grinding & solvent drop
grinding. Apart from solution method and grinding methods, there are also other newly
emerging methods, such as co-crystallisation using supercritical fluid, hot stage microscopy,
and ultrasound assisted co-crystallisation.
Example- Patent on Preparation of choline hydrogen diacid cocrystal of Epalrestat.
Table 2- Patent of certain drug on the basis of various methods.
5. Characterization of Co-crystals[48- 54]
Characterization of cocrystal is of almost importance and there are different analytical
methods ranging from simple melting point determination to complete structural
determination through single crystal X-ray crystallography method. Other methods like
studying the morphology of crystals by microscopic methods, observing changes in crystal
forms with temperature, interpreting molecular motion, phase transition by thermal methods,
Patent office Patent number Inventor Description Date of issue Reference
United state US 8350085 Childs Scott L.
(Atlanta, GA)
Co crystallization of Fluoxetine HCl
and Benzoic Acid
January 8
2013 30
United state US 8399712B2
Nathan C
Schultheiss
(LafayetteUS)
Co Crystals of pterostilbene and
caffeine by grinding
March 19
2013 31
European EP20100801141 Salman Carlos
Ramon Planta
Cocrystal of celecoxib &
venlafaxine by slurring
October 31
2012 33
United state US 8513236B2
Nathan. C
Schultheiss
(Lafayette IN US)
Co crystals of pterostilbene and
carbamazepine
August 20
2013 34
European EP 2323622 A1 Eleni Dokou,
Rehela Gasparac
Preparation of VX-950 and 4-
hydroxybenzoic acid co-crystal by
anti-solvent addition process
May 25
2011 35
United state US20080280858A1 Mazen hanna
Co-crystal of carbamazepine and
acetyl salicylic acid (aspirin) by
supercritical Antisolvent
November 13
2008 40
United state US5023092 James W, fuRoss Cocrystals of sorbitol and mannitol
by hot melt extrusion
June 11
1991 42
European EP 2292585A1 Childs, scott.L
Atlanta
cocrystals of fluoxetine HCL &
benzoic acid by sonication
March 9
2011 44
United state US7670429B2 Stephen R. Quake High throughput screening of
materials
March 2
2010 46
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and chemical environment by the use of vibrational spectroscopy and solid state NMR are
used.
5.1. Solubility
Co-crystallization is a technique most frequently used when the main aim is to enhance the
solubility. Thus the co-crystals usually increase the solubility which is not possible in case if
single molecule.
5.2. Maximum wavelength
When the co-crystal solution is allowed for UV scan the scan gives the peak showing
maximum wavelength of the API. If the conformer is also an API the scan will show two
peaks of lambda max of both the API.
5.3. Stability
Stability is an important parameter to be considered for any formulation. Hence in case of
cocrystals it is also important to ensure the chemical stability, solution stability, thermal
stability and relative humidity. The relative humidity of the cocrystals can be analysed by
water absorption/desorption experiments.
5.4. Crystallographic methods
Crystallographic methods include both single crystal X-ray diffraction as well as powder X-
ray diffraction. The single crystal X-ray diffraction study can provide unambiguous atomic
positions and complete structural information, but obtaining a single crystal suitable for this
study becomes restricted access. In such cases, powder X-ray diffraction studies using
microcrystalline samples become a key tool. In did it have become routine to take powder
diffractograms to ascertain the solid state nature and purity of every batch of synthetic drugs.
An x-ray powder diffractometer works on the principle of keeping the wavelength constant
and varying the angle of incidence. This is due to the fact that not all the molecules in the
sample will be in the same orientation. By keeping the wavelength constant and varying the
angle at which the beam “hits” the sample there is a greater chance that most, if not all, of the
reflections which obey the Bragg equation will be detected.
5.5. Differential Scanning Calorimetry (DSC)
DSC studies the change in heat flow between the sample and a reference. The pans used in
DSC are usually aluminium and only a few milligrams of sample are required. The data is
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laid out on a plot of temperature (x-axis) against heat flow (W/g) (y-axis). The plot appears as
a continuous line with peaks corresponding to endothermic processes and exothermic
processes occurring in opposing directions. DSC can be used to obtain information about the
melting point of a compound as well as any glass transitions, heats of fusion and levels of
crystallinity.
5.6. Thermal analysis
The third important method, which is widely used in pharmaceutical industries for
characterization of polymorphism, purity, salvation, degradation and drug compatibility, is
thermal analysis, which includes Thermogravimetry, Differential Thermal Analysis (DTA).
5.7. Vibrational spectroscopy
The study of molecular motions by use of vibrational spectroscopy is also sometimes
employed in the characterization of polymorphs. This method includes infrared absorption
spectroscopy and Raman spectroscopy.
5.8. Nuclear magnetic resonance
Nowadays solid state NMR is also used for characterization. NMR studies give the chemical
environment of the nuclei which is different in polymorphs because of magnetic non-
equivalence. NMR peaks for the magnetically non-equivalent nuclei will differ in different
polymorphs and can yield very useful information.
5.9. Scanning electron microscopy
Scanning electron microscopy (SEM) was conducted to characterize the surface morphology
of the particles with excellent ease and efficiency. SEM differs from other electron
microscope wherein the image is duly obtained right from the electrons that are strategically
emitted by surface of an object in comparison to the transmitted electrons.
5.10. Melting point
Melting point is an important characteristic of all solids. High melting points are usually
considered to be beneficial. Some times they can contribute to poor solubility and be as
problematic as low melting points that are known to hinder the processing, drying, and
stability of the material. For salts, the enhancement of solubility is obtained primarily due to
the ionization effect. For cocrystals and polymorphs, on the other hand, the role of the
crystalline lattice energy and, consequently, the melting point are of particular importance.
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6. RECENT PROGRESS IN CO-CRYSTAL
The future of co-crystallization research will significantly benefit from the discovery of new
synthons, which are structural units for building a crystal when the ability in crystal structure
design and prediction improves, the high throughput approach will be gradually
marginalized. However, the diverse crystallization conditions provided by high-throughput
screening experiments sometimes lead to exciting serendipitous discoveries.
6.1. Polymorphism of cocrystal
One proposed advantage concerning co-crystallization is their lower tendency to
polymorphism than respective conformers[55, 56]
. However, such a proposition was merely
speculated based on a selected set of compounds. Just like salts, cocrystal can also exhibit
polymorphism. In some cases, it may be possible that a cocrystal may exhibit more complex
polymorphism than individual coformers because of a larger number of possible spatial
arrangements of multiple molecules in the crystal. An increasing number of polymorphic
cocrystals have been discovered in recent years [57-59]
, some of which are trimorphic. Whether
the coformers or the cocrystal is more polymorphic depends on which one gives higher
structural flexibility when crystallizing. Thus, tendency to polymorphism is linked to the total
number of energy minima readily accessed by molecules but not to whether the crystal is
composed of single or multiple components. In this context, it is advisable to screen,
characterize and control polymorphs of a drug cocrystal similar to that for single component
polymorphs.[60]
6.2. Higher-order cocrystals
The screening of cocrystals for an API is usually targeted for two component crystals, that is,
the drug and one coformer. The formation of hydrates or solvates, sometimes serendipitously,
of two component cocrystals suggest the possibility of preparing ternary[61, 62]
quaternary and
possibly even higher-order cocrystals. Such structures can, in theory, significantly expand the
solid-state landscape of drugs. However, research in this direction is still in the nascent step.
One strategy is based on hydrogen bonding preference, where a ditopic base with two
potential H-bond accepting sites to react with two acids of different strengths. A ternary
cocrystal is formed when the stronger H-bond donor in the acid interacts with the stronger
hydrogen bond acceptor site in the base and the weaker donor (acid) interacts with the weaker
H-bond acceptor site.[63]
Another design strategy is to replace a weakly bonding molecule in a
binary cocrystal with a molecular mimic. When a molecule in a binary cocrystal does not
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interact strongly with other molecules, that is, space filler, another molecule that is similar in
size and shape can replace it to form a ternary cocrystal without significantly disrupting the
crystal structure.[64]
6.3. Salt cocrystals
The charge-facilitated strong H-bonds hold the potential for preparing cocrystals between a
Conjugated Acid Base (CAB) pair.[65]
Wide applicability of this approach in API cocrystal
design is expected in light of the recent examples of salt formation of molecules that had been
traditionally thought as non-ionizable.[66]
Unlike the cocrystals formed with a chemically
distinct neutral coformer, CAB cocrystals of an API have the advantages of high potency.
This will likely favour the formulation and manufacturing of drug products because of the
extra formulation space available to excipients when delivering a desired dose. One example
is the valproate hemi sodium salt.[67, 68]
Other possible examples likely come from CAB
cocrystals between hygroscopic salts. For example HCl and sodium salts, and corresponding
neutral bases or acids. Typical API CAB cocrystals require the presence of both neutral and
ionized drug molecules in the crystal structure. In absence of crystal structure data vibrational
spectroscopy can be used to identify the formation of CAB cocrystals since spectroscopic
signatures of both the neutral molecule and salts can be observed, though with slight
modifications due to the hydrogen-bonding interactions between them.[69]
The CAB
cocrystals of an API should not be confused with cocrystals where coformer, instead of the
API, is present in both ionic and neutral forms in the cocrystal.[70, 71]
Moreover, CAB
cocrystal should also be distinguished from cocrystals between neutral molecules and
inorganic salts.[72, 73]
6.4. Other aspects
It has been known that chemical impurities can act as nucleation and growth inhibitors and
hence promoting the formation of stable glasses.[74]
Studies on vitrification of cocrystal melts
may yield interesting insights that help to better understand the crystallization of organic
molecules since one coformer is effectively a chemical impurity to the other. It is likely that
cocrystal glasses are more resistant to crystallization than the pure drug in general. When
cocrystal glasses are used for drug delivery, the mechanical properties of cocrystal glasses are
of importance because the solubility advantage of amorphous glasses can be realized only for
oral solid dosage forms. The unintended cocrystal formation during formulation[75]
and
storage[76]
is another topic of pharmaceutical importance. A common feature among examples
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of unintended co-crystallization is the phase transition mediated by a liquid phase, either
water or formulation vehicle. Water may come from the deliquescence or dehydration of one
of the formulation components during storage[77]
in the same way, cocrystal
disproportionation may also occur when a liquid phase is present during the life time of a
cocrystal. Both problems can be avoided by implementing proper strategies, for example
protective packaging, to isolate drug product from liquids. Thermodynamics of co-
crystallization is another direction that is important for a clear understanding of cocrystals. In
addition solubility phase diagram, the direct measurement of enthalpy of co-crystallization is
expected to play an important role in this direction since it is required for deriving free energy
of co-crystallization.[78]
Finally, as a key element for achieving the ultimate goal of in silicon
design of new cocrystal with desired pharmaceutical properties, computational cocrystal
screening and structure prediction will continue to advance following the recent significant
progress.[79,80]
A more rewarding direction is likely the development of reliable computational
methods capable of yielding accurate relative lattice energy.
CONCLUSION
Drugs in the pharmaceutical industry can always be improved and one of the options of
Pharma industry is to use co-crystals for enhanced solubility, stability, dissolution rate and
bioavailability with respect to the development of APIs. A pharmaceutical co-crystal might
also be used to isolate or purify an API during manufacturing and the co-crystal former may
be recycled. Further APIs, which are obtained only in the amorphous form, perhaps
crystallized as co-crystals. Co-crystallization can also be used for chiral resolution. From
physical properties outlook, a key benefit of co-crystals is the possibility of achieving the
high dissolution rate comparable to that of the amorphous form, whereas maintaining the
long-term chemical and physical stability. The major challenge with this technology lies in
the selection of a suitable cocrystal former. Cocrystal approach is also an opportunity for the
research based pharmaceutical companies to expand their intellectual property portfolios. Co-
crystals are new aspect for pharmaceutical industries and provides new ideas to deal with
weakly soluble drugs. Co-crystals have the potential to be much more useful in
pharmaceutical product than solvates or hydrates. Future research also focused on the scale-
up of co-crystal system and implement manufacturing of final dosage form on commercial
scale. Studies regarding polymorphism of cocrystals provide stringent in order to accelerate
the development of new pharmaceuticals. A future challenging aspect is related to the
development of efficient co-crystals screening technologies. This can be achieved by
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implementation of solid based techniques need grinding and liquid assisted grinding. A key
advantage of co-crystal as a solid form of API is possibility of achieving the high dissolution
rate comparable to that of amorphous form. Future advancement in cocrystal research will
occur in the areas of cocrystal polymorphism, higher-order cocrystal, salt cocrystal and glassy
cocrystal.
ACKNOWLEDGEMENT
I express my benevolent thanks to my reverend guide Mr. V D Prajapati for giving excellent
guidance, Principal Dr. G K Jani for making available facility needed for my work, Librarian
Mr. M S Chunara for allowing me to enhance my intellectual ability by using library facility.
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