CO-CRYSTALLIZATION TECHNIQUE ITS RATIONALE AND …

www.wjpps.com Vol 4, Issue 04, 2015.

1484

Ushma et al. World Journal of Pharmacy and Pharmaceutical Sciences

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

http://www.wjpps.com/


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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


https://www.google.co.in/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Eleni+Dokou%22

https://www.google.co.in/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Rehela+Gasparac%22


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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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