This document discusses co-crystals, which are crystalline materials composed of two or more components in the same crystal lattice. It outlines several advantages of co-crystals such as increased stability and solubility compared to amorphous forms. Common preparation methods include solution methods, grinding, and antisolvent techniques. Key characterization techniques are X-ray powder diffraction, infrared spectroscopy, and solubility analysis. Several marketed drug formulations utilizing co-crystals are also mentioned.

1. Presented by
Kritika Nayak
NIPERAPHD2015PE01
Co-Crystal

2. Flow of Presentation
 Introduction
 Advantages
 Preparation Methods
 Characterization Techniques
 Marketed Formulations
 Reference
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3. Similarity between Co-Crystal and
Eutectic Mixture
3
 Non-Covalent Derivatives
 Made up of two or more components but at end,
homogenous
 Both lack long range order ( Co-Crystal has short
range order)

4. Difference between Co-Crystal and
Eutectic mixture
Co-Crystal Eutectic Mixture
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 Enthalpy advantage
outweighs Entropy Loss
 Necessarily Crystalline
 Primary supramolecular
growth units should be at
least 3 molecules long for
co-crystal to form
 When NCD with crystal
packing shape
compatibility found
 Entropy Gain outweighs
Enthalpy loss
 Not necessary
 Primary supramolecular
growth unit is restricted
to finite heterodimer
 When NCD but without
packing shape
compatibility
NCD = Non-covalent derivative

5. 5
 Contains two eutectic
points and a region of
cocrystal at the
maximum between the
two eutectic points. This
results in a typical W-
shaped phase diagram
 DSC thermal data for
eutectic mixtures results
in a classic V shape
where the minimum
point of the V
represents the molar
ratio and temperature at
the eutectic point

6. 6
Typical DSC
Thermogram of Co-
crystal
Typical DSC
Thermogram of
Eutectic mixture

7. Spring Parachute Effect
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8. 8
 Drug absorbed when it is in supersaturated
solution form
 Supersaturation leads to higher absorption
 Supersaturation leads to Precipitation
(Recrystallization) of drug
 As supersaturation disappear, drug absorption
decreased
 This is called “Spring Effect”

9. 9
 Precipitation inhibitors are used to delay
precipitation
 Leads to longer supersaturation, thus prolonged
absorption of drug
 Drug absorption decreases with time but very
slowly
 This is called “Parachute Effect”

10. 10
 Precipitation inhibitors: Polymers (PVP,HPC,
HPMC, PEG etc)
 They did by hampering nucleation and crystal
growth
 Surfactants (SDS, labrafil etc) by micellar
formation
 Some increases drug solubility, enhance
dissolution rate

11. 11

12. Co-crystal
 No Proper Definition, Persist in knowledge but ill
studied
 By FDA Draft guidiline 2011, these are “Solids
that are crystalline materials composed of two or
more molecules in the same crystal lattice”
 Sometimes named as molecular complex
 Nonionic supramolecular complex
 Crystalline material comprised of API with co-
crystal formers (solid at room temperature)
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13.  Multiple component crystalline solid formed in a
stoichiometric ratio between two compounds that
are crystalline solids under ambient conditions
 The first known co-crystal Quinhydrone, was
studied by Friedrich Wöhler in 1844
 Can be divided into
 Anhydrates of co-crystal
 Hydrates (Solvates) of co-crystal
 Anhydrates of co-crystals of salts
 Hydrates (Solvates) of co-crystal of salts
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14. 14

15. Advantages
 Stable crystalline form as compared to
amorphous form
 Give increased solubility; thus increased
bioavailability
 Technique can be used for purification
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16. 16
Components
API
Co-crystal
coformer

17. Co-crystal coformers
 Most important for co-crystal formation
 Its structure dictate structure of co-crystal
 Also dictate solubility
 Differ from Excipient
 Example: ascorbic acid, gallic acid, nicotinamide,
citric acid, aglutamic acid, histidine, urea,
saccharine, glycine, tyrosine, valine
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18. Difference between Excipient and
Co-crystal coformer
Excipient Co-crystal coformer
 Supposed to be
chemically inert
 Do not become the
part of the crystal
structure
 Involved in final
dosage form
 Participate in
intermolecular
interaction
 Become part of co-
crystal structure
 They need further
processing steps to
be in final dosage
form
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19. Solvents
 Also important component
 Co-crystal formation depend upon selection of
solvent
 Solubility of drug and co-former is considered
while selection of solvent
 Example: ethanol, methanol, acetonitrile and
others organic solvents
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20. Method of Co-crystal preparation
o SOLUTION METHODS
 Evaporative co-crystallization
 Cooling crystallization
o GRINDING METHOD
 Neat/Dry grinding method
 Liquid assisted grinding method
o ANTISOLVENT METHOD
o SLURRY CONVERSION METHOD
o SUPERCRITICAL FLUID TECHNOLOGY
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21. Steps involved in Preparation
 Selection of API
 Selection of co-former
 Empirical and theoretical guidance
 Co-crystal screening
 Co-crystal characterization
 Co-crystal performance
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22.  Synthon: Part/constituent of API and Coformer
involved in intermolecular interaction
 Synthons exist in two distinct categories:
 Supramolecular Homo- synthons that are
composed of identical complementary functional
groups such as carboxylic acid dimers (aspirin)
 Supramolecular Hetero- synthons composed of
different but complementary functional groups
such as acid–weakly basic nitrogen (aspirin–
meloxicam) and acid–amide (aspirin–
carbamazepine)
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23. 23

24. Flowchart for choosing Co-crystal candidate
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25. Evaluation Methods
 PXRD (Powder X-rays diffraction study)
 IR- Spectroscopic
 Scanning Electron Microscope
 Percentage Yield
 Determination Of Melting Point
 Solubility Analysis
 Compatibility Studies (IR Spectroscopy)
 In vitro drug release studies
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26. Marketed formulation
 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-crystal of melamine and cyanuric acid
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27.  Co-crystals of theophylline
 Co-crystals of aceclofenac
 Co-crystal of 5-nitrouracil
 Co-crystals of indomethacin
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28. Reference
• Alsenz, J., et. al. 2012. The Impact of Solubility and
Dissolution Assessment on Formulation Strategy and
implications for oral drug disposition. Encyclopedia of
Drug Metabolism and Interactions. 1-53.
• Aitipamula, S., et. al. 2012. Polymorphs, salts and co-
crystals: What’s in the name?. Cryst. Growth &
Design. 12. 2147-2152.
• Schultheiss, N., et. al. 2009. Cocrystals:
Pharmaceutical cocrystals and their physicochemical
properties. Cryst. Growth and Design. 9. 2950-2967.
• Zalte, A., et. al. 2014. Cocrystals: An Emerging
Approach to Modify Physicochemical Properties of
Drugs. Am. J. Pharm. Tech Res. 4. 179-189.
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