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Pharmaceutical Preformulation PDF
Pharmaceutical Preformulation PDF
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.
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
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
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
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]
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.