Department of pharmaceutics

The structure of a solid compound can be classified as shown:

• Crystal habit: it is the description of the outer appearance of crystal and
includes, for example, acicular (needle-like), prismatic, pyramidal, tabular,
columnar and lamellar.

• Internal structure: it is molecular arrangement within the solid and include

cubic, tetragonal, hexagonal, rhombic, etc.

➢ Crystalline: atoms in crystalline matter are

arranged in regular and repeating patterns in
three dimensions.
➢ Amorphous: atoms or molecules randomly
placed “without a regular atomic arrangement”.
 Crystalline state Amorphous state
High metling point Low metling point
More stable Less stable
Good flow properties Poor flow properties
Less hygroscopic More hygroscopic
Less soluble More soluble

• Amorphous forms are produced by rapid precipitation, lyophilization, rapid cooling of

liquid melt, sudden change in the composition of solvent.
• Amorphous forms have higher solubility and dissolution rate than crystalline forms
because they have higher thermodynamic energy. e.g. amorphous form of Novobiocin is
well absorbed whereas crystalline form results in poor absorption.
• In the presence of acetate buffer, zinc combines with insulin to form a
complex.
• The complex can be crystalline or amorphous depending on pH of acetate
buffer.

INSULIN

Acetate buffer, zinc

Insoluble complex

Semi-lente insulin Ultra-lente insulin

(amorphous, rapidly absorbed, short (crystalline, slowly absorbed, long
duration of action). duration of action).
SO, Crystal habit and internal structure of a drug can
affect physicochemical properties such as; bulk density,
particle size, flowability, solubility and stability.
 Polymorphism
• The word Polymorphism’ comes from the Greek word, Polus = many and
morph = shape.
• Definition: It describes the ability of a substance to exist as two or more
crystalline phases that have different arrangements of the molecules in the
solid state but are otherwise identical in terms of chemical content.
• It is a common phenomenon of crystalline materials.
• The element carbon is the most common example exhibiting polymorphism.
It exists in 3 forms the form of graphite (hexagonal), diamond (cubic) and as
fullerenes (C60, C70(.
• More than 50% APIs is estimated to have more than polymorph form.
Importance of 1-Different polymorphs exhibit different
studying solubility, bioavailability and stability.

polymorphism 2-the effect of pharmaceutical processes on

particles are understood, Eg: granulation,
milling, compression.

3-Effect of storage condition on the dosage

form can be evaluated and predicted, Eg:
crystal growth in suspension , cream.

4-to formulate the desired crystal form

consistently.
 Chocolate

• Some chocolates taste better than others. Why????

• Taste depends on which crystalline forms predominate (Some of these crystalline

forms are not very palatable—others are sensational).

• Cocoa butter
-the main solid fat in chocolate, can crystallize into six polymorphs.
-The form that predominates in the best-tasting chocolate is form V(This
polymorph also makes the chocolate look glossy and melts in the mouth).
Phase transition: the process of transformation of one polymorph into another, which may also
occur on storage or during processing.
Stable polymorph: it has low free energy, low solubility and high melting point.
Metastable polymorph: it is less stable with higher solubility and bioavailability and lower melting
point.

• phase transformation from unstable form to more stable polymorph can cause
changes in crystal size and caking.
• crystal growth as a result of phase transformation can cause grittiness.
• changes in polymorphic forms could cause product with different and
unacceptable melting characteristic (failure to melt after administration or premature melting during
storage). e.g. theobroma oil “suppositories base”.
 What is pseudomorphs?

• Also called Hydrates or solvates of a drug substance.

• The water of crystallization in hydrates and the

organic solvent in solvates are incorporated with the
drug molecule to form a unique structure.

• The physical properties such as melting behavior and

solubility may be varied. Melting behavior can be
observed best in the Hot stage microscope. How?
 1. No of polymorphs.
2. Relative degree of stability.
3. Stabilization of metastable form.
4. Temperature stability range.
5. Solubility of each polymorph.
6. Method of preparation.
7. Effect of micronization.
8. Excipients incompatibility.
➢ Investigation the tableting properties of needle-, cube- and
plate-shaped of paracetamol crystals found that the needle-
shaped powder had the worst compression properties, showing
greater capping and lamination, than the plate- or cube-shaped
crystals.

➢ Crystal morphology or habit is important, since it can influence

Syringeability (Plate easier to inject than needle crystal).
 Conditions of Crystallization can change Crystal Habit.

Rate of precipitation Impurities

e.g. Phenylsalicylate e.g. Carbamazepine
(Rapid rate) +Sodium taurocholate
Solvent
acicular shape. Needle prism
e.g. Ibuprofen
(Low rate) leads to more (Hexane) Elongated
regular shape. needle, Poor flow
properties.
(Methanol)
Equidimentional crystal,
Better flow & compaction
 In order for a drug to enter the systemic circulation to
exert a therapeutic effect, it must first be in solution. So,
the drug must possess some aqueous solubility for
therapeutic efficacy. Relatively insoluble compounds
often exhibit incomplete absorption.

Aqueous solubility of drugs is an important

physicochemical property as it affects the rate of
dissolution and thus affects the rate of absorption and
bioavailability.

The solubility must be determined as a function of pH

over the physiological pH range, pH 1-8. Also should be
determined in water, different co-solvents, in saline, IV
buffer.
 Very soluble Less than 1 part
Freely soluble 1 to 10 parts
Soluble 10 to 30 parts
Sparingly soluble 30 to 100 parts
Slightly soluble 100 to 1000 parts
Very slightly soluble 1000 to 10,000 parts
Practically insoluble or
More
Department than 10,000
of pharmaceutics parts
- O6U - Dr.
insoluble
Shereen Sameh
➢ Biopharmaceutical Classification System (BCS) is a
scientific framework for classifying a drug substance
based on their aqueous solubility and permeability.
Solubility is important to the pharmacist because it
helps him to:
[1] Assess the purity of the drug.
[2] Determine the possible dosage form.
[3] Qualitatively and quantitatively analysis of the drug in the
dosage form.
[4] Expect bioavailability of drugs from solid dosage forms.
[5] Development of appropriate media of dissolution.
[6] Choosing the right solvent for granulation & coating.
➢ The Solubility of drug substance is determined by the
equilibrium solubility method (the analytical method) which
employs a saturated solution of the substance, obtained by
stirring an excess of material in the solvent at constant
temperature until equilibrium achieved.

➢ Solubility should ideally be

measured at two temperatures:
4°C and 37°C.
• 4°C to ensure physical stability.
• 37°C to support biopharmaceutical
evaluation.
 Medicinal agents may be weak acid or weak base.
• Weak acid drugs: phenobarbital, barbiturates, sulphonamide.
•Weak basic drugs: alkaloids, atropine, morphine, antihistamine.
If the drug is ≥ soluble in acid than aqueous solution ~
weak base.
If the drug is ≥ soluble in alkali than aqueous solution ~
weak acid.
If the drug is ≥ soluble in alkali & acid than aq. sol ~
amphoteric.
No change in solubility ~ non-ionizable or neutral
molecule (as steroid).
 ✓ Use the more soluble polymorph form.
✓ Use the amorphous form of drug.
✓ Reduction of particle size.
✓ Salt formation.
✓Temperature change.
✓ Addition of surfactant.
✓ Complexation (cyclodextrins).
✓ Addition of co-solvent.
✓Lipid formulations (SEDDS).
✓ Nanoemulsion, vesicles, nanoparticles,...etc
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