Mr. SUJIT S.
KALE
M. Pharm (Pharmaceutics)
SMBT College of Pharmacy, Dhamangaon
Introduction.
Co-crystals.
Co-crystals Vs. solvent.
Co-crystallization potential.
Preparation methods.
Characterization of co-crystals.
References.
The recent advances in this area have
brought the possibility to produce
pharmaceutical materials by design.
Co-crystallizationof Active Pharmaceutical
Ingredient give improved properties such as
dissolution rate and stability under high
Relative Humidity and at high temperature.
• 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.
• 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.
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.
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.
Formation of a co-crystal solid often offers
scope to transform an amorphous or hard-to-
crystallise API into a readily handled, stable
crystalline
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.
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
Grinding method
• Slurry Conversion method
Solvent
Crystal
Stirring at R.T.
Decantation Drying PXRD
SUPERCRITICAL FLUID TECHNOLOGY
STEPS INVOLVED IN FORMATION OF CO-CRYSTAL
Selection of API
Selection of co-former
Empirical and theoretical guidance
Co-crystal screening
Co-crystal characterization
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.
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.
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.
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).
Co-crystallization by slow evaporation
Crystallization in a slurry
Co-crystallization by freeze draying.
Sublimation
Liquid-assisted grinding
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
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
