One of conditions for physical pharmacy

1. Physical Pharmacy
crystal structure
and solubility
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collection by ph/Aref alshmiry

2. Factors affecting solubility of drug
1. Solute related,
2. Solvent related,
3. Environment related,
4. Formulation related.
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3. Solute related
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1 - Structural features of drug(e.g polar and
nonpolar),
2 - Nature of drug (e.g particle size, surface area
and shape),
3 - Physicochemical properties of drug(e.g melting
and boiling point),
4 - Physical form of drug(e.g amorphous and
crystalline).

4. Solvent related
- Nature of solvent,
- PH of solvent,
- Volume of solvent.
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5. Environment related
- Temperature,
- Pressure.
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6. Formulation related
- Common ion effect,
- Effect of indifferent electrolyte,
- Effect of nonelectrolyte on solubility of electrolyte,
- Effect of electrolyte on solubility of non-electrolyte,
- Effect of complex formation,
- Effect of surface active agent.
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7. Solids and the crystalline state
 A crystalline solid defined as a substance (clear and bright like
crystal) possesses rigid and long-range order.
 In a crystalline solid, atoms, molecules or ions occupy specific
(predicable) positions.
 An amorphous solid defined as a substance does not possess
a will-defined arrangement and long-range molecular order.
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Solids and the crystalline state

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Solids and the crystalline state

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Solids and the crystalline state

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Solids and the crystalline state

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Solids and the crystalline state
The seven possible primitive unit cells

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Solids and the crystalline state

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Solids and the crystalline state

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Solids and the crystalline state
Caesium chloride Zinc sulfide Calcium fluoride

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Solids and the crystalline state
 Molecular crystals:
• Lattice points occupied by molecules.
• held together by weak attraction forces.
• soft, low melting point.
• bad conductors of heat and electricity.
• Common examples include wax, iodine and Sulphur.
wax

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Solids and the crystalline state

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Solids and the crystalline state

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Solids and the crystalline state

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polymorphism
 Some elemental substance such as Carbon and Sulfur,
may exist in more than one crystalline form and are called
allotropic, which is a special case of polymorphism.
 Polymorphism is the ability of a substance to exist in
more than one crystal structure

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polymorphism
 Polymorphs: when two crystals have the same chemical
composition but different internal structure (molecular
packing – molecular conformation or / and inter or intra
molecular interactions) modifications or polymorphs or forms
 Pseudo polymorphs: different crystal forms have molecules of
the same given substances and also contain molecules of
solvent incorporated into a unique structure (solvates or
hydrates (water))

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polymorph

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polymorph

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 Pharmaceutical synthesis include purification and
crystallization, residual solvent can be trapped in
the lattice. (this result in the formation of cocrystal or
solvate.)
 The presence of residual solvent may affect
dramatically the crystalline structure of the solid
depending on the type and/or inter molecular forces
that the solvent may have with crystalline solid.
Solvates

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Cocrystal
 The simplest definition of a cocrystal is a crystalline
structure made up of two or more components in a
definite stoichiometric ration, where each component is
defined as either an atom, ion, or molecule.

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 When the change from one form to another is reversible, it
is called enantiotropic.
 When the transition takes place in one direction only--for
example, from a metastable to a stable form –the change is
called monotropic.
Principle of polymorphism

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Amorphous solid
 An amorphous solid does not possess a well-defined
arrangement and long-range molecular order.
 Amorphous substances, as well as cubic crystal and
isotropic, that is exhibit similar properties in all direction.

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Amorphous solid
Solids that don’t have a definite geometrical shape are known
as amorphous solids.
1. In these solids particles are randomly arranged in three
dimension.
2. They don’t have sharp melting points.
3. Amorphous solids are formed due to sudden cooling of liquid.
4. Amorphous solids melt over a wide range of temperature.

29. Differences between crystalline and amorphous
form
Crystalline forms
 Fixed internal structure,
 More stable than its
amorphous form,
 Lesser solubility than its
amorphous form,
 Lesser tendency to change its
form during storage.
Amorphous forms
 Do not have any fixed internal
structure,
 Higher thermodynamic
energy than its crystalline
form,(less stable)
 Greater solubility than its
crystalline form,
 Tend to change its form
during storage.
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Polymorphism and Industry /
Pharmaceutical
API
Crystallization
Filtration
Drying
Milling
Bulk API
Final form
Granulation
Drying
Milling
Tableting/compaction
Drug product
Solubility

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Crystallization
General crystallization conditions:- The formation of polymorphs crystallization
process, depend upon
 Solvents—different polarities (the packing of a crystal may be different from a polar
versus a nonpolar solvent),
 Concentration of the solutions (super saturated, saturated, diluted) (generally the
higher the concentration above the solubility, the more chance a metastable form is
seen),
 Cooling speed (quenching, slow),
 Temperature (room or lower than room temperature),
 Impurities that may favor a metastable polymorph because of specific inhibition of
growth patterns.

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 Melting point .
 Hardness.
 Optical, electrical magnetic
properties.
 Color.
 IR spectra.
 NMR spectra.
Photochemical reactivity.
 Thermal analysis.
Dissolution rate
Bioavailability
Physical and chemical stability
Solubility and melting point are very important in pharmaceutical
processes including dissolution and formulation.
Polymorphism and Industry /
Pharmaceutical

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Polymorphism and industry/pharmaceutical
 In the case of slightly soluble drugs, this may affect the
rate of dissolution.
 As a result, one polymorph may be more active
therapeutically than another of the same drug.
 the polymorphic state of chloramphenicol palmitate has
a significant influence on the biologic availability of the
drug.

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Polymorphism and industry/pharmaceutical

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Amorphous or crystalline &
therapeutic activity
 The crystalline form of the antibiotic novobiocin
acid is poorly absorbed and has no activity, where
the amorphous form is readily absorbed and
therapeutically active, due to different dissolution
rate.

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Polymorphism and industry/pharmaceutical

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Formulation problems
 Polymorphism with certain crystal habits may be difficult to inject in
suspension form or to formulate as tablets,
 Transformation between polymorphic form during storage can cause
changes in crystal size in suspensions and their eventual caking,
 Crystal growth in cream as result of phase transformation can cause the
cream to become gritty,
 Changes in polymorphism form of vehicles such as Theobroma oil, used to
make suppositories could cause products with different and unacceptable
melting characteristics.
Polymorphism and industry/pharmaceutical

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