1. The document discusses cocrystals for solubility enhancement of APIs. Cocrystals are crystalline materials made of an API and coformer in a stoichiometric ratio. 2. Several methods are described for preparing cocrystals including solvent evaporation, slurry technique, solid state grinding, and spray drying. Characterization techniques like XRD, DSC, and IR are used to analyze the cocrystals. 3. Examples demonstrate how cocrystallization can increase solubility and bioavailability of APIs like sildenafil, danazol, and aceclofenac. The "spring and parachute" concept is discussed for maintaining supersaturation of drugs to enhance absorption.

1. SHREE CHANAKYA EDUCATION SOCIETY,
INDIRA COLLEGE OF PHARMACY, PUNE
COCRYSTALS FOR SOLUBILITY ENHANCEMENT
Guided by : -
Dr. Madhur Kulkarni
Professor & HOD
( Pharmaceutics )
Presented by :
Akshada A. Kolhe
Roll No. : 06
M. Pharm 1st Year

2. CONTENTS
• Introduction
• Composition of cocrystals
• Mechanism for solubility enhancement
• Method of preparation
• Characterization of cocrystals
• Examples
• Reference

3. Introduction
• Pharmaceutical Cocrystal can be defined as “crystalline material comprised of
API and one coformers in stoichiometric ratio ( 1:1, 1:2, 1:3 etc ) which are
solid at room temperature
• Cocrystals can be used as an alternative approach based on crystal engineering
to enhance specific physiochemical and biopharmaceutical properties of API

4. 1.
• Coformer
2. • Excipient
3.
• Solvent
• API
4.
Composition of Co-Crystals

5. 1. Coformers
• Coformers are very important components for designing and screening of cocrystals
• They participate in intermolecular interactions while crystallization
• They become part of crystal structure
• Solubility of cocrystal depends on solubility of coformers
• Commonly used coformers are Nicotinamide, Ascorbic acid, Saccharin, Urea, Citric
acid, Glycine, etc.

6. 2. Excipients
• Excipients are the other formulation additives
• They are chemically inert and do not become part of crystal structure
• Examples – Fillers, Lubricating agents, Flavours, Colorants, etc
3. Solvents
• Solvent mixtures can be used to thermodynamically supress solvate formation in
solution based crystallization techniques
• Cocrystal formation depends on selection of solvent
• Examples – Methanol, Ethanol ,etc

7. Mechanism of solubility enhancement
Hydrogen bonded drug coformer cocrystals are dissociated in biological medium
After disscociation water soluble cocrystal is drawn out of crystal lattice
Hydrophobic drug molecules become supersaturated in biological medium, and this
higher energy form of drug is known as Spring
In order to get benefits from supersaturated state, it has to be maintained for a
sufficient period of time for absorption
It require fugacious inhibition of precipitation by using p’ceutical excipients that
interfere with growth of crystal , this refers to Parachute or precipitation inhibitors
This phase lasts for enough time (120-300 min) to give high dose solubility

8. The spring and parachute concept to
achieve high apparent solubility of
insoluble drugs (1) The crystalline
(stable) form has low solubility. (2) A
short lived metastable species (i.e,
amorphous phase) shows peak
solubility but quickly drops (within
minutes to an hr ) to the low solubility
of the crystalline form . (3) Highly
soluble drug forms are maintained for
a long enough time (usually hrs) in
the metastable zone.

9. Method of
preparation
Solvent
Evaporation
method
Slurry
Technique
Solid State
Grinding
Liquid
assisted
Grinding
Spray
Drying
Hot melt
Extrusion

10. Solvent Evaporation Method :
API and coformer dissolved in
solvent in stoichiometric ratio
Evaporation of solvent
Creation of hydrogen bonds
between functional groups of
API and coformer
Thermodynamically favored
cocrystals formed
Eg. : Cocrystals of Aceclofenac
containing coformer as Gallic
acid, nicotinamide and the
Bioavailability increased by 1.77
– 1.37 times

11. Slurry technique
Slurry is prepared by
addition of different
solvents in mixture of
API and suitable
coformers
Solvent is decanted
and solid material is
dried
Sildenafil co-crystallized with
acetylsalicylic acid in 1:1 molar
ratio and the dissolution rate
increased by 2 folds

12. Solid State Grinding
API and conformer in
stoichiometric amounts
They are pressed and crushed
together in mortar and pestle
or ball mill
Duration ranges from 30 – 60
min
Numerous cocrystals can be
prepared
Eg. : Cocrystals of
Theophylline containing
coformer as oxalic and
malonic acid enhances
relative humidity

13. Liquid assisted Grinding
Modification of solid state grinding by
adding little amount of solvent in mixture of
API and coformer
Solvent effect is catalytic
Enhance cocrystallization
Can be used to prepare high purity crystals
with reduction in preparation time
Allows synthesis of polymorphic form of
cocrystals

14. Hot melt Extrusion
Heating of drug and coformers with
intense mixing
Improves surface contacts without
use of solvents
Cocrystals formed
Limitation : Not suitable for
thermolabile drugs

15. Spray Drying
Solution or suspension
of drug and conformer
is sprayed with hot air
stream
Evaporation of solvents
takes place
Cocrystals are formed
Eg. : Cocrystals of
Theophylline with urea,
saccharin, and
nicotinamide

17. Examples :
1. Cocrystals of Sildenafil :
• Sildenafil co-crystallized with acetylsalicylic acid in 1:1 molar ratio under slurry method.
• In acidic conditions advantageous in case of its oral administration. The cocrystals
characterized by XRD, DSC, IR, etc.
• In case of dissolution studies which are done under Simulated gastric fluid pH 1.2 shows
the dissolution rate was increased almost two fold as compared to sildenafil citrate.
• Thermal analysis shows the melting point of cocrystals is 145 degree Celcius, but the
cocrystrals are thermodynamically stable up to 165 degree celcius.

18. 2. Danazol Cocrystals
• Cocrystals of Danazol : Vanillin (1:1) prepared to overcome solubility
issues of danazol
• Aqueous suspension , when prepared give an increase in area under
the curve by 1.7 times higher than poorly soluble crystals of danazol
• The bioavailability increased almost 10 times by preparation of
aqueous suspension

19. Reference
1. Bansal A.K, Banerjee R, Atipamula S, Biradha K; Polymarphs, salts, and
cocrystals : What’s in a name?, Crystal growth design,(2012); 2147-2152
2. Patole T, Deshpande A; Co-crystallization : A technique for solubility
enhancement, IJPSR, (2014); 3566-3576
3. Bavishi D.D, Borkhtaria C.H; Spring and Parachute: How cocrystals enhance
solubility, (2016); 1-8
4. Minishan G, Xiaojie S, Jiahui C, Ting C; Pharmaceutical cocrystals : A review
of preparations, physicochemical properties and applications, (2021); 2537-2564

20. THANK YOU