PRINCIPLE AND GENERAL METHODS OF PREPARATION OF POLYMORPHS AND HYDRATES.pptx

Polymorphism is the underlying chemistry that allows the substance to be in more than one crystalline form.
Polymorphism causes differences in physical properties with different molecular arrangements.
Polymorphs are solid materials that can exist in different crystallographic structures with varying lattice arrangements.
Polymorphs have wide ranging application including pharmaceuticals, pigments, dyes and foods.
During drug development, altering the physical forms of polymorphs can achieve favorable physicochemical properties of compounds, such as bioavailability, solubility, dissolution and physical/chemical stability.
MONOTROPIC POLYMORPH
Only one form is stable at all temperature below the melting point, with all other polymorph being unstable.

ENANTIOTROPIC POLYMORPH
One form stable over certain pressure and temperature range, while the other polymorph is stable over different pressure and temperature range.
METHODS OF POLYMORPH PREPARATION- SOLVENT EVAPORATION METHOD,
SLOW COOLING APPROACH,SOLVENT DIFFUSION TECHNIQUE,VAPOUR DIFFUSION METHOD
Hydrates are formed during process of crystallization in which solvent (water) gets incorporated in crystal, that is crystalline solid that contain water molecule inside crystal.
The water is trapped in void of crystal lattice by forming H- bonding.
INORGANIC HYDRATES
The water molecules are loosely bonded to the compound and can be easily removed through heating.
ORGANIC HYDRATES
Created when a water molecule is added to a carbonyl group of an aldehyde or ketone.
GAS HYDRATES
Water molecules form a loose framework molecule, which is usually methane.
METHOD OF PREPARATION-Crystallization from Aqueous solution
Organic solvent mixture crystallization
Hydrothermal or Reflux Crystallization ( for Inorganic Hydrates)

1. PRINCIPLE AND GENERAL METHODS OF PREPARATION OF POLYMORPHS AND HYDRATES HONEY HETTY 2 ND SEM MPHARM 2024 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY ST. JAMES’ COLLEGE OF PHARMACEUTICAL SCIENCES, CHALAKUDY 1

2. CONTENTS POLYMORPHS HYDRATES 2

3. POLYMORPH Polymorphism is the underlying chemistry that allows the substance to be in more than one crystalline form. Polymorphism causes differences in physical properties with different molecular arrangements. Polymorphs are solid materials that can exist in different crystallographic structures with varying lattice arrangements. Polymorphs have wide ranging application including pharmaceuticals, pigments, dyes and foods. During drug development, altering the physical forms of polymorphs can achieve favorable physicochemical properties of compounds, such as bioavailability, solubility, dissolution and physical/chemical stability. 3

4. TYPES OF POLYMORPHS 4 MONOTROPIC POLYMORPH Only one form is stable at all temperature below the melting point, with all other polymorph being unstable. Example: Glyceryl stearate, Chloramphenicol palmitate ENANTIOTROPIC POLYMORPH One form stable over certain pressure and temperature range, while the other polymorph is stable over different pressure and temperature range. Example: Sulfur, Carisbamate

5. METHODS OF POLYMORPH PREPARATION 5 SOLVENT EVAPORATION METHOD SLOW COOLING APPROACH SOLVENT DIFFUSION TECHNIQUE VAPOUR DIFFUSION METHOD VACUUM SUBLIMATION

6. SOLVENT EVAPORATION METHOD 6 Prepare saturated solution Pour solution into container Cover with perforated stopper to control evaporation rate Solvent slowly evaporates which increase solute concentration Crystals forms at vessel wall

7. SLOW COOLING APPROACH 7 Saturated solution prepared by minimal amount of solvent at high temperature Transfer solution into container and sealed it properly Cool the solution at room temperature then use refringerator As the temperature decreases, solubility drops, crystal starts to form

8. SOLVENT DIFFUSION TECHNIQUE 8 Dissolve compound in solvent Add less soluble solvent ( antisolvent ) on top, ensuring no initial mixing Seal the container and sit for weeks Crystals will form at interface where two solvents mix slowly

9. VAPOUR DIFFUSION METHOD 9 Prepare a concentrated solution of sample with suitable solvent Place the sample solution as drop on coverslip hanging over a reservoir Place a quantity of a volatile, miscible non-solvent in a larger container or the lower chamber of the setup. 

10. Allow vapour to equilibrate over hours Place the sample container within the chamber containing the non-solvent and seal the system airtight to create a controlled diffusion environment.  Monitor crystal growth under a microscope 10

11. 11 TYPES OF VAPOUR DIFFUSION METHOD

12. HYDRATES Hydrates are formed during process of crystallization in which solvent (water) gets incorporated in crystal, that is crystalline solid that contain water molecule inside crystal. The water is trapped in void of crystal lattice by forming H- bonding. 12

13. TYPES OF HYDRATES 13 INORGANIC HYDRATES The water molecules are loosely bonded to the compound and can be easily removed through heating . Eg . Washing soda (Na 2 CO 3. 10H 2 O), Copper sulphate (CuSO 4. 5H 2 O) ORGANIC HYDRATES Created when a water molecule is added to a carbonyl group of an aldehyde or ketone . Eg . Chloral hydrate ( CCl 3 CH(OH) 2 ) GAS HYDRATES Water molecules form a loose framework molecule, which is usually methane. Eg . Methane hydrate

14. METHOD OF PREPARATION Crystallization from Aqueous solution Organic solvent mixture crystallization Hydrothermal or Reflux Crystallization ( for Inorganic Hydrates) 14

15. CRYSTALLIZATION FROM PURE WATER 15

16. ORGANIC SOLVENT CRYSTALLIZATION 16 Dissolve the organic compound in a suitable organic solvent, often with heating to ensure full dissolution. Carefully add a predetermined amount of water Slowly cool the solution to induce supersaturation and the formation of hydrate crystals.

17. HYDROTHERMAL CRYSTALLIZATION 17 In sealed vessel, dissolve compound in water Heat (80-200⁰C) Cool the saturated solution Allow the solvent to evaporate Filter the solution to separate the formed hydrate crystals Dry the collected crystals

18. REFERENCES Karpinski PH. Polymorphism of active pharmaceutical ingredients. Chemical Engineering & Technology: Industrial Chemistry‐Plant Equipment‐Process Engineering‐Biotechnology. 2006;29(2 ):233-7 . Sun C, Grant DJ. Influence of crystal structure on the tableting properties of sulfamerazine polymorphs. Pharmaceutical research. 2001;18(3 ):274-80 . Eyjolfsson R. Enalapril maleate polymorphs: instability of form II in a tablet formulation. Die Pharmazie . 2002 ;57(5 ):347-8. 18 Sun C, Grant DJ. Influence of crystal structure on the tableting properties of sulfamerazine polymorphs. Pharm Res. 2001;18(3):274–80.

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