Co-crystalization, cocrystal

1. Mr. SUJIT S. KALE
M. Pharm (Pharmaceutics)
SMBT College of Pharmacy, Dhamangaon

2.  Introduction.
 Co-crystals.
 Co-crystals Vs. solvent.
 Co-crystallization potential.
 Preparation methods.
 Characterization of co-crystals.
 References.

3.  The recent advances in this area have
brought the possibility to produce
pharmaceutical materials by design.
 Co-crystallization of Active Pharmaceutical
Ingredient give improved properties such as
dissolution rate and stability under high
Relative Humidity and at high temperature.

4. • Out of the 40% or more NCEs being
generated, nearly 60% of them are poorly
water soluble.
• These poorly water soluble drugs having
slow drug absorption leads to inadequate
and variable bioavailability and
gastrointestinal mucosal toxicity.
• Therefore, enhancing the aqueous
solubility of poorly water soluble drugs is
a major challenge for the pharmaceutical
researchers.

5. • Pharmaceutical co-crystals can be defined as
crystalline materials comprised of an API and
stoichiometric amount of a pharmaceutically
acceptable co-crystal former., which are solids
at room temperature.
 These can be constructed through several types
of interaction including
 hydrogen bonding,
 pi-stacking, and
 van der Waals forces.
• The first known co-crystal Quinhydrone, was studied
by Friedrich Wöhler in 1844.

6. Co-crystals can be divided into:
1- Co-crystal anhydrates
2-Co-crystal hydrates (solvates)
3-Anhydrates of co-crystals of salts
4-Hydrates of co-crystals of salts.

7. ADVANTAGES OF CO-CRYSTAL
•It is a stable crystalline form as compared to
amorphous solid.
•It can enhance the solubility of poorly water
soluble drugs.
•It can also enhance the bioavailability due to
increased solubility.
•Co-crystal formation technique may be used
for purification steps.

9.  Formation of a co-crystal solid often offers
scope to transform an amorphous or hard-to-crystallise
API into a readily handled, stable
crystalline

10.  Co-formers are the most important components
of the co-crystal.
 The co-crystal formation is based on the
structure of the co-formers.
 The solubility of co-crystal is also depends on
the solubility of the co-formers.
 Some examples like ascorbic acid, gallic acid,
nicotinamide, citric acid , aglutamic acid,
histidine, urea, saccharine,
glycine,tyrosine,valine.

11. 1-SOLUTION METHODS-
 Evaporative co-crystallization
 Cooling crystallization
 Reaction crystallization
2-GRINDING METHOD
 Neat/Dry grinding method
 Liquid assisted grinding method
3-ANTISOLVENT METHOD
4-SLURRY CONVERSION METHOD
5-SUPERCRITICAL FLUID TECHNOLOGY

12. Grinding method
• Slurry Conversion method
Solvent
Crystal
Stirring at R.T.
Decantation Drying PXRD

13. SUPERCRITICAL FLUID TECHNOLOGY

14. STEPS INVOLVED IN FORMATION OF CO-CRYSTAL
 Selection of API
 Selection of co-former
 Empirical and theoretical guidance
 Co-crystal screening
 Co-crystal characterization

15.  The main difference between solvates and
co-crystals is the physical state of the
isolated pure components:
 if one component is a liquid at room
temperature, the crystals are designated as
solvates;
 if both components are solids at room
temperature, the crystals are designated as co-crystals.

16.  infrared spectroscopy.
 single crystal x-ray crystallography and powder x-ray
diffraction .
 physical properties- melting point, differential
scanning calorimetry, thermogravimetric analysis).
 pH determination.
 Percentage yield.

17.  By the co-crystallization of antifungal drug
itraconazole with 1, 4-dicarboxylic acids
(succinic acid, L-tartaric acid or L-malic acid) a
modification of the dissolution profile is
achieved compared to the amorphous form of
itraconazole.

18.  Caffein tends to form hydrates at high RH
(relative humidity) while its cocrystals with
oxalic acid or malonic acid do not have this
unwanted property (never form hydrates)
(Jones, 2009).
 A 1:1 carbamazepine/saccharin cocrystal
compared to polymorph III of carbamazepine
(Anticonvulsant Tegretol, Novartis) shows no
polymorphous behaviour and is not prone to
hydration (Morissete et al., 2007).

19. Co-crystallization by slow evaporation
 Crystallization in a slurry
Co-crystallization by freeze draying.
Sublimation
 Liquid-assisted grinding

20.  Pharmaceutical co-crystals of carbamazepine (Tegretol® )
 Pharmaceutical co-crystals of fluoxetine hydrochloride
(Prozac® )
 Pharmaceutical co-crystals of itraconazole (Sporanox® )
 Pharmaceutical co-crystals of sildenafil (Viagra® )
 Co-crystals of theophylline
 Co-crystals of aceclofenac
 Co-crystal of 5-nitrouracil
 Co-crystals of indomethacin

21.  Veerendra N, Manvi F, Shamrez Ali. M, B.
Nanjwade, Meenaxi M., New Trends in the Co-crystallization
of Active Pharmaceutical
Ingredients, Journal of Applied Pharmaceutical
Science 01 (08); 2011: 01-05
 Cooke C.L, Davey R.J. On the solubility of
saccharinate salts and co-crystals. Cryst Growth
Des 2008; 8: 3483–3485.

 Andrew V, Motherwell S, Jones W,
Pharmaceutical crystallization: Engineering a
remedy for caffeine hydration, 05(3);2004: 1013-
1021