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Preformulation

Pharmaceutical Technology-I

Preformulation starts when a newly synthesized drug shows sufficient pharmacological action
in animal model to warrant evaluation in man.
It should focus on those physicochemical properties of the new compound that could affect drug
performance and development of dosage form. It provides a rationale for formulation design or support
the need for molecular modification.
If deficiency is detected, then it should be decided on the molecular modification that would
most likely improve the drugs properties.

Major area of preformulation research:


I.
Bulk Characterization
- Crystallinity and polymorphism
- Hygroscopicity
- Fine particle characterization
- Bulk density
- Powder flow properties
II.
Solubility Analysis
- Ionization constant- PKa
- PH solubility profile
- Solubilization
- Partition coefficient
- Dissolution
III.
Stability Analysis
- Solution stability
- Solid state stability
- Bulk stability
- Compatibility
Crystallinity and polymorphism
Crystal habit: It is the description of the outer appearance of a crystal.
Internal structure: Molecular arrangement within the solid.
A single internal structure for a compound can have several different habit, depending on the
crystals.
Crystal habit and the internal structure of a drug can affect bulk and physicochemical properties
which range from flowability to chemical stability.

[Fig: Different habits of crystal]

Course Instructor: Mohammad Borhan Uddin, Lecturer, NSU

Preformulation

Pharmaceutical Technology-I

Solvate: Involve entrapped solvent molecules within the lattice. e.g. A compound with solvate is
CuSO4.5H2O
Hydrate: When the incorporated solvent is water, the complex is called a hydrate.
Anhydrous: A compound not containing any water within its crystal structure.

g/ml

Ampicillin serum conc.

The more soluble anhydrous form produced higher and earlier peaks in the blood serum levels than the
less soluble hydrate form.
An example of the importance of solvate forms:

2.1
1.8
1.5
1.2
0.9
0.6
0.3
1

Hours

Fig: Mean serum concentration of ampicillin after oral administration of 250mg doses of two solvate
forms of the drug suspension.
Hydrate form Dissolution rate Absorption
Anhydrous form is more soluble than hydrate.
Polymorphism: It is the ability of chemical compound to exist more than one crystalline form.
Polymorph has same chemical properties but their physical properties are different. e.g. melting point,
boiling point.
According to stability, they are of three types:
I.
stable
II.
Metastable
III.
Unstable
According to conversion they are of two types:
I. Enatiotropic: One polymorph can be reversibly changed into another by
varying temperature and pressure. e.g. Sulphur
II. Monotropic: One polymorphic form is unstable at all temperature and
pressure. e.g. Glyceryl stearates
Hygroscopicity: Many drug substances, particularly water soluble salt forms have a tendency to adsorb
atmospheric moisture.
Moisture content can depend upon:
- Atmospheric humidity
- Temperature
- Surface area
- Exposure

Course Instructor: Mohammad Borhan Uddin, Lecturer, NSU

Preformulation

Pharmaceutical Technology-I

With most hygroscopic materials changes in moisture level can influence many important
parameters, such as:
-

Chemical stability
Flowacility
Compactibility

Fine particle characterization: Bulk flow, formulation homogeneity and surface area controlled
processes. such as dissolution and chemical reactivity are directly affected by
- Size
- Shape
- Surface morphology of drug particles
Bulk density: Usually bulk density is of great importance in considering the size of high dose capsule
product or in the homogeneity of low dose formulation in which there is large difference in drug and
excipient densities.
Powder flow properties: Most flow properties are significantly affected by changes in- Particle size
- Density
- Shape
- Adsorbed moisture

Solubility analysis:
Technique: Analytical methods that are useful for solubility measurement include
- HPLC
- UV spectroscopy
- Fluorescence spectroscopy
- Gas chromatography
Factors: Solubility and dissolution experiment should have some factors
- PH
- Temperature
- Ionic strength
- Buffer concentration
Solvent:

Distilled water
0.9% NaCl
0.1M HCl
0.01M HCl
0.1M NaOH at room temperature

Importance: Important for suspension or liquid preparation.

Course Instructor: Mohammad Borhan Uddin, Lecturer, NSU

Preformulation

Pharmaceutical Technology-I

PKa Determination:
Determination of the dissociation constant for a drug capable of ionization within a PH range of
1-10 is important for solubility and absorption can be altered by changing PH.
The Henderson-Hasselbalch equation provides an estimate of the ionized and un-ionized drug
concentration at a particular PH.
For acidic compounds,
[Ionized drug]
PH= PKa + log
[Un-ionized drug]
For basic compounds,
[un-ionized drug]
PH= PKa + log
[Ionized drug]

PKa> 3, Drug unionized in stomach but ionized in the intestine


PKa~8-9, Drug ionized in both stomach & intestine
Unionized drug molecules are absorbed from the GIT.
Solubilization:
For increasing solubility the addition of a cosolvent to the aqueous system. The solubility of
poorly soluble nonelectrolytes can often be improved by adding suitable cosolvents. Such as ethanol,
propylene glycol and glycerin.
The cosolvents solubilize drug molecule by disrupting the hydrophobic interactions of water at
the nonpolar solute/water interfaces.
Partition coefficient:
The partition coefficient is defined as the ratio unionized drug distributed between the organic
and aqueous phases at equilibrium.
Po/w =

Coil
Cwater

) equilibrium

Dissolution:
Dissolution is the affinity of a drug to go solution. Dissolution of a drug particle is controlled by
several physicochemical properties. Such as
- Chemical form
- Crystal habit
- Particle size
- Solubility
- Surface area
Dissolution of solvate and polymorphic forms of a drug can have a significant impact on bioavailability
and drug delivery.

AND LECTURE NOTES

Course Instructor: Mohammad Borhan Uddin, Lecturer, NSU