SRM COLLEGE OF PHARMACY

KATTANKULATHUR, TAMILNADU 603203

MASTER OF PHARMACY
IN
PHARMACEUTICAL CHEMISTRY

SUBJECT-PHARMACEUTICAL PROCESS
CHEMISTRY
SAYANI BANERJEE
M. PHARM (1ST YEAR)

REGISTRATION NO-
RA2322253010010
 Hydrates
• Most solid chemical compounds will contain some water if they have
been exposed to the atmosphere for any length of time. In most cases
the water is present in quite small amounts and is only adsorbed on the
surface of the crystals. This adsorbed water can usually be removed by
gentle heating. Other solid compounds will contain larger amounts of
water that is bound to the compound more strongly. These compounds
are called hydrates, and they are usually ionic salts.
 PREPARATION
Deliquescence and Efflorescence
Place a few crystals of sodium sulfate decahydrate, Na2SO4•10H2O, on a watch glass or a sheet of
paper. On a separate watch glass, place a few pieces of anhydrous calcium chloride, CaCl2. Observe
both samples occasionally as you proceed with other parts of the experiment.
Reversibility of Hydration
1. Grind a few crystals of CuSO4•5H2O in a mortar. Then gently heat the powder in a Pyrex test tube
fastened in a horizontal position by a clamp on a ring stand. Observe whether any water can be seen
(as a mist or droplets) condensing inside the test tube. Note the appearance of the solid residue after
heating. When the residue seems to be completely dehydrated, allow it to cool. Then add a few
drops of water to the residue in the tube.
2. 2. The same test can be repeated with crystals of cobalt chloride hexahydrate (CoCl2•6H2O).
Because of the color changes associated with hydration and 32 dehydration of these two
substances, the two anhydrous salts (CuSO4 or CoCl2) can be used to detect small quantities of
water.
 PREPARATION
Evaporation Method (EM)
A nearly saturated solution of approximately 2 g of
the commercially available ionic hydrates was
prepared in an 8-in. test tube or 50-mL beaker by
adding small amounts of water (usually about 3–5
mL) until the solid dissolved. A 0.5-mL portion of
2-propanol was added to the solution and the test
tube was placed in a water bath or sand bath
maintained at a fairly constant temperature (an
ordinary hot-plate provided sufficient temperature
control) within the stability range of the desired
hydrate .The solution was allowed to evaporate
until crystals formed. In no case was the solution
allowed to evaporate to dryness. The rate of
evaporation was slowed in some cases by covering
the test tube or beaker with Parafilm tape into
which several holes were punched. The crystals
were isolated by suction filtration, washed with 2-
propanol, and placed in a desiccator overnight.
PREPARATION
 PREPARATION
• Solvent Addition Method (SAM)
A working solution of an ionic hydrate from Table 1 was
formed as described in the EM procedure. The test tube
or beaker containing the working solution was placed
into a water or sand bath maintained at a temperature
within the stability range of the target hydrate. After the
temperatures equilibrated, 2-propanol was added
dropwise until a precipitate formed. (Other weakly
complexing solvents that are miscible with water but less
effective than water at solubilizing ionic materials could
also be used to precipitate the hydrate. 2-propanol is a
good choice because it is readily available, reasonably
safe, and inexpensive.) The crystals were isolated by
suction filtration, washed with 2- propanol, and placed in
the desiccator overnight.
 PREPARATION
• Direct Heating (DH)
Approximately 2 g of the starting
hydrate was heated in an oven for
24 h at a temperature within the
stability range for the hydrate
desired. The product hydrate was
stored in a desiccator until
analyzed.
 Solvates
Solvates of a drug substance, similar to polymorphs, are crystal
modifications of a drug substance. This characteristic of solvate formation
is sometimes known as pseudo morphism.
An important specific example of solvation is hydration, where the
solvent is water. In general, the rule of like-attracts-like applies to
solvation: Polar solutes such as sodium chloride are solvated by polar
solvents such as water; they are not solvated by non-polar solvents such
as benzene.
 Preparation
1.Solvent Recrystallization: This method involves dissolving the drug substance in
a suitable solvent and allowing it to crystallize under controlled conditions. By
adjusting the temperature, concentration, and rate of solvent evaporation, solvates
with desired properties can be obtained.
2.Slurry Conversion: In this method, the drug substance is suspended in a solvent,
and a second solvent or anti-solvent is added to induce crystallization. The choice
of solvents and their ratios can influence the formation of solvates.
3.Co-crystallization: Co-crystallization involves the formation of crystalline
complexes between the drug molecule and another compound (co-former). The
co-former can act as a solvent and become part of the crystal lattice, resulting in
the formation of solvates.
4.Supercritical Fluid Processing: Supercritical fluids such as carbon dioxide can
be used as solvents for crystallization. By adjusting the pressure and temperature
conditions, solvates can be formed under supercritical fluid processing .
 Preparation
4. Antisolvent Crystallization: In this method, the drug substance is dissolved in a
solvent, and an antisolvent is added to induce rapid precipitation. The rapid decrease
in solvent concentration promotes the formation of solvates.
5. Solvent Vapor Annealing: This technique involves exposing the drug substance
to solvent vapors under controlled conditions. Solvent molecules are absorbed by
the crystal lattice, leading to the formation of solvates.
6. Spray Drying: Spray drying involves atomizing a solution of the drug substance
and solvent into a hot drying gas. The rapid evaporation of the solvent results in the
formation of solid particles, which can crystallize into solvates under appropriate
conditions.
7. Sono crystallization: Ultrasound-assisted crystallization can promote the
nucleation and growth of crystals. By applying ultrasound energy to the solvent-
drug solution, solvates can be obtained more efficiently.
 Amorphous API
• Amorphous forms are, by definition, non-crystalline
materials which possess no long-range order. Their structure
can be thought of as being similar to that of a frozen liquid
with the thermal fluctuations present in a liquid frozen out,
leaving only "static" structural disorder.
 Preparation
Preparation Methods
• – Melt quench (Heat stable compounds)
• – Grinding (Physically stable compounds)
• – Precipitation or spray drying (Organic solvent soluble compounds)
(Fluid bed-spray onto support (Sporonox))
• – Freeze-drying(Water soluble compounds)
 Preparation
Melt Quench
• Amorphous can be made by melting
crystalline
• material and quenching quickly
• – Place crystals in clean vial
• – Heat sample to just above melting point
(~10 C)
• – Quench sample
• • Place sample vial at reduced temperature
(ice bath, liquid nitrogen, etc)
• • Pour molten liquid into a mortar
containing liquid nitrogen and grind into a
powder
Grinding
• Methods
– Mortar and pestle
– Ball mill (Wig-L-bug)
– Cryogrinder
• Disperses heat during grinding
Cimetidine – Ground in cryogrinder 180 min.
Not all materials will convert to amorphous during
grinding
• 23 compounds examined •
Cryoground for up to 3 hours • 12 fully
amorphous(52%) • 3 partially amorphous (13%) • 8
remained crystalline (35%) •
Grinding time to produce amorphous •
Range of 1-5 hours
• Some samples remained crystalline even after 5 hrs
 Preparation
• Drying
• Trehalose Precipitation
• – Three known forms: dihydrate, anhydrate, Can be used to make amorphous API
amorphous or dispersions
• – Form obtained upon drying dihydrate • Sodium indomethacin:
depends on particle size, rate, drying indomethacin amorphous mixtures
conditions – API dissolved in anhydrous methanol
at 60 °C
– Solid completely dissolved
– Solvent removed with rotary
evaporator up to 63 °C Ostwald’s Rule of Stages
– Variety of concentrations produced – Metastable form will
– Samples remained amorphous for 14 crystallize first
months at 4 °C – Need to trap amorphous
XRPD patterns of dihydrate dried under metastable form before it
(a) slow conditions (1 K/min) to form dissolves and
anhydrate crystallizes into the stable
(b) fast conditions (>50 K/min) to form form
amorphous
 Conclusion
• In pharmaceutical development, the choice of solid-state form for an API depends on various
factors, including its physicochemical properties, intended dosage form, stability
requirements, and regulatory considerations. It is essential to understand the implications of
selecting a specific solid-state form on formulation development, manufacturing processes,
storage conditions, and product performance.
• Furthermore, thorough characterization and analysis techniques, such as X-ray powder
diffraction (XRPD), differential scanning calorimetry (DSC), solid-state nuclear magnetic
resonance (NMR), and microscopy, are crucial for identifying and characterizing hydrates,
solvates, and amorphous forms of APIs throughout the drug development process.
• Overall, a comprehensive understanding of the properties and behavior of hydrates, solvates,
and amorphous forms of APIs is essential for ensuring the safety, efficacy, and quality of
pharmaceutical products. Pharmaceutical scientists and researchers continue to explore
innovative strategies for the development, characterization, and utilization of these solid-state
forms to optimize drug delivery and patient outcomes.
THANK YOU